abiraterone-acetate and Prostatic-Neoplasms--Castration-Resistant

There is a paucity of information on the use of novel hormonal agents in Southeast Asian patients. We reviewed the clinical roles of novel hormonal therapy (NHT), namely abiraterone acetate (AA), enzalutamide, apalutamide and darolutamide, in the management of advanced prostate cancer, and data on its use in Asian patients, in order to extrapolate these findings to the Southeast Asian patient population. There are some differences in the molecular features between the NHTs, which influenced their respective permeabilities through the blood-brain barrier. The Asian sub-analyses of the landmark studies of each NHT were limited. The primary endpoints of the Asian sub-analyses generally reflect the efficacy outcomes of the respective landmark study. Hypertension, fatigue, musculoskeletal disorders, rash, and hot flushes were among the common toxicities observed in Asian patients. Real-world data on AA in the Asian setting is favourable, but data is limited for enzalutamide, apalutamide and darolutamide. Based on the sub-analyses and real-world data, the efficacy and safety of NHTs in the Asian patients showed a similar trend to the respective landmark studies. The lack of clinical trials in the Southeast Asian region hampers the ability to make a robust conclusion on any specific efficacy or safety differences that may be present; clinicians must assume that the broader Asian sub-analyses and real-world data reflects Southeast Asian patients' outcomes.

Topics: Abiraterone Acetate; Asia, Southeastern; Benzamides; Humans; Male; Phenylthiohydantoin; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

Patients with bone metastatic castration-resistant prostate cancer (mCRPC) might benefit from radium-223 (

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Fractures, Bone; Humans; Male; Network Meta-Analysis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium

While abiraterone acetate (AA) has demonstrated survival benefit in advanced prostate cancer (APC), meaningful cardiotoxicity is observed. It is unclear whether the magnitude differs based on disease indication and concurrent steroid administration.. We performed a systematic review and meta-analysis of phase II/III RCTs of AA in APC published as of August 11, 2020. Primary outcomes examined were all- and high-grade (grade ≥ 3) hypokalemia and fluid retention, and secondary outcomes included hypertension and cardiac events. We performed random effects meta-analysis comparing intervention (AA + steroid) and control (placebo ± steroid), stratified by treatment indication and whether patients received steroids.. Among 2,739 abstracts, we included 6 relevant studies encompassing 5901 patients. Hypokalemia and fluid retention were observed more frequently among patients receiving AA (odds ratio [OR] 3.10 [95% CI 1.69-5.67] and 1.41 [95% CI 1.19-1.66]). This was modified by whether patients in the control received steroids: trials where control patients did not demonstrated a larger association between AA and hypokalemia (OR 6.88 [95% CI 1.48-2.36] versus OR 1.86 [95% CI 4.97-9.54], P < .0001) and hypertension (OR 2.53 [95% CI 1.91-3.36] vs. OR 1.55 [95% CI 1.17-2.04], P = .1) than those where steroids were administered. We observed heterogeneity due to indication: there were greater effects on hypokalemia (P < 0001), hypertension (P = .03), and cardiac disorders (P = .01) among patients treated for mHSPC than mCRPC.. The magnitude of cardiotoxicity with AA differs based on trial design and disease indication. These data are valuable in treatment decisions and highlight utilization of appropriate data for counseling.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Cardiotoxicity; Humans; Hypertension; Hypokalemia; Male; Mineralocorticoids; Prednisone; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Treatment Outcome

Recently, several new treatment regimens have been approved for treating metastatic hormone-sensitive prostate cancer, building on androgen deprivation therapy alone. These include docetaxel androgen deprivation therapy, abiraterone acetate-prednisone androgen deprivation therapy, apalutamide androgen deprivation therapy, enzalutamide androgen deprivation therapy, darolutamide-docetaxel androgen deprivation therapy, and abiraterone-prednisone androgen deprivation therapy with docetaxel. There are no validated predictive biomarkers for choosing a specific regimen. The goal of this study was to conduct a health economic outcome evaluation to determine the optimal treatment from the US public sector (Veterans Affairs).. We developed a partitioned survival model in which metastatic hormone-sensitive prostate cancer patients transitioned between 3 health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan-Meier curves using a Bayesian network meta-analysis of 7 clinical trials (7208 patients). The effectiveness outcome in our model was quality-adjusted life-years (QALYs). Cost input parameters included initial and subsequent treatment costs and costs for terminal care and for managing grade 3 or higher drug-related adverse events and were obtained from the Federal Supply Schedule and published literature.. Average 10-year costs ranged from $34 349 (androgen deprivation therapy) to $658 928 (darolutamide-docetaxel androgen deprivation therapy) and mean QALYs ranged from 3.25 (androgen deprivation therapy) to 4.57 (enzalutamide androgen deprivation therapy). Treatment strategies docetaxel androgen deprivation therapy, enzalutamide androgen deprivation therapy docetaxel, apalutamide androgen deprivation therapy, and darolutamide-docetaxel androgen deprivation therapy were eliminated because of dominance (ie, they were more costly and less effective than other strategies). Of the remaining strategies, abiraterone acetate-prednisone androgen deprivation therapy was the most cost-effective strategy at a willingness-to-pay threshold of $100 000/QALY (incremental cost-effectiveness ratios = $21 247/QALY).. Our simulation model found abiraterone acetate-prednisone androgen deprivation therapy to be an optimal first-line treatment for metastatic hormone-sensitive prostate cancer from a public (Veterans Affairs) payer perspective.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Bayes Theorem; Cost-Effectiveness Analysis; Docetaxel; Humans; Male; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

The phase 3 trial ERA223 demonstrated an increased fracture rate and no survival advantage for metastatic castration resistant prostate cancer (mCRPC) patients on Radium-223 (Ra-223) with abiraterone, leading to regulatory restrictions on combination therapy. However, less than half of trial patients received bone health agents (BHA). We reviewed electronic health record (EHR) data evaluating fracture rates for patients on BHA receiving Ra-223, androgen deprivation therapy and either abiraterone or enzalutamide.. We conducted a retrospective, cohort analysis of EHR data of mCRPC patients on Ra-223 treated at a single community center by a single provider between 2010 and 2018. The primary objective was evaluating fracture rates for patients on BHA receiving Ra-223 and abiraterone. We conducted a secondary analysis for enzalutamide.. One hundred seventy-seven patients received Ra-223 concurrently with abiraterone or enzalutamide between November 2010 and August 2018. The median age was 73 at first Ra-223 dose (range 40-93). The median follow-up time from last Ra-223 dose was 30 months (range 2-106). One hundred sixty-four patients (93%) received BHAs. One hundred fifty-nine patients (89%) were on a BHA before and/or during Ra-223. Sixty-seven patients received denosumab (38%), 63 received zoledronic acid (36%), and 29 received both nonconcurrently (16%). Eleven patients (6.2%) experienced a fracture after starting Ra-223, 9 of which occurred while on prior and/or concurrent BHA. We observed a 5.7% fracture rate for mCRPC patients who received combination therapy and denosumab or zoledronic acid.. This real-world analysis demonstrating a low fracture rate in patients with mCRPC receiving a BHA while on Ra-223 and abiraterone or enzalutamide may inform current clinical practice.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Androgens; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Density; Denosumab; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radium; Retrospective Studies; Zoledronic Acid

Current guidelines suggest radiotherapy as a first-line treatment for prostate cancer, along with prostatectomy, and androgen deprivation therapy. Abiraterone is a first-in-class medicinal product recommended in the treatment of metastatic castration resistant prostate cancer (mCRPC) that targets androgen receptors and inhibits systemic synthesis. However, successful therapy with this drug may pose some challenges. It has to be administered as an inactive prodrug - abiraterone acetate. It is also dissolved and absorbed poorly with large interindividual variability and exhibits considerable food effects. Additionally, the recommended daily dose of the drug is high (1000 mg abiraterone acetate), and the cost of the therapy is burdensome. The following review focuses on the strategies to optimize therapy with abiraterone acetate. First, it summarizes current findings on abiraterone pharmacokinetics and accentuates the need for utilizing therapeutic monitoring in clinical practice. Next, it extensively describes the options for improving the low bioavailability of the drug. The two major approaches are the utilization of the positive food effect to increase the exposure and development of supergenerics. The review emphasizes how different formulation approaches lead to increased solubility and impact the outcomes of pre-clinical and clinical trials. The review concludes with a discussion on possible future directions that may lead to the increase of the therapeutic efficacy of abiraterone.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Drug Monitoring; Humans; Male; Pharmaceutical Preparations; Prostatic Neoplasms, Castration-Resistant

The assessment of "soft" endpoints such as health-related quality of life (HRQOL) is increasingly relevant when evaluating the optimal treatment sequence of novel therapeutic options in patients with advanced prostate cancer (PCa).. To systematically review contemporary data regarding HRQOL outcomes in patients with advanced PCa.. A systematic review of the literature published between January 2011 and March 2019 was performed using the PubMed/Medline Database. In total, 873 articles were screened, and 14 articles including 12 661 patients were selected for synthesis and included in the current analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) and European Association of Urology recommendations.. Regarding HRQOL assessment, the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire was used in 11 of 14 studies, the European Quality of Life 5-Dimensions (EQ-5D) questionnaire in six of 14 studies, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) in two of 14, and its prostate-specific amendment QLQ-PR25 was used in one of 14 studies. Three studies included patients with metastatic castration-sensitive prostate PCa, and found beneficial HRQOL effects for abiraterone acetate and docetaxel compared with standard androgen deprivation therapy. Two studies included patients with nonmetastatic castration-resistant PCa, and positive HRQOL effects for enzalutamide and apalutamide were observed. Nine studies focused on patients with metastatic castration-resistant PCa. Hereby, beneficial HRQOL outcomes were described for enzalutamide, abiraterone acetate, and radium-223. Evidence synthesis was mostly based on studies with a low risk of bias based on standardized risk of bias assessment. Limitations include hampered comparability between different validated questionnaires, lack of baseline values, and unclear impact of supportive care on HRQOL outcomes.. There is strong evidence from several phase III trials supporting a beneficial effect of current systemic treatment options on HRQOL outcomes in patients with advanced PCa compared with standard androgen deprivation therapy.. In this systematic review, we provide an overview of contemporary data from large clinical trials on the effect of current treatment strategies on patients' health-related quality of life (HRQOL). We summarize the assessment tools that have been used to measure HRQOL and show that there are robust data for positive HRQOL effects of numerous agents in different clinical stages of advanced prostate cancer.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Humans; Male; Orchiectomy; Prostatic Neoplasms, Castration-Resistant; Quality of Life

Optimal treatment sequencing of abiraterone and enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) is challenging. Real-world data (RWD) allow a better understanding of health economic implications in the real world.. To determine survival and cost outcomes for two real-world treatment sequences, comparing abiraterone to enzalutamide (AA → ENZ) with enzalutamide to abiraterone (ENZ → AA).. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Searches were performed in Medline, Embase, and Web of Science.. Seventeen studies met our inclusion criteria. Of studies with survival outcomes, 10 featured AA → ENZ treatment sequences (n = 575), four ENZ → AA sequences (n = 205), and three both sequences. Better survival outcomes were demonstrated in the AA → ENZ cohorts in several studies reporting prostate-specific antigen (PSA) progression-free survival (PSA-PFS), combined PSA-PFS, and PSA decline ≥50%. Three studies showed shorter treatment duration in cohorts receiving second-line enzalutamide compared with abiraterone. Collectively, six RWD costing studies described patients with mCRPC who experienced treatment with enzalutamide (n = 4195), abiraterone (n = 10 372), AA → ENZ (n = 443), and ENZ → AA (n = 91). No study estimated the cost of treatment sequencing of AA → ENZ or ENZ → AA.. No head-to-head studies were found, but we hypothesise that the AA → ENZ sequence may be less costly than ENZ → AA, because time on treatment tends to be longer for a first-line treatment and abiraterone is less costly than enzalutamide. There are indications that PFS of AA → ENZ is superior to that of ENZ → AA, which supports the former sequence as more cost-effective.. Better survival outcomes were reported in several studies where patients with advanced prostate cancer received the abiraterone to enzalutamide sequence compared with the enzalutamide to abiraterone sequence. No study estimated the cost of sequencing either treatment approach.

Topics: Abiraterone Acetate; Androstenes; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Abiraterone acetate is an inhibitor of androgens biosynthesis, approved as first-line treatment in castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer. Abiraterone has been rarely associated with severe rhabdomyolysis, but the mechanism of muscle toxicity is unknown.. We hereby present a case of severe rhabdomyolysis resulting in acute on chronic kidney injury following abiraterone initiation in a patient previously under rosuvastatin.. Rhabdomyolysis was resolutive after rosuvastatin and abiraterone discontinuation, and kidney function recovered. There was no recurrence of muscle toxicity after re-initiation of abiraterone alone.. Abiraterone selectively inhibits CYP17 as well as the hepatic transporter OATP1B1. OATP1B1 is an efflux transporter, whose function is to extract several drugs from the portal blood, allowing them to undergo hepatic metabolism. We hypothesize that abiraterone-induced inhibition of plasmatic uptake of rosuvastatin by OATP1B1 increased plasmatic concentration of rosuvastatin, leading to toxicity on muscle cells. We therefore suggest that the association between rosuvastatin and abiraterone should be avoided.

Topics: Abiraterone Acetate; Acute Kidney Injury; Aged; Humans; Liver-Specific Organic Anion Transporter 1; Male; Prostatic Neoplasms, Castration-Resistant; Rhabdomyolysis; Rosuvastatin Calcium

Topics: Abiraterone Acetate; Adenocarcinoma; Adrenal Cortex Hormones; Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Contraindications, Drug; COVID-19; Humans; Immunosuppressive Agents; Male; Meta-Analysis as Topic; Neoplasms, Hormone-Dependent; Oxygen; Pandemics; Practice Guidelines as Topic; Prospective Studies; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Respiration, Artificial; Risk; SARS-CoV-2

To evaluate the impact of the hormonal treatment sequencing including abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) in mCRPC, and determine which sequence provides more benefits for patients.. Studies published in English between 1 January 2013 and 30 September 2017 were identified in PubMed and EMBASE electronic databases. Studies assessing the efficacy of treatment sequences, based on AAP and ENZ, in mCRPC patients, were eligible for analysis.. Seventeen studies met the inclusion criteria. Two assessed both treatment sequences AAP → ENZ and ENZ → AAP; it was found that sequence of AAP → ENZ showed a statistically significantly longer PSA-PFS than the observed in ENZ → AAP (pooled HR: 0,54; 95% CI; 0,36-0,82; p < 0,05). The nine studies analysing Doc → AAP → ENZ sequence, revealed favourable results in terms of PFS. The 5 studies which analysed AAP → ENZ sequence, show a decrease in PSA levels ≥ 50% in 11-41% of patients treated with enzalutamide after previous treatment with AAP. In the two studies that analysed the Doc → ENZ → AAP sequence, PSA response rates were much lower than those reported with Doc → AAP → ENZ, with decreases in PSA ≥ 30 of 3-18% and PSA ≥ 50 of 8-11%.. Significant clinical efficacy of AAP administered as the first-line treatment in mCRPC patients followed by enzalutamide, delaying disease progression, compared with the ENZ → AAP sequence. However, more studies and randomized trials are needed, to validate the best treatment sequencing.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Abiraterone acetate plus prednisone is approved in metastatic castration-resistant prostate cancer. There is some evidence in favour of the steroid switch from prednisone to dexamethasone in patients who progressed whilst on abiraterone acetate plus prednisone or prednisolone.. The aim of this review is to discuss the results from the clinical studies available, examining potential mechanisms of action and patient selection criteria for this treatment option.. A total of four studies were evaluated. Among possible eligibility criteria for steroid switch, we found: PSA progression without any radiological or clinical progression during abiraterone acetate + prednisone; no high-grade adverse events related to CYP-17 inhibition; and unfitness for chemotherapy or radium-223.. Although large randomized prospective trials are warranted, steroid switch seems to offer a good option for certain patients treated with abiraterone acetate plus prednisone or prednisolone.

Topics: Abiraterone Acetate; Adrenal Cortex Hormones; Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Male; Middle Aged; Patient Selection; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Metastatic castration-resistant prostate cancer (CRPC) is a potentially symptomatic disease with an eventual lethal outcome. Novel pharmaceutical agents are continuously studied with encouraging results in CRPC.. In this perspective, the authors present established and promising pharmacotherapeutic strategies for the management of CRPC; both with and without metastases. Apart from the different treatment strategies, the authors present the relevant sequence of treatment through disease progression.. Usually, docetaxel should be considered the first line treatment in mCRPC. Abiraterone acetate (AA) plus prednisone or enzalutamide (ENZ) could be alternative treatments in chemotherapy naïve patients. Sipuleucel-T has been approved for the treatment of asymptomatic or minimally symptomatic mCRPC. Ra-223 has been approved for patients with mCRPC with symptomatic bone metastases (not visceral metastases). Cabazitaxel has been approved as the second line treatment to docetaxel in mCRPC. No differences in the overall survival has been observed between sequences starting with docetaxel versus AA/ENZ. Between AA-to-ENZ and ENZ-to-AA sequence, the AA-to-ENZ sequence appeared to be more favorable than the ENZ-to-AA regarding progression-free survival but not overall survival. Carbazitaxel seemed to retain its activity regardless of the treatment sequence. Of note, ENZ and apalutamide have been approved in non-metastatic CRPC.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials as Topic; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Humans; Immunotherapy; Male; Nitriles; Phenylthiohydantoin; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Radium; Taxoids; Tissue Extracts

Metastatic prostate cancer is a life-threatening disease and an important public health concern with prevalence rates varying drastically between high- and low-income countries. Androgen-deprivation therapy alone has been the first-line treatment option for decades, temporarily controlling disease until invariable tumor regression. At the castration-resistant stage, metastatic disease becomes lethal. In recent years several new treatments, including second-generation hormone therapies, have proven to be life-prolonging in metastatic castration-resistant prostate cancer, and at an earlier hormone-sensitive stage. Abiraterone acetate in combination with prednisone was the first approved hormone therapy demonstrating survival benefit, and represents, to date, an alternative, or a second-line treatment after taxane-based chemotherapy, in addition to androgen-deprivation therapy, in hormone sensitive, and metastatic castration-resistant prostate cancer.. We performed a literature review of papers from 2012 to 2020 using PubMed, Web of Science, and Embase searching for the safety and efficacy of abiraterone acetate in prostate cancer management. Search results were limited to phase III-IV trials and post hoc analysis of Phase III trials evaluated Abiraterone acetate in the English language.. This literature review confirms the role of abiraterone acetate in the therapeutic landscape with well-proven safety and efficacy, demonstrated in trials and post-approval studies.

Topics: Abiraterone Acetate; Androgen Antagonists; Animals; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Survival Rate

CYP17 inhibitors can block androgen production both intratumorally and systemically, thus attenuating the progression of prostate cancer (PCa). Many randomized controlled trials (RCTs) showed promising results that men with metastatic castration-resistant PCa (mCRPC) might benefit from treatment with CYP17 inhibitors such as abiraterone acetate and orteronel. The goal of this study was to evaluate the efficacy of CYP17 inhibitors for the prognosis in patients with mCRPC.. Studies were identified in PubMed/MEDLINE, the Cochrane Library, and the Web of Science. The RCTs with mCRPC patients focusing on the efficacy of CYP17 inhibitors were involved. Then, we analyzed the patients' prognosis such as overall survival (OS) and radiographic progression-free survival (RPFS).. A meta-analysis of the pooled data from seven randomized Phase III clinical trials was performed to compare 5516 mCRPC patients with CYP17 inhibitors versus that with placebo. Compared to placebo, the CYP17 inhibitors significantly increased the OS (pooled hazard ratios [HR]: 0.816, 95% confidence interval [CI]: 0.750-0.887), RPFS (pooled HR: 0.647, 95% CI: 0.557-0.752), and time to prostate-specific antigen (PSA) progression (pooled HR: 0.599, 95% CI: 0.517-0.693). Additional endpoints such as PSA response rate, objective response assessed by Response Evaluation Criteria in Solid Tumors, and time to initiation of chemotherapy were included in this study and were found having significant improvement with CYP17 inhibitors compared to placebo.. This research showed that CYP17 inhibitors had a significant improvement on prognosis of patients with mCRPC within a relative safety profile both in pre- and post-chemotherapy trials. These expected results provide evidence for the use of CYP17 inhibitors to treat mCRPCs.

Topics: Abiraterone Acetate; Clinical Trials, Phase III as Topic; Cytochrome P-450 Enzyme Inhibitors; Humans; Male; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Steroid 17-alpha-Hydroxylase; Survival Rate

Accumulating evidence has shown that intracrinology in prostate cancer (PCa) has a pivotal role in survival of cancer cell. PCa cells are able to produce androgens from different androgen precursors, such as dehydroepiandrosterone, thereby maintaining androgen receptor signaling. Several drugs have been developed that target intracrinology, some of which are now being used as standard treatment for the so-called castrate-resistant prostate cancer (CRPC) patients. Recently, the US FDA approval has changed the indication of drugs targeting intracrinology, e.g., abiraterone and enzalutamide where it evolved from post-chemotherapy CRPC to hormone-naive metastatic PCa cases. This approval raises question whether those drugs can also be used as the first-line treatment in localized stage PCa cases. In addition, development of additional drugs targeting major components of intracrinology is ongoing. Application of these new drugs and administration of combinations of existing drugs will ultimately lead to an increase in the efficacy of such treatments as well as to reduce the toxicity of the therapy and to prevent the risk of resistance.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Antineoplastic Agents; Benzamides; Dehydroepiandrosterone; Dihydrotestosterone; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Testosterone

In few years the scenario of metastatic prostate carcinoma treatment has radically changed due to improved knowledge of those mechanisms responsible of prostatic cancer cells survival and proliferation. Five new therapeutic agents (abiraterone acetate, enzalutamide, cabazitaxel, radium-223, sipuleucel-T), all able to improve overall survival, have been introduced in the management of metastatic castration-resistant prostate cancer. Moreover, recent evidences showed that adding docetaxel chemotherapy or abiraterone acetate to androgen deprivation therapy significantly increases overall survival of de novo castration-sensitive metastatic prostate cancer patients. Due to this rapid therapeutic evolution clinicians face one crucial challenge: the choice of the best treatment sequencing. In particular, there are no prospective data to guide clinical decision in patients with progressive disease after docetaxel or abiraterone acetate treatment for castration sensitive disease. In this review we provide an overview of the therapeutic agents available for both castration-sensitive and castration-resistant prostate cancer. We propose some biological and clinical insights helpful in selecting the most appropriate treatment for patients progressing after metastatic castration-sensitive prostate cancer treatment with docetaxel or abiraterone acetate.

Topics: Abiraterone Acetate; Benzamides; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radium; Taxoids; Tissue Extracts

Prostate cancer is one of the most common cancers in the United States, with an estimated incidence of 164,690 cases, accounting for 9.5% of all new cancer diagnoses. The mainstay of therapy for metastatic prostate cancer involves suppressing testosterone production through androgen deprivation therapy. However, nearly all patients on androgen deprivation therapy will develop resistance to hormone therapy. An improved understanding of the biology of castration resistance has allowed for the development of novel inhibitors of the androgen axis. Agents such as abiraterone acetate, which provides additional androgen suppression by inhibiting cytochrome P450 17A (CYP17A), have improved survival outcomes of patients with advanced prostate cancer. The longest experience with abiraterone acetate is in the metastatic castration-resistant setting. However, more recent trials have demonstrated that abiraterone acetate is an option for treatment earlier in the prostate cancer paradigm. This review will cover the current use of abiraterone acetate in combination with prednisone for the treatment of castration-resistant prostate cancer.

Topics: Abiraterone Acetate; Androgen Antagonists; Drug Therapy, Combination; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase

Prostate cancer is the second most frequent cancer worldwide, with a very high rate of progression despite treatment. The most aggressive form of the disease is known as castration-resistant prostate cancer, which carries a poor prognosis. We reviewed available literature regarding the combination of abiraterone acetate antihormonal drug and ablative radiation therapy for the treatment of metastatic castration-resistant prostate cancer. This dual treatment may enhance the effects of second-line hormonal therapy, as radiotherapy renders cancer cells more prone to immune-mediated cytotoxicity. Moreover, radiotherapy exerts its effect both on directly irradiated cells and on other distant tissues, with an abscopal effect, already demonstrated in other solid tumors. This combination treatment is safe and effective, with few adverse events. Moreover, it is of paramount importance in patients with oligoprogression of the primary disease, when current guidelines recommend continuing abiraterone treatment. Ablative radiation therapy is a noninvasive, nontoxic treatment with very high efficacy on local tumor growth control. In the available literature, the combination of radiation therapy and abiraterone acetate has prolonged both overall survival and progression-free survival, with a positive impact also on locoregional recurrence and distant metastases.

Topics: Abiraterone Acetate; Combined Modality Therapy; Disease-Free Survival; Humans; Male; Neoplasm Recurrence, Local; Prostatic Neoplasms, Castration-Resistant; Radiotherapy

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Middle Aged; Prognosis; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Risk Assessment; Survival Analysis; Taxoids; Treatment Outcome

Among all cancer-related death, prostate cancer accounts for the second prominent reason for cancer-associated death in men. Despite the castration mediated reduction in testosterone synthesis, adrenal glands, as well as tissues of prostate cancer, continue to produce androgens, which ultimately lead to the growth of prostate cancer. This phase is referred as metastatic castration-resistant prostate cancer, which throws an obstacle to treatment. Androgen antagonists, in addition to deprivation of hormone, is being used for reducing the level of prostate-specific antigen but has not successfully come in front as a choice for prolonging the life of patients suffering from prostate cancer. In this prevailing scenario, abiraterone acetate (AA) has proved to be a boon for patients suffering from prostate cancer. AA selectively inhibits the actions of enzymes C17, 20-lyase and 17α-hydroxylase on cytochrome P450 (CYP) 17 when administered orally. The signaling of androgen receptor, being important for primary to metastatic phases of prostate cancer, CYP17 is essential for the synthesis of androgen. Herein, the in-detail pharmacological profile of AA, including androgen signaling, mechanism of action of AA, mechanism of AA resistance, pharmacokinetics, latest clinical findings, predictive markers, optimal treatment sequence, toxicity, and food interaction profiles have been reviewed.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Antineoplastic Agents; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

Most men with advanced prostate cancer will develop bone metastases, which have a substantial impact on quality of life. Bone metastases can lead to skeletal-related events (SREs), which place a burden on patients and healthcare systems. For men with castration-resistant prostate cancer (CRPC) and bone metastases, the treatment landscape has evolved rapidly over the past few years. The relatively recent approvals of the hormonal agents abiraterone acetate and enzalutamide, second-line chemotherapy cabazitaxel, and the radiopharmaceutical radium-223 dichloride (radium-223), have provided clinicians with a greater choice of treatments. These compounds have benefits in terms of overall survival based on the results of pivotal phase 3 studies. The bisphosphonate zoledronic acid and the RANK ligand inhibitor denosumab are indicated for the prevention of SREs in men with metastatic CRPC but studies of these compounds have not demonstrated a survival benefit. The important question of the role of bisphosphonates or denosumab in combination with these new agents has thus materialised. Current and emerging evidence from clinical studies of abiraterone acetate, enzalutamide and radium-223, suggest that addition of bisphosphonates or denosumab to these new therapies may provide further clinical benefits for patients with prostate cancer and bone metastases. This evidence may help to shape clinical practice but are based largely on post hoc analyses of clinical trial data. It is therefore apparent that further data are required from both clinical studies and real-world settings to enable physicians to understand the efficacy and safety of combination therapy with the new agents plus bisphosphonates or denosumab.

Topics: Abiraterone Acetate; Benzamides; Bone Density Conservation Agents; Bone Neoplasms; Clinical Trials, Phase III as Topic; Denosumab; Diphosphonates; Humans; Imidazoles; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Randomized Controlled Trials as Topic; Taxoids; Zoledronic Acid

Advanced prostate cancer includes a wide spectrum of disease ranging from hormone naïve or hormone sensitive to castration resistant, both containing populations of men who have demonstrable metastatic and non-metastatic states. The mainstay of treatment for metastatic hormone-sensitive prostate cancer is androgen deprivation therapy (ADT). However, recent level 1 evidence demonstrates that the addition of chemotherapy or abiraterone acetate to ADT results in significant survival advantage as compared with ADT alone. Furthermore, in non-metastatic castration-resistant prostate cancer (M0 CRPC), two second-generation anti-androgens, apalutamide and enzalutamide, when used in combination with ADT, have demonstrated a significant benefit in metastasis-free survival. Here, we review the most recent studies leading to these significant changes in the treatment of advanced prostate cancer.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents; Disease Management; Disease-Free Survival; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

Für die Therapie des metastasierten kastrationsresistenten Prostatakarzinoms (mCRPC) stehen inzwischen mehrere moderne Wirkstoffe zur Verfügung. Sie verdrängen zunehmend die aufgrund mangelnder Alternativen lange Jahre üblichen sekundären Hormonmanipulationen, denn neuere Substanzen konnten - im Gegensatz zu den konventionellen antihormonellen Therapien - das Überleben in Phase-III-Studien verlängern. So ist der Beginn der mCRPC-Therapie gemäß Leitlinie der European Association of Urology in den letzten Jahren im Krankheitsverlauf nach vorne gerückt. Für den Androgen-Biosynthese-Inhibitor Abirateronacetat, einen dieser modernen Wirkstoffe, liefern mehrere Analysen zusätzliche Hinweise, wann die Behandlung begonnen werden könnte.

Topics: Abiraterone Acetate; Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Europe; Evidence-Based Medicine; Humans; Male; Medical Oncology; Practice Guidelines as Topic; Prostatic Neoplasms, Castration-Resistant; Secondary Prevention; Treatment Outcome

Abirateronacetat, das in Kombination mit Prednison/Prednisolon verabreicht wird, spielt eine wichtige Rolle in der Therapie des metastasierten kastrationsresistenten Prostatakarzinoms. Im Folgenden wurden besondere Aspekte der Therapie im klinischen Alltag zusammengestellt. Sie betreffen unter anderem die Dosierung - auch vor dem Hintergrund der Markteinführung einer neuen Formulierung von Abirateronacetat. Hinzu kommt die Verträglichkeit, vor allem in Bezug auf kardiovaskuläre und Kortikoid-bedingte Nebenwirkungen. Des Weiteren werden Kriterien genannt, nach denen die Therapie nicht zu früh umgestellt werden sollte.

Topics: Abiraterone Acetate; Adenocarcinoma; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Europe; Evidence-Based Medicine; Humans; Male; Prednisolone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

When advanced prostate cancer recurred during hormonal therapy and became the castration-resistant prostate cancer, "vintage hormonal therapy," such as antiandrogen alternating therapy or estrogen-related hormonal therapy, was widely carried out in Japan until 2013. This vintage hormonal therapy controlled the progression of castration-resistant prostate cancer. When castration-resistant prostate cancer relapses during these therapies, chemotherapy using docetaxel has been carried out subsequently. Since new hormonal therapies using abiraterone acetate and enzalutamide, which improve the prognosis of castration-resistant prostate cancer, became available in Japan from 2014, therapeutic options for castration-resistant prostate cancer have increased. Furthermore, the improvement of the further prognosis is promising by using cabazitaxel for docetaxel-resistant castration-resistant prostate cancer and radium-223 for castration-resistant prostate cancer with bone metastasis. An increase in therapeutic options gives rise to many questions, including best timing to use them and the indication. Furthermore, physicians have to consider the treatment for the recurrence after having carried out chemotherapy. We want to argue the difference in hormonal therapy between Japan and Western countries, and problems when carrying out new treatments, and the importance of imaging in the present review article.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Disease Progression; Docetaxel; Humans; Japan; Male; Neoplasm Recurrence, Local; Nitriles; Phenylthiohydantoin; Prognosis; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Radium; Taxoids

Health-related quality of life (HRQoL) deteriorates rapidly in patients with advanced-stage cancer, with patients seriously disturbed by fatigue, sleep disorders, bone pain, constipation and other disease related symptoms. As treatment and prognosis continues to improve, reducing symptoms and improving quality of life with minimum of toxicities have become important therapeutic goals. The effectiveness of abiraterone acetate and enzalutamide in both prolonging life and improving quality of life in asymptomatic or mildly symptomatic patients with metastatic castrations-resistant prostate cancer (mCRPC) has been clinically proven.. Mit dem Auftreten von Metastasen verschlechtert sich zusehends auch die gesundheitsbezogene Lebensqualität von Karzinom-Patienten. Vor allem Fatigue, Schlafstörungen, Knochenschmerzen, Obstipation und andere krankheitsassoziierte Symptome belasten die Betroffenen sehr. Infolge der verbesserten Behandlungsmöglichkeiten und längeren Überlebenszeiten stellen auch Symptomkontrolle und Verbesserung der Lebensqualität wichtige Ziele der Tumortherapie dar. Bei Patienten mit metastasiertem kastrationsresistentem Prostatakarzinom (mCRPC) konnte für Abirateronacetat und Enzalutamid neben der signifikanten Überlebensverlängerung auch ein signifikanter Nutzen hinsichtlich mehrerer Parameter der Lebensqualität gezeigt werden.

Topics: Abiraterone Acetate; Benzamides; Bone Neoplasms; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Survival Rate; Treatment Outcome

Treatments currently available for metastatic castration-resistant prostate cancer (mCRPC) include abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, and radium-223. However, the optimal sequence of these agents is still unclear, and markers to predict treatment response and facilitate patient selection remain an unmet need. In terms of overall survival, it is crucial that patients receive all treatment options currently available. This requires early detection of progression as an indication for a treatment switch. In this context, a structured monitoring of treatment is important in clinical practice.. Für die Behandlung des metastasierten kastrationsresistenten Prostatakarzinoms (mCRPC) stehen aktuell als Therapieoptionen Abirateronacetat, Enzalutamid, Docetaxel, Cabazitaxel und Radium-223 zur Verfügung, wobei die optimale Abfolge in der Therapiesequenz noch unklar ist. Es existieren auch noch keine verlässlichen prädiktiven Biomarker zur Vorhersage des Therapieansprechens und damit zur besseren Patientenselektion. Für das Gesamtüberleben ist entscheidend, dass jeder Patient möglichst alle verfügbaren Therapieoptionen erhält. Dies setzt ein frühzeitiges Erkennen einer Progression als Indikation für einen Therapiewechsel voraus. In diesem Zusammenhang ist die Durchführung eines strukturierten Therapiemonitorings im klinischen Alltag wichtig.

Topics: Abiraterone Acetate; Benzamides; Biomarkers, Tumor; Combined Modality Therapy; Disease Progression; Docetaxel; Humans; Male; Neoplastic Cells, Circulating; Nitriles; Outcome and Process Assessment, Health Care; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radium; Taxoids

Oral abiraterone acetate (Zytiga

Topics: Abiraterone Acetate; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Neoplasm Metastasis; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant

Abiraterone acetate is a CYP-17 inhibitor approved for the treatment of prostate cancer. Abiraterone acetate (AA) therapy is associated with toxicities, including hypokalemia, hypertension, liver function test abnormalities and cardiac events. These adverse events are traditionally managed with a standard dose of corticosteroids. However, preliminary data are available on the use of a lower dose of corticosteroids. The aim of this report is to perform a pooled analysis evaluating the risk ratio (RR) of AA-related adverse events of special interest associated with low or standard dose of corticosteroids. A total of 5374 cases from 4 randomized clinical trials were included. Subgroup analysis according to corticosteroids dosage revealed a higher RR of adverse events associated with a dose of 5 mg, compared to 10 mg. In particular, there was a statistically significant higher RR of hypokalemia and ALT/AST increase, and only a modest risk increase for cardiac disorders and hypertension. In conclusion, given the limitations of a literature-based study, in comparison with a meta-analysis based on individual patients' data, our study identified a relatively small increase in RR for hypertension and cardiac disorders and a bigger increase of RR for hypokalemia and ALT/AST toxicity when 5 mg, rather than 10 mg of corticosteroids were administered to manage adverse events of special interest from AA. Further studies with specified end-points are awaited to confirm these results.

Topics: Abiraterone Acetate; Adrenal Cortex Hormones; Antineoplastic Agents; Aspartate Aminotransferases; Dose-Response Relationship, Drug; Humans; Hypertension; Hypokalemia; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic

Two new drugs, the CYP17 inhibitor abiraterone acetate and the androgen receptor (AR) antagonist enzalutamide, have recently shown to prolong OS prior chemotherapy or in docetaxel treated mCRPC patients, using steroidal therapy or placebo as control group. Updated analyses underlined the role of these new agents on two prostate-specific endpoints as radiographic progression-free survival (rPFS) and time to first skeletal-related event (tSRE). On the basis of these reports, we made an indirect comparison between abiraterone and enzalutamide. We obtained a clinically but not significant difference favouring enzalutamide over abiraterone in terms of rPFS (HR 0.48, 95% CI 0.22-1.02). No significant difference was shown in term of tSRE (HR 0.99, 95% CI 0.83-1.17). In conclusion, abiraterone and enzalutamide have both demonstrated to significantly delay the bone progression resulting in similar improvements in bone-related endpoints in patients with mCRPC.

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Benzamides; Bone Neoplasms; Cytochrome P-450 Enzyme Inhibitors; Disease Progression; Disease-Free Survival; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Treatment Outcome

Both docetaxel+androgen deprivation therapy (ADT) and abiraterone acetate 1000mg/d+prednisone/prednisolone 5mg/d+ADT improved survival in patients with metastatic castration-naive prostate cancer. Their use should be offered and guided by patient's own characteristics.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Humans; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Treatment decisions are challenging in patients with metastatic castration-resistant prostate cancer with progression after or under docetaxel. The current review systematically searched the published literature on all treatment options, and assessed the risk of bias and quality of evidence. It found the best available evidence for effective prolongation of overall survival and progression-free survival for abiraterone acetate plus prednisone versus placebo plus prednisone and enzalutamide versus placebo. Other treatment modalities could be beneficial for individual patients by taking into consideration the: selection criteria of the randomized clinical trials, risk of bias, subgroup analyses, and quality of life and adverse events. Further research is needed to determine the sequence, timing asnd combination of different treatments.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Docetaxel; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Drug Costs; Drug Therapy, Combination; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Quality-Adjusted Life Years; Technology Assessment, Biomedical; United Kingdom

The androgen receptor (AR) plays a key role in progression to metastatic castration-resistant prostate cancer (mCRPC). Despite the recent progress in targeting persistent AR activity with the next-generation hormonal therapies (abiraterone acetate and enzalutamide), resistance to these agents limits therapeutic efficacy for many patients. Several explanations for response and/or resistance to abiraterone acetate and enzalutamide are emerging, but growing interest is focusing on importance of AR splice variants (AR-Vs) and in particular of AR-V7. Increasing evidences highlight the concept that variant expression could be used as a potential predictive biomarker and a therapeutic target in advanced prostate cancer. Therefore, understanding the mechanisms of treatment resistance or sensitivity can help to achieve a more effective management of mCRPC, increasing clinical outcomes and representing a promising and engaging area of prostate cancer research.

Topics: Abiraterone Acetate; Alternative Splicing; Antineoplastic Agents; Benzamides; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Staging; Nitriles; Patient Selection; Phenylthiohydantoin; Predictive Value of Tests; Prognosis; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Taxoids

With an ageing population and associated increasing multimorbidity and polypharmacy, the potential for drug-drug interactions (DDIs) becomes increasingly important. In general, DDIs are more likely to be clinically significant for drugs with a narrow therapeutic index, necessitating dosage adjustments or replacement of co-administered drugs. Many DDIs are a result of pharmacokinetic interactions of the cytochrome P450 enzymes. In particular, the CYP3A4 isoenzyme is involved in the metabolism of about 50 % of currently used drugs. Accordingly, many commonly used drugs in patients with prostate cancer are substrates of Cyp3A4. Hence enzalutamide, a strong Cyp3A4 inductor, has the potential to substantially decrease plasma concentrations and the effects of many co-medications in this patient population, whereas abiraterone acetate, a strong Cyp2D6 inhibitor, is less of a concern with respect to Cyp450 inhibition, since the Cyp2D6-mediated metabolism is much smaller and Cyp2D6 substrates are prescribed to a lesser extent in patients with prostate cancer.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Carcinoma; Drug Interactions; Evidence-Based Medicine; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Two novel oral drugs that target androgen signaling have recently become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate inhibits the synthesis of the natural ligands of the androgen receptor, whereas enzalutamide directly inhibits the androgen receptor by several mechanisms. Abiraterone acetate and enzalutamide appear to be equally effective for patients with mCRPC pre- and postchemotherapy. Rational decision making for either one of these drugs is therefore potentially driven by individual patient characteristics. In this review, an overview of the pharmacokinetic characteristics is given for both drugs and potential and proven drug-drug interactions are presented. Additionally, the effect of patient-related factors on drug disposition are summarized and the limited data on the exposure-response relationships are described. The most important pharmacological feature of enzalutamide that needs to be recognized is its capacity to induce several key enzymes in drug metabolism. The potency to cause drug-drug interactions needs to be addressed in patients who are treated with multiple drugs simultaneously. Abiraterone has a much smaller drug-drug interaction potential; however, it is poorly absorbed, which is affected by food intake, and a large interpatient variability in drug exposure is observed. Dose reductions of abiraterone or, alternatively, the selection of enzalutamide, should be considered in patients with hepatic dysfunction. Understanding the pharmacological characteristics and challenges of both drugs could facilitate decision making for either one of the drugs.

Topics: Abiraterone Acetate; Antineoplastic Agents; Area Under Curve; Benzamides; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Induction; Fasting; Half-Life; Humans; Liver Failure; Male; Metabolic Clearance Rate; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemoradiotherapy; Clinical Trials, Phase II as Topic; Humans; Male; Prednisone; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Radioisotopes; Radium; Treatment Outcome

For >6 yr, docetaxel with prednisone was the only treatment with survival benefits for metastatic castration-resistant prostate cancer (mCRPC). More recently, in clinical practice, abiraterone acetate has been commonly administered prior to docetaxel for the treatment of mCRPC. Our study aimed to review the activity of docetaxel after prior abiraterone. To this end, we analyzed all retrospective reports in the literature describing the overall survival (OS) of mCRPC patients treated with docetaxel after previous abiraterone. The mean OS observed was 12.7 mo, which suggested a significant decrement compared with the 19.2 mo seen in the updated analysis of the TAX 327 study; however, the data are quite similar to the OS of 13.6 mo (95% confidence interval, 12.1-15.1 mo) described in a retrospective single-institution study of 357 men with mCRPC treated with docetaxel with no prior abiraterone mostly in routine practice (86.3%). Because the characteristics of patients recruited in phase 3 trials tend to differ from the real-world setting, we deemed this data set a relevant comparison. Consequently, despite the limitations of retrospective cross-study comparisons, the data suggest that docetaxel retains activity when used as second-line therapy after abiraterone for mCRPC patients.. We reviewed the activity of docetaxel after prior use of abiraterone and considered the results in the light of the outcomes of docetaxel used as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC) patients in routine practice. We noted that docetaxel retains reasonable activity and is a useful agent for the treatment of mCRPC patients before or after abiraterone.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids

Abiraterone acetate (AA) is a selective irreversible inhibitor of CYP 17, a key enzyme in androgen biosynthesis. The efficacy and safety of AA in improving survival and quality of life in metastatic castration resistant prostate cancer (mCRPC) has been demonstrated in two landmark clinical trials (COU-AA-301 and COU-AA-302). This article will review the rationale, pharmacology, clinical indications and contraindications, administration, and adverse effects of AA administration in mCRPC.

Topics: Abiraterone Acetate; Antineoplastic Agents; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

To examine the current literature and identify key consensus findings from the available studies to better educate urologists and medical oncologists on agents used in the treatment of metastatic prostate cancer (mPC).. Following PRISMA guidelines, we conducted a systematic review of the available literature on reported trials of systemic therapies for mPC. Two search terms were used: 'metastatic prostate cancer' and 'treatment'.. A variety of agents have demonstrated improved overall survival in patients with mPC. Twenty recently documented trials were reported in the literature with a focus on enzalutamide, abiraterone acetate, docetaxel and other newer agents. These studies were grouped based on patient populations.. The increasing number of high-quality clinical trials, with overlapping patient populations has made defining the correct therapy for men with mPC challenging for urologists and medical oncologists. The data suggests that the optimal sequence of drugs is not only unknown but also not necessarily the same for each patient. As such, we suggest a more individualized approach to the treatment of prostate cancer depending on patient and disease factors.

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Docetaxel; Humans; Immunotherapy; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Precision Medicine; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radium; Randomized Controlled Trials as Topic; Taxoids; Tissue Extracts

New treatments, such as sipuleucel-T and androgen receptor- (AR-) directed therapies (enzalutamide (Enz) and abiraterone acetate (AA)), have emerged and been approved for the management of castration-resistant prostate cancer (CRPC). There are still debates over their efficacy and clinical benefits. This meta-analysis aimed to investigate the efficacy and safety of sipuleucel-T and AR-directed therapies in patients with CRPC. RevMan 5.1 was used for pooled analysis and analysis of publication bias. Seven studies were included in the meta-analysis, with three studies in sipuleucel-T (totally 737 patients, 488 patients in treatment group, and 249 patients in placebo group) and four in AR-directed therapies (totally 5,199 patients, 3,015 patients in treatment group, and 2,184 patients in placebo group). Treatment with sipuleucel-T significantly improved overall survival in patients with CRPC and was not associated with increased risk of adverse event of grade ≥3 (

Topics: Abiraterone Acetate; Antineoplastic Agents; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Tissue Extracts

There are emerging data regarding the therapeutic benefit of enzalutamide (ENZ) in the treatment of patients with castration-resistant prostate cancer (CRPC) pretreated with docetaxel and abiraterone acetate. To systematically evaluate the evidence regarding the efficacy of ENZ after docetaxel and abiraterone acetate treatment in CRPC, we performed a pooled analysis of all available studies. Studies that enrolled CRPC patients treated with ENZ after docetaxel and abiraterone acetate treatment were identified using PubMed, Web of Science, SCOPUS, The Cochrane Register of Controlled Trials, and EMBASE. A systematic review was conducted to calculate the pooled response rate (RR) and the 95% confidence interval (CI). Pooled median progression-free survival (PFS) and overall survival (OS), weighted on the number of patients of each of the selected trials, were also calculated. We tested for significant heterogeneity using the Cochran χ(2) test and the I(2) index. Ten publications were selected for inclusion in this analysis. The number of included patients was 536 (range, 23-137). Overall, the pooled RR (reduction of prostate-specific antigen by > 50%) was 22.9% (95% CI, 19.3%-27.1%). The median PFS was 3.1 months (range, 1.4-4.9 months). The median OS was 8.3 months (range, 2.85-10.6 months). In patients sensitive to abiraterone, the RR to ENZ was 35% (95% CI, 27.2%-43.7%). ENZ is moderately effective in CRPC patients who were pretreated with chemotherapy and abiraterone acetate. The greater benefit is confined in patients who responded to abiraterone acetate. Further prospective evaluations of ENZ are required and the mechanisms of resistance have to be better understood.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Docetaxel; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Taxoids; Treatment Outcome

Over the past decade, treatment options for men with metastatic castration-resistant prostate cancer (CRPC) have expanded with the addition of abiraterone acetate (AA), enzalutamide, sipuleucel-T, radium-223, docetaxel and cabazitaxel. The optimal sequencing of therapies in the context of efficacy and known cross-resistance remains uncertain.. We review the development of enzalutamide (MDV3100, Xtandi), a novel second-generation androgen receptor (AR), and AA (Zytiga), a selective, irreversible inhibitor of cytochrome P17. In addition to discussing the clinical evidence, we also address evolving evidence of mechanisms of resistance and clinical cross-resistance during sequential therapy with these agents.. AA and enzalutamide have both demonstrated tolerability and clinical benefit for multiple outcomes in patients with CRPC, in both post-chemotherapy and pre-chemotherapy settings. Both agents target the androgen-signaling pathway and have similar efficacy; however, they differ in prednisone use and their toxicity profiles, impacting the decision of upfront therapy. Mechanisms of resistance emerging after treatment include both alterations in AR signaling as well as mechanisms that bypass the AR. Retrospective analyses have demonstrated evidence that sequential treatment with these agents results in limited clinical benefit, supporting mechanisms of cross-resistance. Trials are ongoing to determine optimal timing, sequence and combination of these agents.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Antineoplastic Agents; Benzamides; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Steroid 17-alpha-Hydroxylase

Androgen signaling axis (ASA) continues to play a crucial role in castration-resistant prostate cancer (CRPC). One of the proposed mechanisms is the activation of ASA by adrenal and intratumoral androgens. Targeted therapy to deplete such androgen sources should be effective in treating men with CRPC.. Abiraterone acetate (AA) is a selective irreversible inhibitor of CYP 17. It is orally administered and is converted to its active metabolite abiraterone by the liver. Increased adrenocorticotrophic hormone drive, however, results in increased risks of hypertension and hypokalemia. In Phase III trials, AA with prednisone was shown to improve survivals in men with metastatic CRPC (mCRPC). The overall tolerability and safety profiles were acceptable.. It is now accepted that CRPC is not independent of androgen signaling, and targeted therapies to suppress ASA have recently been developed. With multiple high-level evidences of efficacy and safety, AA is considered a breakthrough in the treatment of mCRPC. Current clinical challenge, however, is to better delineate the mechanisms of the disease progression for developments of resistance to targeted therapies. Identification of the drug-resistance patterns would allow better patient selection for each treatment modality.

Topics: Abiraterone Acetate; Androgens; Antineoplastic Agents; Disease Progression; Drug Resistance, Neoplasm; Humans; Male; Molecular Targeted Therapy; Neoplasm Metastasis; Patient Selection; Prostatic Neoplasms, Castration-Resistant; Survival Rate

Topics: Abiraterone Acetate; Androstenes; Animals; Clinical Trials as Topic; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Tablets; Xenograft Model Antitumor Assays

Abiraterone acetate is a novel CYP17A1 inhibitor demonstrated to prolong survival in castration-resistant prostate cancer (CRPC). This review explores key stages in the almost 20-year history of abiraterone acetate׳s development, starting with a program aiming to develop inhibitors of androgen synthesis at the Institute of Cancer Research, London. Clinical development was initially slow owing to insufficient data supporting targeting of androgen synthesis as a therapeutic approach in CRPC and safety concerns of adrenocortical insufficiency from suppression of cortisol. Regulatory authorities approved abiraterone acetate in 2011 after a survival benefit was demonstrated when given in combination with prednisone as compared with prednisone alone in docetaxel-treated men. Licensing approval extended to include chemotherapy-naive patients with CRPC in 2012 following a significant increase in radiographic progression-free survival. Ongoing research focuses on identifying predictive biomarkers and understanding mechanisms of resistance to improve its administration.

Topics: Abiraterone Acetate; Antineoplastic Agents; Disease Progression; Disease-Free Survival; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive prostate cancer progression. Since the approval of docetaxel, four additional agents that show a survival benefit have been registered on the basis of randomized phase 3 trials. These have included enzalutamide and abiraterone, two agents designed specifically to affect the androgen axis, sipuleucel-T, which stimulates the immune system and cabazitaxel, a chemotherapeutic agent. Denosumab was shown to significantly delay skeletal-related events. Clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision making more complex. The induction of constitutively-active AR splice variants (AR-Vs) driving clonal proliferation of AR-negative and AR-independent metastases may be one major potential mechanism of resistance to new hormone therapies.

Topics: Abiraterone Acetate; Androstenes; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Bone Neoplasms; Clinical Trials, Phase III as Topic; Denosumab; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Tissue Extracts

New agents for metastatic castration-resistant prostate cancer (CRPC) developed in the past 3 years include cabaziataxel (Cbz), abiraterone acetate (AA) and enzalutamide (E). In this review, the results of clinical studies in which one of these drugs is included as the third line of treatment are discussed. Our review suggests that AA and E have limited activity, while Cbz seems to retain its efficacy. Prospective studies that further examine sequential treatments are warranted.

Topics: Abiraterone Acetate; Benzamides; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

Until 2010, docetaxel was the only agent with proven survival benefit for castration-resistant prostate cancer. The development of cabazitaxel, abiraterone acetate, enzalutamide, radium-223, and sipuleucel-T has increased the number of treatment options. Because these agents were developed concurrently within a short period of time, prospective data on their sequential use efficacy are scarce. The challenge now is to reach a consensus on the best way to sequence effective treatments, ideally by the use of an approach specific to patient subgroups. However, the absence of robust surrogates of survival and the lack of predictive biomarkers makes data for the sequential use of these agents difficult to obtain and interpret.

Topics: Abiraterone Acetate; Androstenes; Benzamides; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Taxoids; Tissue Extracts; Treatment Outcome

Abiraterone acetate is a novel irreversible inhibitor of CYP17 that was recently approved for men with post-chemotherapy or chemo-naive castration-resistant prostate cancer. Unfortunately, this agent is not curative, and patients often ultimately develop resistance. However, men who progress after treatment with this new hormonal agent may be considered for another line of chemotherapy-based treatment. In 2004, docetaxel (D) and prednisone were found to improve survival compared with older regimens. More recently, cabazitaxel (C), a novel taxane chemotherapy, has been found to prolong survival in patients who exhibit disease progression during or after D chemotherapy. Here, we review the first clinical studies in which castration-resistant prostate cancer patients received chemotherapy with D or C after progression during abiraterone acetate treatment.

Topics: Abiraterone Acetate; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytochrome P-450 Enzyme Inhibitors; Docetaxel; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Taxoids; Young Adult

Persistent androgen receptor (AR) axis is a functionally important pathway for prostate cancer cells and it is currently regarded as a critical therapeutic target. Although the impressive clinical activity of new hormonal agents, such as the second-generation AR antagonist enzalutamide (formerly MDV3100) and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone acetate (AA), in patients with metastatic castration-resistant prostate cancer (mCRPC), innate or acquired resistance invariably arises. To date, emerging hypotheses are different, but the mechanisms of resistance to these drugs have not yet been clarified. The aim of this review is to summarize the main data available on the evaluation of the multiple levels of development of resistance to next-generation AR-directed therapies. Understanding how the AR is activated may have clinical implications in defining which patients will respond to existing therapeutic agents and provide a proof for making novel strategies.

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Benzamides; Drug Resistance, Neoplasm; Humans; Male; Molecular Targeted Therapy; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant

We performed a systematic review of the literature to assess the efficacy and the safety of second-line agents targeting metastatic castration-resistant prostate cancer (mCRPC) that has progressed after docetaxel. Pooled-analysis was also performed, to assess the effectiveness of agents targeting the androgen axis via identical mechanisms of action (abiraterone acetate, orteronel).. We included phase III randomized controlled trials that enrolled patients with mCRPC progressing during or after first-line docetaxel treatment. Trials were identified by electronic database searching. The primary outcome of the review was overall survival. Secondary outcomes were radiographic progression-free survival (rPFS) and severe adverse effects (grade 3 or higher).. Ten articles met the inclusion criteria for the review. These articles reported the results of five clinical trials, enrolling in total 5047 patients. The experimental interventions tested in these studies were enzalutamide, ipilimumab, abiraterone acetate, orteronel and cabazitaxel. Compared to control cohorts (active drug-treated or placebo-treated), the significant overall survival advantages achieved were 4.8 months for enzalutamide (hazard ratio for death vs. placebo: 0.63; 95% CI 0.53 to 0.75, P < 0.0001), 4.6 months for abiraterone (hazard ratio for death vs. placebo: 0.66, 95% CI 0.58 to 0.75, P < 0.0001) and 2.4 months for cabazitaxel (hazard ratio for death vs. mitoxantrone-prednisone: 0.70, 95% CI 0.59 to 0.83, p < 0.0001). Pooled analysis of androgen synthesis inhibitors orteronel and abiraterone resulted in significantly increased overall and progression-free survival for anti-androgen agents, compared to placebo (hazard ratio for death: 0.76, 95% CI 0.67 to 0.87, P < 0.0001; hazard ratio for radiographic progression: 0.7, 95% CI 0.63 to 0.77, P < 0.00001). Androgen synthesis inhibitors induced significant increases in risk ratios for adverse effects linked to elevated mineralocorticoid secretion, compared to placebo (risk ratio for hypokalemia: 5.75, 95% CI 2.08 to 15.90; P = 0.0008; risk-ratio for hypertension: 2.29, 95% CI 1.02 to 5.17; P = 0.05).. In docetaxel-pretreated patients enzalutamide, abiraterone-prednisone and cabazitaxel-prednisone can improve overall survival of patients, compared to placebo or to best of care at the time of study (mitoxantrone-prednisone). Agents targeting the androgen axis (enzalutamide, abiraterone, orteronel) significantly prolonged rPFS, compared to placebo. Further investigation is warranted to evaluate the benefit of combination or sequential administration of these agents. Large-scale studies are also necessary to evaluate the impact of relevant toxic effects observed in a limited number of patients (e.g., enzalutamide-induced seizures, orteronel-induced pancreatitis, and others).

Topics: Abiraterone Acetate; Androstenes; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease Progression; Evidence-Based Medicine; Humans; Imidazoles; Ipilimumab; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Risk Factors; Survival Analysis; Taxoids; Time Factors; Treatment Outcome

Androgen deprivation therapy is the standard of care for patients with advanced hormone-sensitive prostate cancer. Despite an initial response, most patients progress to castration-resistant prostate cancer (CRPC). The realization that CRPC remains driven by androgen receptor (AR) signaling has formed the basis for a new generation of agents targeting the AR axis. Two of these agents, abiraterone acetate and enzalutamide, have been shown to prolong overall survival in patients with CRPC. Several other AR inhibitors are currently in development for the treatment of CRPC. The present article reviews ODM-201, a new-generation AR inhibitor with a unique molecular structure, in the treatment of CRPC. The design of an ongoing Phase III trial (ARAMIS) of ODM-201 in men with non-metastatic CRPC is also discussed, at a disease stage for which there is currently no approved treatment.

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Animals; Benzamides; Drug Design; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Survival Rate

Prostate cancer treatment remains a challenge for the urologist. Medical control in locally advanced or metastatic prostate cancer is usually performed with LHRH analogues and/or antiandrogens. Different treatments have been proposed when there is biochemical and clinical progression of the disease and other new ones have changed the patients' perspective and life expectancy.. This review has aimed to establish the current role of Abiraterone Acetate in the treatment of castration-resistant prostate cancer and facilitate decision-making by the Urologist by means of a Treatment Algorithm.. A search of current evidence on Abiraterone treatment in patients with castration- resistant metastatic prostate cancer was performed in PubMed, mainly analyzing those studies designed as clinical trials. In addition, we reviewed and updated the role of hormone therapy and androgen receptors in prostate cancer.. There are currently basically two clinical trials that demonstrate the effectiveness of Abiraterone in metastatic prostate cancer compared to placebo. The study COU-AA 302 shows a clear benefit with Abiraterone prior to chemotherapy in patients with castration-resistant prostate cancer, this making it possible to establish an algorithm for initial treatment that facilitates decision-making by the urologist.. Abiraterone is a pre-chemotherapy treatment option in selected patients with castration resistant metastatic prostate cancer, although it is necessary to improve the cost and to design more multicenter clinical trials to optimize the cost/benefit ratio.

Topics: Abiraterone Acetate; Algorithms; Antineoplastic Agents; Drug Therapy, Combination; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase

Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel-T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Radium; Randomized Controlled Trials as Topic; Taxoids; Tissue Extracts

Recently, the standard of care for metastatic Castration Resistant Prostate Cancer (mCRPC) has changed considerably. Persistent androgen receptor (AR) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer. Androgen receptor gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells, making them extremely sensitive to low levels of circulating androgens. Additionally, prostate cancer cells are able to maintain dihydrotestosterone (DHT) concentration in excess of serum concentrations to support tumor growth. For many years ketoconazole was the only CYP17 inhibitor that was used to treat mCRPC. However, significant toxicities limit its use. Newly approved chemotherapeutic agents such as Abiraterone (an oral selective inhibitor of CYP17A), which blocks androgen biosynthesis both within and outside the prostate cancer cells), and enzalutamide (blocks AR signaling) have improved overall survival. There are also ongoing phase III trials for Orteronel (TAK- 700), ARN- 509 and Galeterone (TOK-001), which targets androgen signaling. In this review, we will present the rationale for the newly approved hormonal treatments, their indications and complications, and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents. Finally, we will talk about the potential upcoming hormonal treatments for mCRPC.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Androstenes; Antineoplastic Agents; Benzamides; Benzimidazoles; Combined Modality Therapy; Humans; Imidazoles; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Thiohydantoins

To evaluate the safety and efficiency of using abiraterone and prednisone in the treatment of patient with metastatic castration resistant prostate cancer (mCRPC) no prior chemotherapy.. Three mCRPC no prior chemotherapy patients accepted abiraterone and prednisone treatment. The clinical data were analyzed retrospectively and the safety and efficiency of this treatment option were discussed. The Gleason scores of the three mCRPC patients were 5, 9, and 9. The clinical stages were T3aNxM0, T3aNxM1b, and T3aNxM1b. The patients received abiraterone 1 000 mg daily and prednisone 5 mg twice daily and androgen deprivation therapy in the treatment. Their blood pressure, complete blood count, prostate specific antigen (PSA), biochemical parameters, whole body CT scan and bone scan were done regularly to monitor the progression of the diseases.. In this study, the general condition improved in two patients. Two of the three patients experienced decrease of PSA and no progression. One patient experienced disease progression. Generally, abiraterone and prednisone resulted in prolonged radiographic progression-free survival and delayed in PSA progression in mCRPC no prior chemotherapy. There were no severe side effects, such as hypokalemia, hypertension, and water-sodium retention. The patient's tolerance was good.. Abiraterone and prednisone are safe and can improve mCRPC no prior chemotherapy patient's life quality and may prolong the overall survival.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Retrospective Studies

Prostate cancer is the second leading cause of cancer-related deaths in men in most western countries. New agents for metastatic castration-resistant prostate cancer (CRPC) developed in the past 3 years include abiraterone acetate (AA) and enzalutamide (ENZ), which inhibit signaling by and synthesis of androgens, respectively. Because they share the same target, potential clinical cross-resistance between AA and E is possible. In this review, we discuss the results of clinical studies in which CRPC patients were treated with AA and E either separately or in sequence after first-line treatment with docetaxel. Our review suggests that sequential administration of AA and E in either order has limited activity after docetaxel therapy. Prospective studies that further examine sequential treatments with AA and E are warranted.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials as Topic; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC).. The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature.. When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib.. Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or combinations of therapies. Palliative care should be offered to all patients.

Topics: Abiraterone Acetate; Androstadienes; Benzamides; Docetaxel; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Practice Guidelines as Topic; Prednisone; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Randomized Controlled Trials as Topic; Taxoids

Androgen and androgen receptor (AR) play a critical role in the development of prostate cancer. Androgen deprivation therapy (ADT) has become the therapeutic mainstay for patients with metastatic prostate cancer. ADT can reduce the serum testosterone level from the normal range between 500 and 600 ng/dl to the castrate level. Following surgical castration, the serum testosterone level decreases to less than 20 ng/dL (0.69 nmol/L) in about three quarters of the patients. Although insufficient suppressions of the serum testosterone level following ADT have not been well recognized to date, the failure in achieving the castrate level of testosterone may have an adverse impact on survival in men with prostate cancer. Although circulating testosterone levels following castration do not necessarily reflect the amount of intraprostatic testosterone or dihydrotestosterone, testosterone during ADT mainly derives from intratumorally synthesized precursors and adrenal androgens. The advent of new agents represented by abiraterone acetate and enzalutamide, which target adrenal or intraprostatic androgen biosynthesis and AR signaling, respectively, has retrieved interest in testosterone levels during ADT. We critically reviewed androgen metabolism and its significance in prostate cancer biology and treatment to promote their better understanding and management of men with prostate cancer.

Topics: Abiraterone Acetate; Androgens; Androstenes; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Testosterone

The arrival of several new agents--cabazitaxel, abiraterone acetate, enzalutamide, and radium-223--is changing the treatment options and management of patients with metastatic castration-resistant prostate cancer (mCRPC). Many other novel agents are also being investigated. As new drugs become approved, new treatment strategies and markers to best select which patients will best respond to which drug are needed. This review article is a summary of a European Treatment Practices Meeting, which was convened to discuss these latest data on novel agents and current treatment strategies in the mCRPC setting.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials as Topic; Docetaxel; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

Abiraterone acetate is the first second-line hormonal agent proven to improve survival in metastatic castration-resistant prostate cancer. It selectively inhibits cytochrome P450 17 (CYP17) α-hydroxylase and cytochrome17,20 (C17,20)-lyase, which are enzymes critical for androgen synthesis. Abiraterone acetate was initially approved in the United States in 2011 after demonstrating a 4-month survival benefit in docetaxel-refractory metastatic prostate cancer. The FDA recently expanded its indication for use in the pre-chemotherapy setting after it elicited significant delays in disease progression and a strong trend for increased overall survival in phase III studies. Ongoing investigations of abiraterone are evaluating its efficacy in earlier disease states, exploring its synergy in combination with other therapeutic agents, and assessing the necessity for administration of concurrent steroids and gonadal suppression. The identification and development of predictive biomarkers will optimize the incorporation of abiraterone into the management of advanced prostate cancer.

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents, Hormonal; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Treatment Outcome

Abiraterone acetate plus prednisone significantly improves radiographic progression-free survival in asymptomatic or mildly symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer compared with prednisone alone. We describe analyses of data for patient-reported pain and functional status in a preplanned interim analysis of a phase 3 trial.. Between April 28, 2009, and June 23, 2010, patients with progressive, metastatic castration-resistant prostate cancer were enrolled into a multinational, double-blind, placebo-controlled trial. Patients were eligible if they were asymptomatic (score of 0 or 1 on item three of the Brief Pain Inventory Short Form [BPI-SF] questionnaire) or mildly symptomatic (score of 2 or 3) and had not previously received chemotherapy. Patients were randomly assigned (1:1) to receive oral abiraterone (1 g daily) plus prednisone (5 mg twice daily) or placebo plus prednisone in continuous 4-week cycles. Pain was assessed with the BPI-SF questionnaire, and health-related quality of life (HRQoL) with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. We analysed data with prespecified criteria for clinically meaningful pain progression and deterioration in HRQoL. All patients who underwent randomisation were included in analyses.. 1088 patients underwent randomisation: 546 were assigned to abiraterone plus prednisone and 542 to placebo plus prednisone. At the time of the second prespecified interim analysis, median follow-up was 22·2 months (IQR 20·2-24·8). Median time to progression of mean pain intensity was longer in patients assigned to abiraterone plus prednisone (26·7 months [95% CI 19·3-not estimable]) than in those assigned to placebo plus prednisone (18·4 months [14·9-not estimable]; hazard ratio [HR] 0·82, 95% CI 0·67-1·00; p=0·0490), as was median time to progression of pain interference with daily activities (10·3 months [95% CI 9·3-13·0] vs 7·4 months [6·4-8·6]; HR 0·79, 95% CI 0·67-0·93; p=0·005). Median time to progression of worst pain was also longer with abiraterone plus prednisone (26·7 months [95% CI 19·4-not estimable]) than with placebo plus prednisone (19·4 months [16·6-not estimable]), but the difference was not significant (HR 0·85, 95% CI 0·69-1·04; p=0·109). Median time to HRQoL deterioration was longer in patients assigned to abiraterone plus prednisone than in those assigned to placebo plus prednisone as assessed by the FACT-P total score (12·7 months [95% CI 11·1-14·0] vs 8·3 months [7·4-10·6]; HR 0·78, 95% CI 0·66-0·92; p=0·003) and by the score on its prostate-cancer-specific subscale (11·1 months [8·6-13·8] vs 5·8 months [5·5-8·3]; HR 0·70, 95% CI 0·60-0·83; p<0·0001).. Abiraterone plus prednisone delays patient-reported pain progression and HRQoL deterioration in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. These results provide further support for the efficacy of abiraterone in this population.

Topics: Abiraterone Acetate; Activities of Daily Living; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Australia; Canada; Cost of Illness; Disease Progression; Double-Blind Method; Drug Administration Schedule; Europe; Humans; Kaplan-Meier Estimate; Male; Pain; Pain Measurement; Prednisone; Proportional Hazards Models; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Surveys and Questionnaires; Time Factors; Treatment Outcome; United States

Abiraterone acetate (Zytiga(®)) is an orally administered, selective inhibitor of the 17α-hydroxylase and C17,20-lyase enzymatic activities of cytochrome P450 (CYP) 17. CYP17 is required for androgen biosynthesis, with androgen receptor signalling crucial in the progression from primary to metastatic prostate cancer. Abiraterone acetate is approved in the European Union and the US, in combination with prednisone or prednisolone, for the treatment of men with metastatic castration-resistant prostate cancer (CRPC). When administered in combination with prednisone in a placebo-controlled, multinational phase III study, abiraterone acetate significantly prolonged overall survival and radiographic progression-free survival (rPFS) in men with metastatic CRPC who had previously received docetaxel. In men with metastatic CRPC who had not previously received chemotherapy participating in a placebo-controlled, multinational phase III study, there was a strong trend towards an overall survival benefit, a significant prolongation in rPFS and significant delays in clinical decline, the need for chemotherapy and the onset of pain observed. Given the nature of the therapy, the overall tolerability profile of abiraterone acetate, in combination with prednisone, was acceptable in men with metastatic CRPC. Abiraterone acetate is associated with hypokalaemia, hypertension, and fluid retention or oedema, secondary to its mechanism of action, and with cardiac adverse events and hepatotoxicity; however, in the phase III studies the incidences of the most frequently reported grade 3 or 4 adverse events of special interest were relatively low. Although the final overall survival data in men with metastatic CRPC who have not previously received chemotherapy are awaited, current evidence indicates that abiraterone acetate is a useful option for the treatment of metastatic CRPC.

Topics: Abiraterone Acetate; Androstadienes; Clinical Trials, Phase III as Topic; Disease-Free Survival; Docetaxel; Humans; Male; Multicenter Studies as Topic; Prednisone; Prostatic Neoplasms, Castration-Resistant; Taxoids

Abiraterone acetate has increased the overall survival of patients with metastatic castration-resistant prostate cancer. However, despite an initial response to treatment, many patients develop resistance to the drug. In this paper we present different hypotheses that may explain the emergence of resistance.. This review was conducted from the PubMed database. The most relevant articles were selected and analyzed.. The molecular mechanisms of resistance to abiraterone acetate remain largely elusive. We detailed some of them including the reactivation of the androgen receptor through alternative biosynthesis of androgens, over expression or mutation of the androgen receptor gene, or the action of co-activators. The over expression of CYP17A1 or the alteration of other genes' expression involved in steroidogenesis could also contribute to the resistance.. Some of the molecular mechanisms involved in the resistance to abiraterone acetate were detailed. Better understanding of these mechanisms is a key step to allow the emergence of new therapeutic options and personalized treatments of castration resistant prostate cancer.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Male; Mutation; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Steroid 17-alpha-Hydroxylase; Survival Analysis

Abiraterone acetate plus prednisone with androgen deprivation therapy is a standard treatment option for patients with high-risk metastatic castration-sensitive prostate cancer (mCSPC). However, no data are available on the optimal subsequent treatment option in patients treated with abiraterone acetate plus prednisone for high-risk mCSPC.. We aimed to compare the clinical outcomes of subsequent therapy after discontinuation of abiraterone acetate plus prednisone in patients with high-risk mCSPC.. Overall survival and time to treatment failure from initiation of subsequent therapies were estimated by applying a marginal structural Cox proportional hazards model using inverse probability of treatment weighting with a change of time scale to time on treatment.. A total of 217 patients received subsequent therapies: 127 received chemotherapy, 49 received non-chemotherapy, and 41 received other treatments. For overall survival, when adjusted with the marginal structural Cox proportional hazards model using inverse probability of treatment weighting, the hazard ratio was 1.212 (95% confidence interval [CI] 0.742-1.979) for chemotherapy versus non-chemotherapy, 0.534 (95% CI 0.267-1.066) for non-chemotherapy versus other treatments, and 0.635 (95% CI 0.317-1.271) for chemotherapy versus other treatments. For time to treatment failure, the hazard ratio was 1.287 (95% CI 0.832-1.989) for chemotherapy versus non-chemotherapy, 0.785 (95% CI 0.486-1.269) for non-chemotherapy versus other treatments, and 0.898 (95% CI 0.612-1.318) for chemotherapy versus other treatments.. No differences were observed between the treatment effects of chemotherapy and non-chemotherapy in patients with high-risk mCSPC after abiraterone acetate plus prednisone. These findings suggest that life-extending subsequent therapy after abiraterone acetate plus prednisone for mCSPC should be chosen at the physician's discretion and patient's preference.. ClinicalTrials.gov, NCT01715285, registered 26 October, 2012.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Castration; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

The development of a novel therapy to overcome primary and acquired resistance to abiraterone is an unmet need. This study aimed to evaluate the efficacy and safety of adding 5α-reductase inhibitor dutasteride to abiraterone, explore proof of concept, and identify candidates suitable for combination therapy. This phase II, single-arm, and open-label study enrolled second-generation antiandrogen- and chemotherapy-naïve patients with castration-resistant prostate cancer. Patients received abiraterone and prednisolone for 4 weeks, followed by adding dutasteride. The primary end point was a 50% prostate-specific antigen response rate. Serum concentrations of abiraterone and its metabolites as well as HSD3B1 and SRD5A2 genotypes were measured. The association between drug metabolism and genotypes and their impact on the efficacy of combination therapy were assessed. Among 21 patients, 18 (85.7%) achieved ≥50% PSA reduction. Median time to treatment failure was not reached during the median follow-up of 15.4 months. No patients experienced grade ≥3 adverse events. Although dutasteride reduced serum 3-keto-5α-abiraterone concentrations, higher serum 3-keto-5α-abiraterone concentrations on combination therapy were associated with a shorter time to treatment failure. HSD3B1 and SRD5A2 genotypes were associated with serum Δ4-abiraterone and 3-keto-5α-abiraterone concentrations before adding dutasteride, respectively. Time to treatment failure was longer in patients with homozygous wild-type HSD3B1, but comparable between those with the SRD5A2 genotype. The promising outcomes of this study warrant further investigation of combination therapy in a randomized trial. Stratification by HSD3B1 and SRD5A2 genetic profiles might identify patients suitable for combination therapy.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Dutasteride; Humans; Male; Membrane Proteins; Multienzyme Complexes; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Although androgen receptor-targeted agents prolong the lives of patients with metastatic prostate cancer, patients develop therapy resistance and most ultimately succumb to the disease. The PI3K/AKT/PTEN pathway has been associated with the development of resistance, raising the possibility that pathway inhibitors may produce a clinical benefit. This open-label phase Ib study examined the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of adding capivasertib - a potent, selective inhibitor of AKT1/2/3 - to approved abiraterone acetate therapy.. Twenty-seven patients with metastatic castration-resistant prostate cancer who had undergone at least 1 prior line of systemic therapy received abiraterone acetate 1000 mg (orally administered once daily), plus oral prednisone 5 mg (twice daily) with capivasertib 400 mg (orally, twice daily, with an intermittent schedule of 4 days on, 3 days off).. No dose-limiting toxicity was observed. The most frequent adverse events (all grade) were diarrhea (30%), anemia (26%), asthenia (22%), and nausea (22%). The most frequent grade 3 or higher adverse events were acute kidney injury (19%), hyperglycemia (7%), rash (7%), abdominal pain (7%), and asthenia (7%). Capivasertib and abiraterone PK were consistent with previously reported results from monotherapy dosing. Nine participants (33%) showed a 20% or greater decrease in prostate-specific antigen during study treatment.. The combination of capivasertib and abiraterone acetate had an acceptable tolerability profile consistent with the known profile of each agent. These data support further evaluation of capivasertib and abiraterone acetate in patients with advanced prostate cancer.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Humans; Male; Phosphatidylinositol 3-Kinases; Prednisone; Prostatic Neoplasms, Castration-Resistant

Adding ipatasertib to abiraterone and prednisone/prednisolone significantly improved radiographic progression-free survival for patients with metastatic castration-resistant prostate cancer (mCRPC) with PTEN-loss tumours by immunohistochemistry in the IPATential150 trial (NCT03072238). Here we characterise the safety of these agents in subpopulations and assess manageability of key adverse events (AEs).. In this randomised, double-blind, phase 3 trial, patients with previously untreated asymptomatic or mildly symptomatic mCRPC were randomised 1:1 to receive ipatasertib-abiraterone or placebo-abiraterone (all with prednisone/prednisolone). AEs were analysed, focusing on key AEs of diarrhoea, hyperglycaemia, rash and transaminase increased.. 1097 patients received study medication and were assessed for safety (47% with PTEN-loss tumours by immunohistochemistry and 20% were Asian). Ipatasertib was associated with increased Grade 3/4 AEs and AEs leading to treatment discontinuation vs placebo. The rate of discontinuation of ipatasertib was 18% in patients with PTEN-loss and 21% overall. The frequencies of all-grade, Grade 3/4 and serious AEs were similar between the PTEN-loss and overall populations. Diarrhoea, hyperglycaemia, rash and transaminase elevation were more frequent in ipatasertib-treated patients, appearing rapidly after treatment initiation (median onset: 8-43 days for ipatasertib arm and 56-104 days for placebo). The ipatasertib discontinuation rate was 32% and 18% in Asian and non-Asian patients, respectively, despite similar baseline characteristics and Grade 3/4 AE frequencies between groups.. Ipatasertib plus abiraterone had an overall tolerable safety profile consistent with known toxicities. More AEs leading to drug discontinuation were observed with ipatasertib than placebo, but incidence would likely be lessened with prophylactic measures.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Exanthema; Humans; Hyperglycemia; Male; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant

Men with localized prostate cancer are often treated with local therapy (LT). However, a proportion of these patients will eventually develop recurrence and progression requiring systemic therapy. Whether primary LT affects the response to this subsequent systemic treatment is unclear.. We investigated whether the receipt of prior prostate-directed LT influenced the response to first-line systemic therapy and survival in docetaxel-naïve metastatic castrate-resistant prostate cancer (mCRPC) patients.. This is an exploratory analysis of the COU-AA-302 trial, a multicentric double-blinded phase 3 randomized controlled trial in which mCRPC patients with no to mild symptoms were randomized to receive abiraterone plus prednisone or placebo plus prednisone.. We compared the time-varying effects of first-line abiraterone in patients with and without prior LT using a Cox proportional hazard model. The cut points were chosen using grid search, and were 6 and 36 mo for radiographic progression-free survival (rPFS) and overall survival (OS), respectively. We also investigated whether there was any difference in treatment effect on score change (relative to baseline) in various patient-reported outcomes (measured by Functional Assessment of Cancer Therapy-Prostate [FACT-P]) over time depending on the receipt of prior LT. The adjusted association of prior LT with survival was determined using weighted Cox regression models.. Among 1053 eligible patients, 64% (n = 669) received prior LT. We did not find any statistically significant heterogeneity of time-dependent treatment effect from abiraterone on rPFS in patients with (hazard ratio [HR]: 0.36 [95% confidence interval: 0.27-0.49] at ≤6 mo; 0.64 [0.49-0.83] at >6 mo) or without (HR: 0.37 [0.26-0.55] at ≤6 mo; 0.72 [0.50-1.03] at >6 mo) prior LT. Similarly, there was no significant heterogeneity in time-dependent treatment effect on OS with (HR: 0.88 [0.71-1.10] at ≤36 mo; 0.76 [0.52-1.11] at >36 mo) or without (0.78 [0.60-1.01] at ≤36 mo; 0.55 [0.30-0.99] at >36 mo) prior LT. We did not find sufficient evidence of a difference in treatment effect from abiraterone on score change over time in prostate cancer subscale (interaction p = 0.4), trial outcome index (interaction p = 0.8), and FACT-P total score (interaction p = 0.6) depending on the receipt of prior LT. Receipt of prior LT was associated with a significant improvement in OS (average HR: 0.72 [0.59-0.89]).. This study demonstrates that the efficacy of first-line abiraterone and prednisone in docetaxel-naïve mCRPC do not vary significantly based on the receipt of prior prostate-directed LT. Further studies are needed to explore the plausible mechanisms of the association of prior LT with superior OS.. This secondary analysis of the COU-AA-302 trial suggests that survival benefits and temporal changes in quality of life with first-line abiraterone in docetaxel-naïve mCRPC do not differ significantly among patients who received versus those who did not receive prior prostate-directed local therapy.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Receptors, Androgen; Treatment Outcome

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including. MAGNITUDE (ClinicalTrials.gov identifier: NCT03748641) is a phase III, randomized, double-blinded study that evaluates niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in patients with (HRR+, n = 423) or without (HRR-, n = 247) HRR-associated gene alterations, as prospectively determined by tissue/plasma-based assays. Patients were assigned 1:1 to receive niraparib + AAP or placebo + AAP. The primary end point, radiographic progression-free survival (rPFS) assessed by central review, was evaluated first in the. Median rPFS in the. Combination treatment with niraparib + AAP significantly lengthened rPFS in patients with HRR+ mCRPC compared with standard-of-care AAP.. [Media: see text].

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

Niraparib (NIRA) is a highly selective inhibitor of poly (adenosine diphosphate-ribose) polymerase, PARP1 and PARP2, which play a role in DNA repair. The phase II QUEST study evaluated NIRA combinations in patients with metastatic castration-resistant prostate cancer who were positive for homologous recombination repair gene alterations and had progressed on 1 prior line of novel androgen receptor-targeted therapy. Results from the combination of NIRA with abiraterone acetate plus prednisone, which disrupts androgen axis signaling through inhibition of CYP17, showed promising efficacy and a manageable safety profile in this patient population.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting.. Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments.. In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 [95% CI, 30.5 to 35.4] months for enzalutamide. The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Nitriles; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival.. We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m. Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8-86·9) in the abiraterone group versus 45·7 months (41·6-52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53-0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9-81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3-59·0) in the standard of care group (HR 0·65 [0·55-0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83-1·32]; p. Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years.. Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Docetaxel; Humans; Male; Meta-Analysis as Topic; Prednisolone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic

Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2).. Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed.. Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed.. MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Recombinational DNA Repair; Treatment Outcome

This trial of 81 men with mCRPC determined the radiographic progression-free survival (rPFS), prostate-specific antigen (PSA) progression-free survival, overall objective response, and safety of AAP or AAP + C. Equally allocated patients received AAP followed by switching to cabazitaxel upon radiographic progression (arm 1) or upfront with AAP + C (arm 2). Patients were stratified into high-/low-risk groups by the Halabi nomogram. Real-time assessment of. Both treatment arms were well-tolerated. Median rPFS in AAP was 6.4 months (95% CI, 3.8 to 10.6) and median overall survival (OS) 18.3 months (95% CI, 14.4 to 37.6), respectively. Fifty-six percent of patients showed ≥50% decline in PSA. Median rPFS in AAP + C was 14.8 months (95% CI, 10.6 to 16.4), and median OS 24.5 months (95% CI, 20.4 to 35.0). There was a ≥50% decline in PSA in 92.1% of men. Neither. AAP + C was safe with improved rPFS, OS duration, and a higher proportion of PSA declines. This suggests that AAP + C given earlier rather than sequentially may benefit some men. Further work is needed to identify this population.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

A post-hoc analysis of the phase-3 LATITUDE study assessed the impact of abiraterone acetate plus prednisone (AA+P) on overall survival (OS) and radiographic progression-free survival (rPFS) in men with metastatic castration-sensitive prostate cancer (mCSPC) and visceral metastases (VM).. Newly diagnosed mCSPC patients were randomized (1:1) to AA+P and androgen deprivation therapy (ADT) or placebo+ADT. Patients with VM in liver or lungs with or without other soft tissue and bone metastases (based on CT/MRI) at baseline were analyzed, after 51.8 months' median follow-up. Co-primary endpoints, OS and rPFS, were analyzed.. Among 1199 patients enrolled, 228 (19%) had VM at baseline (114 each in AA+P and placebo groups), of which 53 (23.2%; AA+P = 29, Placebo = 24) had liver metastases and 117 (51.3%; AA+P = 60, Placebo = 57) had lung metastases. In patients with VM, treatment with AA+P versus placebo showed an improvement in OS (median 55.4 vs 33.0 months; HR = 0.582; 95%CI = 0.406-0.835;P = 0.0029) and rPFS (median 30.7 vs 18.3 months; HR = 0.527; 95%CI = 0.366-0.759;P = 0.0005), comparable to that of patients without VM. AA+P versus placebo in lung metastases patients was associated with greater improvement in OS (HR = 0.60; 95%CI = 0.35-1.04;P = 0.0678) than in liver metastases patients (HR = 0.82; 95%CI = 0.41-1.66;P = 0.5814). AA+P versus placebo showed improvement in rPFS in lung metastases patients (HR = 0.50; 95%CI = 0.29-0.89;P = 0.0157), but not in liver metastases patients (HR = 1.05; 95%CI = 0.53-2.09; P = 0.8970).. AA+P treatment improved both rPFS and OS in men with mCSPC and visceral disease, especially those with lung metastases. Men with liver metastases had a poorer prognosis and their optimal treatment remains to be defined.. ClinicalTrials.gov, number NCT01715285.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Castration; Humans; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms, Second Primary; Prednisone; Prostatic Neoplasms, Castration-Resistant

Patients with metastatic castration-resistant prostate cancer (mCRPC) frequently receive docetaxel after they develop resistance to abiraterone or enzalutamide and need more efficacious treatments.. To evaluate the efficacy and safety of pembrolizumab plus docetaxel and prednisone in patients with mCRPC.. The trial included patients with mCRPC in the phase 1b/2 KEYNOTE-365 cohort B study who were chemotherapy naïve and who experienced failure of or were intolerant to ≥4 wk of abiraterone or enzalutamide for mCRPC with progressive disease within 6 mo of screening.. Pembrolizumab 200 mg intravenously (IV) every 3 wk (Q3W), docetaxel 75 mg/m. The primary endpoints were safety, the prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included time to PSA progression; the disease control rate (DCR) and duration of response (DOR) according to RECIST v1.1 by BICR; ORR, DCR, DOR, and radiographic progression-free survival (rPFS) according to Prostate Cancer Working Group 3-modified RECIST v1.1 by BICR; and overall survival (OS).. Among 104 treated patients, 52 had measurable disease. The median time from allocation to data cutoff (July 9, 2020) was 32.4 mo, during which 101 patients discontinued treatment, 81 (78%) for disease progression. The confirmed PSA response rate was 34% and the confirmed ORR (RECIST v1.1) was 23%. Median rPFS and OS were 8.5 mo and 20.2 mo, respectively. Treatment-related adverse events (TRAEs) occurred in 100 patients (96%). Grade 3-5 TRAEs occurred in 46 patients (44%). Seven AE-related deaths (6.7%) occurred (2 due to treatment-related pneumonitis). Limitations of the study include the single-arm design and small sample size.. Pembrolizumab plus docetaxel and prednisone demonstrated antitumor activity in chemotherapy-naïve patients with mCRPC treated with abiraterone or enzalutamide for mCRPC. Safety was consistent with profiles for the individual agents. Further investigation is warranted.. We evaluated the efficacy and safety of the anti-PD-1 antibody pembrolizumab combined with the chemotherapy drug docetaxel and the steroid prednisone for patients with metastatic prostate cancer resistant to androgen deprivation therapy , and who never received chemotherapy. The combination showed antitumor activity and manageable safety in this patient population. This trial is registered on ClinicalTrials.gov as NCT02861573.

Topics: Abiraterone Acetate; Androgen Antagonists; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Humans; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Follow-Up Studies; Hormones; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Although the benefit of androgen deprivation therapy (ADT) continuation in metastatic castration-resistant prostate cancer (mCRPC) remains controversial, clinical evidence is lacking. Recent results indicated that treatment with abiraterone acetate (AA) plus prednisone (P) further suppresses serum testosterone levels over ADT alone, suggesting that continuation of ADT in the treatment of mCRPC may not be necessary.. In this exploratory phase 2 study, mCRPC patients were randomized with a 1:1 ratio to receive either continued ADT plus AA + P (Arm A) or AA + P alone (Arm B). The primary endpoint was the rate of radiographic progression-free survival (rPFS) at month 12. Secondary endpoints included PSA-response rate, objective response, time to PSA progression and safety.. A total of 68 patients were equally randomized between the two study arms. Median testosterone-levels remained below castrate-levels throughout treatment in all patients. According to the intention-to-treat analysis the rPFS rate was 0.84 in Arm A and 0.89 in Arm B. Moderate and severe treatment-emergent adverse events were reported for 72% of the patients in Arm A and for 85% of the patients in Arm B.. AA + P treatment without ADT may be effective in mCRPC patients and ADT may not be necessary in patients receiving AA + P.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Gonadotropin-Releasing Hormone; Humans; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Testosterone; Treatment Outcome

The associations of metformin and statins with overall survival (OS) and prostate specific antigen response rate (PSA-RR) in trials in metastatic castration-resistant prostate cancer remain unclear.. To determine whether metformin or statins ± abiraterone acetate plus prednisone/prednisolone (AAP) influence OS and PSA-RR.. COU-AA-301 and COU-AA-302 patients were stratified by metformin and statin use. Cox proportional hazards models were used to estimate hazards ratio (HR) stratified by concomitant medications, and a random effects model was used to pool HR. We compared PSA-RR using Chi χ. In COU-AA-301-AAP, metformin was associated with improved PSA-RR (41.1% versus 28.6%) but not prolonged OS. In COU-AA-301-placebo-P, there was no association between metformin and prolonged OS or PSA-RR. In COU-AA-302-AAP, metformin was associated with prolonged OS (adjHR 0.69, 95% CI 0.48-0.98) and improved PSA-RR (72.7% versus 60.0%). In COU-AA-302-P, metformin was associated with prolonged OS (adjHR 0.66, 95% CI 0.47-0.93). In pooled analysis, OS was prolonged among those treated with metformin (pooled HR 0.77, 95% CI 0.62-0.95).In COU-AA-301-AAP, statins were associated with an improved OS (adjHR 0.76, 95% CI 0.62-0.93), while there was no difference in COU-AA-301-P. There was no association with statins and OS in either COU-AA-302 groups. When pooling HR, OS was prolonged among those treated with statins (pooled HR 0.78, 95% CI 0.68-0.88).. Within the limitations of post-hoc sub-analyses, metformin and statins are associated with a prolonged OS and increased PSA-RR, particularly in combination with AAP.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Castration; Disease-Free Survival; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Metformin; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Enzalutamide and abiraterone acetate plus prednisone (AAP) have similar efficacy in metastatic castration-resistant prostate cancer (mCRPC). Herein, we compare fatigue, health-related quality-of-life (HRQoL) and metabolic changes in men with mCRPC treated with enzalutamide and AAP.. In this single-centre, open-labelled, phase IV trial, patients with metastatic prostate cancer progressing on androgen deprivation therapy were randomly assigned to enzalutamide (160 mg daily) or AAP (1000 mg abiraterone acetate and 10 mg prednisone daily) as first-line mCRPC treatment. The primary outcome was the difference in changed fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire). The secondary outcomes were differences in changed HRQoL (Functional Assessment of Cancer Therapy-Prostate questionnaire), body composition, weight, glucose homeostasis, lipid profile and blood pressure. All outcomes were assessed at baseline and at 12-week follow-up.. clinicaltrialsregister.eu (2017-000099-27).. 170 patients were randomised (1:1) to enzalutamide or AAP. The primary outcome was positive with a clinically meaningful difference in fatigue, favouring AAP (3.4 points, 95% CI 1.2; 5.6, P = 0.003). The group difference in changed HRQoL did not reach clinical significance. The most important metabolic finding was a higher increase in glycated haemoglobin (HbA1c) for AAP than enzalutamide (3.4 mmol/mol, 95% CI 2.1; 4.8, P = 0.001). Eight patients developed type 2 diabetes (T2D) in the AAP group and none in the enzalutamide group. No treatment-related serious adverse event was observed.. AAP resulted in less fatigue than enzalutamide in a randomised setting. This was at the expense of a higher HbA1c increase and incidence of T2D.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Diabetes Mellitus, Type 2; Fatigue; Glycated Hemoglobin; Hot Temperature; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Treatment Outcome

ARTO trial was designed to evaluate the difference in terms of outcomes between patients affected by oligo metastatic castrate resistant prostate cancer (mCRPC) treated with Abiraterone acetate and randomized to receive or not SBRT on all sites of disease. Here, we present a preliminary analysis conducted on patients enrolled at promoting institution.. To present a preliminary overview about population features, clinical outcomes, adverse events, quality of life and explorative translational research.. ARTO (NCT03449719) is a phase II trial including patients affected by oligo mCRPC, randomized to receive standard of care (GnRH agonist or antagonist plus abiraterone acetate 1000 mg and oral prednisone 10 mg daily) with or without SBRT on all metastatic sites of disease. All subjects have < 3 bone or nodal metastases. All patients are treated in I line mCRPC setting, no previous lines of treatment for mCRPC are allowed.. Data about a mono-centric cohort of 42 patients enrolled are presented in the current analysis, with focus on baseline population features, PSA drop at 3 months, biochemical response, and quality of life outcomes. Descriptive statistics regarding translational research are also presented.. Significant difference in terms of PSA drop at three months was not detected (p = 0.68). Biochemical response (PSA reduction > 50%) was reported in 73.7 versus 76.5% of patients in control vs SBRT arm, respectively (p = 0.84). All patients are alive. Progression occurred in 1 versus 0 patients in the control versus SBRT arm, respectively. After 3 months, an average decrease of 13 points in terms of Global Health Score was reported for the overall population. However, complete recovery was noticed at 6 months. Circulating tumor cells detection rate was 40%.. SBRT + Abiraterone treatment was safe and well tolerated, non-significant trend in terms of PSA drop and biochemical response at 3 months was detected in SBRT arm. Interestingly, CTCs detection in this selected cohort of oligo-mCRPC was lower if compared to historical data of unselected mCRPC patients.

Topics: Abiraterone Acetate; Androstenes; Chemoradiotherapy; Clinical Trial Protocols as Topic; Cohort Studies; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Radiosurgery; Treatment Outcome

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Follow-Up Studies; Hormones; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

The paper aims to evaluate the efficacy and safety of. Median rPFS was 5.5 months (95% CI 5.3-5.5). Median rPFS of patients with AR-V7(-) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2-not reached) and was significantly greater for AR-V7(-) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01).

Topics: Abiraterone Acetate; Androgen Antagonists; Benzamides; Bone Neoplasms; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radium; Receptors, Androgen

The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC.. ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone-prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone-prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736.. 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone-prednisone; 490 to abiraterone-prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0-28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4-27·4) in the apalutamide plus abiraterone-prednisone group versus 16·6 months (13·9-19·3) in the abiraterone-prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58-0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5-58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7-27·5) versus 16·6 months (13·9-19·3; HR 0·70, 95% CI 0·60-0·83; p<0·0001). The most common grade 3-4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone-prednisone and 49 [10%] of 489 receiving abiraterone-prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone-prednisone and 181 (37%) patients receiving abiraterone-prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone-prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone-prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death).. Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone-prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC.. Janssen Research & Development.

Topics: Abiraterone Acetate; Aged; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Neoplasm Metastasis; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors; Survival Rate; Thiohydantoins

Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC.. In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety.. From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years.. There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Dasatinib; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Random Allocation; Sunitinib; Treatment Outcome; Tumor Microenvironment

In an era of multiple life-prolonging therapies for metastatic castration resistant prostate cancer (mCRPC), the optimal timing of initiation and duration of antiresorptive bone targeted therapy (BTT) to prevent skeletal related events (SREs) is unknown.. To assess practice patterns of BTT use and its associations with clinical outcomes in a high-volume center in the modern era of metastatic CRPC management, a retrospective cohort of patients treated for mCRPC with BM between 2007 and 2017 was identified from a single institutions clinical research database. Study endpoints included time from the diagnosis of CRPC to the onset of SRE or OS. Cox proportional hazards model assessed association of BTT use with time to first SRE and OS.. In total, 249 patients were identified; median follow-up was 7.7 (95%CI: 5.7-10.2) years. On multivariable analysis, patients with 4 or more BM at diagnosis of mCRPC who received BTT with abiraterone acetate or enzalutamide as first line therapy had a 42% reduced risk of developing an SRE (HR 0.58; 95%CI: 0.36-0.95) compared to those who never received BTT or received it in second line. No such effect was observed in patients with 1-3 BM. No OS difference was noted in patients who received BTT, whether with first line therapy or without. This study is limited by retrospective nature at a single institution.. Our hospital registry data indicate a potential benefit in terms of SRE prevention for early use of antiresorptive BTT in combination with life prolonging CRPC therapies for patients with CRPC and at least 4 BM.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Density Conservation Agents; Bone Diseases; Follow-Up Studies; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Practice Patterns, Physicians'; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; United States

The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy.. Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (<4.0 ng/mL) during first-line androgen deprivation therapy were enrolled and administered abiraterone acetate (1000 mg) plus prednisolone (10 mg). A minimum of 48 patients were required according to Simon's minimax design. The primary endpoint was prostate-specific antigen response rate (≥50% prostate-specific antigen decline by 12 weeks), secondary endpoints included prostate-specific antigen progression-free survival and overall survival. Safety parameters were also assessed.. For efficacy, 49/50 patients were evaluable. Median age was 73 (range: 55-86) years. The median duration of initial androgen deprivation therapy was 32.4 (range: 13.4-84.1) weeks and 48 patients experienced prostate-specific antigen progression within 1-year after initiation of androgen deprivation therapy. prostate-specific antigen response rate was 55.1% (95% confidence interval: 40.2%-69.3%), median prostate-specific antigen-progression-free survival was 24.1 weeks, and median overall survival was 102.9 weeks (95% confidence interval: 64.86 not estimable [NE]). Most common adverse event was nasopharyngitis (15/50 patients, 30.0%). The most common ≥grade 3 adverse event was alanine aminotransferase increased (6/50 patients, 12.0%).. Abiraterone acetate plus prednisolone demonstrated a high prostate-specific antigen response rate of 55.1%, suggesting tumor growth still depends on androgen synthesis in patients with early metastatic castration-resistant prostate cancer. However, prostate-specific antigen-progression-free survival was shorter than that reported in previous studies. Considering the benefit-risk profile, abiraterone acetate plus prednisolone would be a beneficial treatment option for patients with chemotherapy-naive metastatic prostate cancer who show early castration resistance.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgens; Antineoplastic Combined Chemotherapy Protocols; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Prednisolone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

In metastatic castration-resistant prostate cancer (mCRPC), assessing treatment response and bone lesions with technetium-99m is limited by image resolution and subjectivity. We evaluated bone scan lesion area (BSLA), a quantitative imaging assessment of response in patients with mCRPC receiving radium-223 alone or in combination with androgen receptor pathway inhibitors (abiraterone/prednisone or enzalutamide).. This randomized, non-comparative phase IIa three-arm trial (NCT02034552) evaluated technetium-99m-based BSLA response rate (RR), safety, radiologic progression-free survival (rPFS), and time to first symptomatic skeletal event (SSE) in men with mCRPC and bone metastases receiving radium-223 with/without abiraterone/prednisone or enzalutamide. The primary endpoint was week 24 BSLA RR.. Overall, 63 patients received treatment (abiraterone/prednisone combination, n = 22; enzalutamide combination, n = 22; radium-223 monotherapy, n = 19). Median treatment duration (first to last dose of any study treatment) was 12 months (abiraterone/prednisone combination), 10 months (enzalutamide combination), and 3 months (radium-223 monotherapy). Week 24 BSLA RR was 58% [80% confidence interval (CI) 41% to 74%; one-sided P < 0.0001; 11/19 patients] with abiraterone/prednisone combination, 50% (32% to 68%; one-sided P < 0.0001; 8/16 patients) with enzalutamide combination, and 22% (10% to 40%; one-sided P = 0.0109; 4/18 patients) with radium-223 monotherapy. Median rPFS was not evaluable for combination arms and 4 months (80% CI 4 to 12) for monotherapy. SSEs were reported in 32% of patients; median time to first SSE was not estimable. Fatigue and back pain were the most commonly reported treatment-emergent adverse events (TEAEs); more patients receiving combination therapy than monotherapy had TEAEs. Fractures were reported in 18% receiving abiraterone/prednisone, 32% receiving enzalutamide, and 11% receiving radium-223 monotherapy. Fracture rates were lower in patients taking bone health agents versus not taking bone health agents at baseline.. Technetium-99m imaging BSLA may offer objective, quantifiable assessment of isotope uptake changes, and potentially treatment response, in patients with mCRPC and bone metastases treated with radium-223 alone or in combination with abiraterone/prednisone or enzalutamide. In this largely treatment-naive population, BSLA RR was numerically lower with radium-223 monotherapy versus combination therapy, indicating a limited role as first-line treatment. Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium; Tomography, X-Ray Computed

Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification before commencing a new treatment. We hypothesized that a second sample collected after one cycle of treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment.. Plasma DNA [128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression] from 151 chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients in a phase II study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes: TP53, AR, RB1, PTEN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2 and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS).. Plasma tumor DNA detection was associated with shorter OS [hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, P ≤ 0.0001] and PFS (HR: 2.05; 95% CI: 1.36-3.11, P < 0.001). Using a multivariable model including plasma tumor DNA, patients who had a TP53, RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53: HR 7.13, 95% CI 2.37-21.47, P < 0.001; RB1: HR 6.24, 95% CI 1.97-19.73, P = 0.002; PTEN: HR 11.9, 95% CI 3.6-39.34, P < 0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared with those who were undetectable pre-treatment (P = 0.48, P = 0.43, P = 0.5, respectively). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients.. Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit.

Topics: Abiraterone Acetate; Biomarkers, Tumor; Gene Conversion; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Treatment Outcome

Radium-223, abiraterone, and enzalutamide have each been shown to significantly improve survival as monotherapy in patients with metastatic castration-resistant prostate cancer. However, effects of combination radium-223 plus abiraterone or enzalutamide on survival and safety remain unclear.. This single-center retrospective cohort study used electronic health record data of patients with metastatic castration-resistant prostate cancer and bone metastases who were treated with radium-223 between April 1, 2014 and February 19, 2019. Patients who received radium-223 monotherapy were compared to patients who received a combination of radium-223 plus either abiraterone or enzalutamide. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to symptomatic skeletal event, symptomatic skeletal event-free survival, and incidence of drug-related adverse events. Time-to-event analyses were estimated by log rank tests using Kaplan-Meier curves. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazards models. Chi-square tests evaluated difference in serious adverse events between the two arms.. A total of 60 patients met inclusion criteria (n = 41 in the monotherapy arm, n = 19 in the combination arm). Differences in median overall survival were not observed (12.7 vs. 12.8 months; HR 1.15, 95% CI 0.59-2.23; P = 0.68), but median progression-free survival was significantly longer in the combination arm (7.6 vs. 4.9 months; HR 1.94, 95% CI 1.11-3.40; P = 0.02). Significant differences were not observed in time to first SSE (P = 0.97), SSE-free survival (P = 0.16), or in the overall incidence of serious adverse events (P = 0.45).. Combination radium-223 plus abiraterone or enzalutamide did not improve overall survival, but prolonged progression-free survival without increasing the incidence of serious adverse events in metastatic castration-resistant prostate cancer patients with bone metastases. However, these results are limited by small numbers and patient selection inherent in retrospective analysis.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Chemoradiotherapy; Follow-Up Studies; Humans; Male; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Radium; Retrospective Studies; Survival Rate

In the CARD study (NCT02485691), cabazitaxel significantly improved median radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone/enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel and progressed ≤12 mo on the alternative agent (abiraterone/enzalutamide).. To assess cabazitaxel versus abiraterone/enzalutamide in older (≥70 yr) and younger (<70 yr) patients in CARD.. Patients with mCRPC were randomized 1:1 to cabazitaxel (25 mg/m. Analyses of rPFS (primary endpoint) and safety by age were prespecified; others were post hoc. Treatment groups were compared using stratified log-rank or Cochran-Mantel-Haenszel tests.. Of the 255 patients randomized, 135 were aged ≥70 yr (median 76 yr). Cabazitaxel, compared with abiraterone/enzalutamide, significantly improved median rPFS in older (8.2 vs 4.5 mo; hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.38-0.89; p = 0.012) and younger (7.4 vs 3.2 mo; HR = 0.47; 95% CI = 0.30-0.74; p < 0.001) patients. The median OS of cabazitaxel versus abiraterone/enzalutamide was 13.9 versus 9.4 mo in older patients (HR = 0.66; 95% CI = 0.41-1.06; p = 0.084), and it was 13.6 versus 11.8 mo in younger patients (HR = 0.66; 95% CI = 0.41-1.08; p = 0.093). Progression-free survival, prostate-specific antigen, and tumor and pain responses favored cabazitaxel, regardless of age. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 58% versus 49% of older patients receiving cabazitaxel versus abiraterone/enzalutamide and 48% versus 42% of younger patients. In older patients, cardiac adverse events were more frequent with abiraterone/enzalutamide; asthenia and diarrhea were more frequent with cabazitaxel.. Cabazitaxel improved efficacy outcomes versus abiraterone/enzalutamide in patients with mCRPC after prior docetaxel and abiraterone/enzalutamide, regardless of age. TEAEs were more frequent among older patients. The cabazitaxel safety profile was manageable across age groups.. Clinical trial data showed that cabazitaxel improved survival versus abiraterone/enzalutamide with manageable side effects in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel and the alternative agent (abiraterone/enzalutamide), irrespective of age.

Topics: Abiraterone Acetate; Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Abiraterone acetate (AA) has been proven effective for metastatic castration-resistant prostate cancer (mCRPC), and it has been proposed that adaptive AA may reduce toxicity and prolong time to progression, when compared to continuous AA. We developed a simple quantitative model of prostate-specific antigen (PSA) dynamics to evaluate prostate cancer (PCa) stem cell enrichment as a plausible driver of AA treatment resistance. The model incorporated PCa stem cells, non-stem PCa cells and PSA dynamics during adaptive therapy. A leave-one-out analysis was used to calibrate and validate the model against longitudinal PSA data from 16 mCRPC patients receiving adaptive AA in a pilot clinical study. Early PSA treatment response dynamics were used to predict patient response to subsequent treatment. We extended the model to incorporate metastatic burden and also investigated the survival benefit of adding concurrent chemotherapy for patients predicted to become resistant. Model simulations demonstrated PCa stem cell self-renewal as a plausible driver of resistance to adaptive therapy. Evolutionary dynamics from individual treatment cycles combined with metastatic burden measurements predicted patient response with 81% accuracy (specificity=92%, sensitivity=50%). In those patients predicted to progress, simulations of the addition of concurrent chemotherapy suggest a benefit between 1% and 11% reduction in probability of progression when compared to adaptive AA alone. This study developed the first mCRPC patient-specific mathematical model to use early PSA treatment response dynamics to predict subsequent responses to adaptive AA, demonstrating the putative value of integrating mathematical modeling into clinical decision making.

Topics: Abiraterone Acetate; Antineoplastic Agents; Humans; Longitudinal Studies; Male; Models, Theoretical; Neoplastic Stem Cells; Patient-Specific Modeling; Pilot Projects; Predictive Value of Tests; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Few studies have examined patient-reported outcomes (PROs) with abiraterone acetate plus prednisone (abiraterone) versus enzalutamide in metastatic castration-resistant prostate cancer (mCRPC).. To determine the impact of abiraterone and enzalutamide on PROs.. AQUARiUS (NCT02813408) was a prospective, 12-mo, observational study in patients with mCRPC from Denmark, France, and the UK.. Abiraterone or enzalutamide treatment according to routine practise.. PROs were collected over 12 mo using Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), Brief Fatigue Inventory-Short Form (BFI-SF), Brief Pain Inventory-Short Form, and European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (QLQ-C30) at baseline and routine visits. Outcomes included mean change in PROs, patients with clinically meaningful worsening (CMW) in PROs, and safety. Data were analysed using repeated measures linear and logistic models adjusted for baseline characteristics.. Abiraterone-treated (N = 105) and enzalutamide-treated (N = 106) patients were included. Key PRO items (cognitive impairments and fatigue) were significantly (p < 0.05) in favour of abiraterone versus enzalutamide during the study. "Perceived cognitive impairment" and "comments from others" (FACT-Cog); "fatigue right now", "usual level of fatigue", and "worst level of fatigue" (BFI-SF); and "cognitive functioning" and "fatigue" (QLQ-C30) were significantly in favour of abiraterone over enzalutamide for three or more consecutive periods up to month 12. From study initiation, significantly fewer patients receiving abiraterone experienced one or more CMW episode in cognition and fatigue. Fatigue and asthenia (adverse events) were lower with abiraterone than with enzalutamide (5% vs 15% and 10% vs 11%, respectively). There were no treatment-related deaths. Limitations included lack of randomisation.. In a real-world setting, this 12-mo analysis suggests an advantage of abiraterone acetate plus prednisone over enzalutamide on fatigue and cognitive function; this finding occurred early after treatment initiation. This difference should be considered when choosing treatment.. This study looked at the effect of two treatments (abiraterone acetate plus prednisone and enzalutamide) for metastatic castration-resistant prostate cancer on patient quality of life over 12 mo. Using established questionnaires, patients reported that they experienced less fatigue and cognitive impairments (including memory loss and reduced thinking abilities) with abiraterone acetate plus prednisone than with enzalutamide.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Male; Neoplasm Metastasis; Nitriles; Patient Reported Outcome Measures; Phenylthiohydantoin; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Time Factors

ERA 223 compared concurrent abiraterone acetate/prednisolone (AAP) plus radium-223 with AAP plus placebo in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. We report data from a subgroup of Japanese patients in ERA 223.. Patients were randomized to radium-223 (55 kBq/kg) or placebo once every 4 weeks (max. 6 cycles), and also received oral abiraterone acetate 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily during and after radium-223/placebo treatment, until a symptomatic skeletal event (SSE). The primary endpoint was SSE-free survival (SSE-FS); overall survival (OS) was a secondary endpoint.. Of 806 patients randomized in ERA 223, 114 patients (57 per arm) were enrolled in Japan. SSE-FS was not improved significantly in the radium-223 arm [25.5 months, 95% CI 20.6-not estimated (NE)] compared with the placebo arm (28.7 months, 95% CI 19.7-NE) (HR = 0.907, 95% CI 0.501-1.642). OS and other secondary endpoints were not improved significantly in the radium-223 arm. The incidence of fracture was 23% and 11% in the radium-223 and placebo arms, respectively. The incidence of death was 32% and 36%, respectively.. In the Japanese ERA 223 subgroup, concurrent treatment with AAP and radium-223 did not significantly improve SSE-FS and increased the incidence of fracture, similar to outcomes achieved in the overall population, while an increased incidence of death was not evident. The combination of radium-223 with AAP is not recommended in Japanese patients with asymptomatic or mildly symptomatic mCRPC and bone metastases.. Clinical trial registration no: NCT02043678.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asian People; Bone Neoplasms; Disease-Free Survival; Double-Blind Method; Fractures, Bone; Humans; Male; Middle Aged; Placebos; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium; Treatment Outcome

The unmet need for predictive biomarkers emerged from the unpredictable pattern of response to androgen signalling inhibition in metastatic castration-resistant prostate cancer (mCRPC). Here, we report on the testing of a previously identified candidate androgen signalling signature associated with response to androgen signalling inhibition.. We report on the outcome of the first module of a phase II trial on abiraterone acetate (AA) followed by combination with dasatinib or sunitinib. Bone marrow biopsies (BMBs) with matched bone marrow aspirate and blood samples were collected at baseline and upon progression. End-points included assessment of a prespecified molecular signature consisting of nuclear androgen receptor (AR) overexpression, cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17) expression, and AR-C-/N terminal expression ratio of ≥0.8 by immunohistochemistry (IHC) in patients with benefit versus primary resistance to AA (i.e. progression within 4 months). Tumour markers also included v-ets avian erythroblastosis virus E26 oncogene homologue (ERG), androgen receptor splice variant (ARV7) by IHC and steroids by liquid chromatography-tandem mass spectrometry.. Of 170 patients accrued from 03/2011 to 02/2015, 44 (26%) were primary resistant to AA. Forty-eight patients had tumour infiltrated BMB at baseline. Pretreatment androgen signalling signature was linked to benefit from AA (p < 0.001). Presence of ERG was associated with benefit (p = 0.05), whereas nuclear ARV7 presence and 20 or more bone lesions at baseline with primary resistance (p = 0.04 and p = 0.0006, respectively).. Testing of a prespecified androgen signalling signature was highly supportive of its predictive value in maximal androgen deprivation strategies in mCRPC. Further validation is under way.. ClinicalTrials.gov NCT01254864.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Biomarkers, Tumor; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; ROC Curve

Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC).. Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8.. Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess-related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor-naïve patients and 14% (6/42) of AR signaling inhibitor-treated patients.. Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cross-Over Studies; Drug Administration Schedule; Drug Interactions; Humans; Kallikreins; Male; Middle Aged; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome

A common polymorphism (1245A>C) in the HSD3B1 gene is associated with increased de novo synthesis of androgens and worse outcomes in men treated with androgen-deprivation therapy for metastatic castration-sensitive prostate cancer. The objective of the study was to determine whether this polymorphism is associated with outcomes for metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide.. A total of 547 patients treated with abiraterone or enzalutamide from two prospective cohorts were evaluated. The HSD3B1 genotype was determined by targeted sequencing and/or TaqMan single-nucleotide polymorphism genotyping. In cohort 1, patients were randomized to receive abiraterone + prednisone or enzalutamide. In cohort 2, patients received either agent according to investigator's choice. Prostate-specific antigen (PSA) response rate, time to PSA progression (TTPP), time to progression (TTP) and overall survival were determined. Associations between HSD3B1 genotypes and outcomes were evaluated via univariate Cox regression. Multivariable Cox model was used to determine the independent association of each covariate.. The HSD3B1 variant genotype (CC) was present in 15% of patients and was associated with worse TTP [hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.02-1.67, P = 0.032] and PSA response rates (48% for CC versus 62% and 65% for AA and AC, respectively [P = 0.019]), with no significant difference in TTPP (HR 1.28, 95% CI 0.99-1.66, P = 0.064). The effect of genotype was similar for treatment with abiraterone or enzalutamide with a negative test for interaction for TTPP (P = 0.997) and TTP (P = 0.749). Multivariable analysis did not show a significant association between genotype and TTP or TTPP.. The HSD3B1 (CC) genotype was associated with shorter TTP and lower PSA response rate in patients with mCRPC treated with abiraterone or enzalutamide. However, the CC genotype did not provide prognostic information beyond that conferred by standard clinical variables, suggesting that it may not be a suitable stand-alone biomarker in mCRPC.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Benzamides; Germ Cells; Humans; Male; Multienzyme Complexes; Nitriles; Phenylthiohydantoin; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Unequivocal clinical progression (UCP)-a worsening of clinical status with or without radiographic progression (RAD)-represents a distinct mode of disease progression in metastatic prostate cancer. We evaluated the prevalence, risk factors and the impact of UCP on survival outcomes.. A post-hoc analysis of the COU-AA-302, a randomised phase 3 study of abiraterone plus prednisone (AAP) versus prednisone was performed. Baseline characteristics were summarised. Cox proportional-hazards model and Kaplan-Meier method were used for survival and time to event analyses, respectively. Iterative multiple imputation method was used for correlation between clinicoradiographic progression-free survival (crPFS) and overall survival (OS).. Of 736 patients with disease progression, 280 (38%) had UCP-only and 124 (17%) had UCP plus RAD. Prognostic index model high-risk group was associated with increased likelihood of UCP (p<0.0001). Median OS was 25.7 months in UCP-only and 33.0 months for RAD-only (HR 1.39; 95% CI 1.16 to 1.66; p=0.0003). UCP adversely impacted OS in both treatment groups. Lowest OS was seen in patients with prostate specific antigen (PSA)-non-response plus UCP-only progression (median OS 22.6 months (95% CI 20.7 to 24.4)). Including UCP events lowered estimates of treatment benefit-median crPFS was 13.3 months (95% CI 11.1 to 13.8) versus median rPFS of 16.5 months (95% CI 13.8 to 16.8) in AAP group. Finally, crPFS showed high correlation with OS (r=0.67; 95% CI 0.63 to 0.71).. UCP is a common and clinically relevant phenomenon in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with AAP or prednisone. UCP is prognostic and associated with inferior OS and post-progression survival. A combination of PSA-non-response and UCP identifies patients with poorest survival. When included in PFS analysis, UCP diminishes estimates of treatment benefit. Continued study of UCP in mCRPC is warranted.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prednisone; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant

The objective of this study was to evaluate differences in tolerability in patients with metastatic castration-resistant prostate cancer treated with enzalutamide (ENZA) or abiraterone acetate plus prednisone (AA+P).. This was a phase IV, prospective, open-label, multicenter, real-world study. Patients were prescribed ENZA or AA+P at the treating physician's discretion. Computerized tests of 4 cognitive domains (Cogstate), patient-reported outcomes (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-30], Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue], Functional Assessment of Cancer Therapy-Cognitive Function [FACT-Cog]), and patient/caregiver surveys were assessed at baseline and 2 months. Safety data were collected.. Of 100 treated patients, 92 were evaluable (46/arm). Baseline characteristics were similar, with mild cognitive impairment observed in ∼20% of patients. The FACIT-Fatigue demonstrated a statistically significant worsening from baseline of -4.00 (95% confidence interval, -6.61 to -1.39) for ENZA compared with AA+P, -0.01 (95% confidence interval, -2.40 to 2.38). Overall, more adverse events (AEs) and more AEs of fatigue were reported with ENZA versus AA+P (52% vs. 36% and 26% vs. 8%, respectively). Grade 3/4 AEs were similar (4% vs. 6%). Unique neuropsychiatric AEs reported with ENZA included amnesia, cognitive disorders, memory impairment, and confusional state; those for AA+P included cerebrovascular accident, presyncope, and spinal cord compression. Clinically meaningful cognitive decline was seen in 4 patients on ENZA versus 1 patient on AA+P. However, the overall mean changes from baseline for the Cogstate tests, the EORTC QLQ-C30, and the FACT-Cog assessment were similar and showed no meaningful change. Caregiver survey responses noted more fatigue with ENZA and more moodiness with AA+P compared with patient responses.. Although baseline values were similar, more fatigue and neurocognitive differences were observed with ENZA compared with AA+P.

Topics: Abiraterone Acetate; Affect; Aged; Aged, 80 and over; Amnesia; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Caregivers; Cognitive Dysfunction; Confusion; Fatigue; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Surveys and Questionnaires; Treatment Outcome

Abiraterone acetate is used at a fixed oral dose of 1000 mg once daily (OD) taken fasted. By administering abiraterone acetate with food, a reduced dose can potentially be given while maintaining equivalent abiraterone exposure. Moreover, administering abiraterone acetate with a breakfast is considered more patient friendly. The aim of this study was to establish the bio-equivalent lower dose of abiraterone when taken with a continental breakfast (CB) compared to the standard intake of 1000 mg OD fasted.. In this phase I, randomized cross-over, multi-center study, abiraterone pharmacokinetics (PK) were evaluated in patients with metastatic castration-resistant prostate cancer who were treated for 14 days with 1000 mg abiraterone acetate taken fasted, followed by 14 days of treatment with 500 mg taken with a CB.. 14 patients were enrolled into the study, of whom 12 were eligible for PK analysis. The geometric mean ratio (GMR) (fed/fasted) was 0.88 (90% CI 0.73-1.07) for area-under-the-curve (AUC. In conclusion, a bioequivalent lower dose of abiraterone taken with food could not be established in our study. Although based on the absence of a exposure-toxicity relationship, the strict bioequivalence margins as defined by the FDA guidelines could be applied more flexible for abiraterone. Information on the effect of food on abiraterone pharmacokinetics as presented in our study can be used for patients with difficulties taken their medication fasted.

Topics: Abiraterone Acetate; Administration, Oral; Aged; Aged, 80 and over; Area Under Curve; Biological Availability; Breakfast; Cross-Over Studies; Dose-Response Relationship, Drug; Fasting; Food-Drug Interactions; Humans; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Therapeutic Equivalency

Abiraterone acetate plus prednisone and enzalutamide are both used for the treatment of metastatic castration-resistant prostate cancer. We aimed to determine the best sequence in which to use both drugs, as well as their second-line efficacy.. In this multicentre, randomised, open-label, phase 2, crossover trial done in six cancer centres in British Columbia, Canada, we recruited patients aged 18 years or older with newly-diagnosed metastatic castration-resistant prostate cancer without neuroendocrine differentiation and Eastern Cooperative Oncology Group performance status 2 or less. Patients were randomly assigned (1:1) using a computer-generated random number table to receive either abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily until PSA progression followed by crossover to enzalutamide 160 mg orally once daily (group A), or the opposite sequence (group B). Treatment was not masked to investigators or participants. Primary endpoints were time to second PSA progression and PSA response (≥30% decline from baseline) on second-line therapy, analysed by intention-to-treat in all randomly assigned patients and in patients who crossed over, respectively. The trial is registered with ClinicalTrials.gov, NCT02125357.. Between Oct 21, 2014, and Dec 13, 2016, 202 patients were enrolled and randomly assigned to either group A (n=101) or group B (n=101). At the time of data cutoff, 73 (72%) patients in group A and 75 (74%) patients in group B had crossed over. Time to second PSA progression was longer in group A than in group B (median 19·3 months [95% CI 16·0-30·5] vs 15·2 months [95% CI 11·9-19·8] months; hazard ratio 0·66, 95% CI 0·45-0·97, p=0·036), at a median follow-up of 22·8 months (IQR 10·3-33·4). PSA responses to second-line therapy were seen in 26 (36%) of 73 patients for enzalutamide and three (4%) of 75 for abiraterone (χ. Enzalutamide showed activity as a second-line novel androgen receptor pathway inhibitor, whereas abiraterone acetate did not, leading to a longer time to second PSA progression for the sequence of abiraterone followed by enzalutamide than with the opposite treatment sequence. Our data suggest that using a sequencing strategy of abiraterone acetate followed by enzalutamide provides the greatest clinical benefit.. Canadian Cancer Society Research Institute, Prostate Cancer Canada, Movember Foundation, Prostate Cancer Foundation, Terry Fox New Frontiers Program, BC Cancer Foundation, Jane and Aatos Erkko Foundation, Janssen, and Astellas.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cross-Over Studies; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prednisone; Prognosis; Prostatic Neoplasms, Castration-Resistant; Survival Rate

LATITUDE was the first phase 3 trial examining the survival benefit of adding abiraterone acetate (AA) + prednisone (P) to androgen-deprivation therapy (ADT) in newly diagnosed metastatic, castration-sensitive prostate cancer (mCSPC). Due to significant improvement in overall survival after the first interim analysis, patients in the placebos + ADT arm could switch to AA + P + ADT during an open-label extension. As in other studies where switching is allowed, statistical adjustments are needed to assess the real benefit of new drugs.. This was a post hoc analysis to estimate the true survival benefit of AA + P + ADT in patients with newly diagnosed mCSPC by applying statistical adjustments commonly used to adjust for treatment switching.. Of 112 patients still receiving placebos + ADT at the first interim analysis, 72 switched to AA + P + ADT during the open-label extension. Final analysis was conducted after median follow-up of 51.8 months. Compared to the placebos + ADT arm, the risk of death in the AA + P + ADT arm was 34% lower [hazard ratio (HR) = 0.663 (95% confidence interval 0.566-0.778)] by unadjusted intent-to-treat analysis, 37% lower [HR = 0.629 (95% confidence interval 0.526-0.753)] by rank preserving structure failure time modeling, and 38% lower [HR = 0.616 (95% confidence interval 0.524-0.724)] by inverse probability of censoring weights.. Analyses adjusting for treatment switching using two different statistical approaches confirm the improved survival benefit of adding AA + P to ADT in patients with newly diagnosed mCSPC.. ClinicalTrials.gov identifier NCT01715285.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asia; Canada; Double-Blind Method; Drug Substitution; Europe; Humans; International Agencies; Latin America; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Survival Rate; Treatment Outcome

Abiraterone acetate suppresses adrenal androgens and glucocorticoids through the inhibition of CYP17; however, given the risk of mineralocorticoid excess, it is administered with glucocorticoids. Herein, the authors performed a phase 2, single-arm study that was designed to assess the safety of abiraterone acetate without steroids in patients with castration-resistant prostate cancer.. Eligible patients had castration-resistant prostate cancer with controlled blood pressure and normal potassium. Patients initially received abiraterone acetate at a dose of 1000 mg daily alone. Those with persistent or severe mineralocorticoid toxicity received treatment with prednisone initiated at a dose of 5 mg twice daily. Therapy was continued until radiographic progression, toxicity, or withdrawal. The primary objective of the current study was to determine the percentage of men requiring prednisone to manage mineralocorticoid toxicity. Toxicity was graded according to Common Terminology Criteria for Adverse Events, version 4.0.. A total of 58 patients received at least 1 dose of abiraterone acetate; the majority had metastases (53 patients; 91.4%). Sixteen patients (27.6%) received prior chemotherapy, 6 patients (10.3%) received prior enzalutamide, and 4 patients (7%) received prior ketoconazole. Grade 3 to 4 adverse events of interest included hypertension (9 patients; 15.5%) and hypokalemia (4 patients; 7%). There was no grade ≥3 edema. Seven patients (12%) initiated prednisone therapy for mineralocorticoid toxicity, 3 patients for hypertension (5%), and 4 patients for hypokalemia (7%). Two patients initiated prednisone therapy for fatigue (3%). Forty patients (68%) experienced a decline in prostate-specific antigen of ≥50% with the use of abiraterone acetate alone. Patients with lower baseline levels of androstenedione (P = .04), androsterone (P = .01), dehydroepiandrosterone (P = .03), and 17-hydroxyprogesterone (P = .03) were found to be more likely to develop mineralocorticoid toxicity.. Treatment with abiraterone acetate without steroids is feasible, although clinically significant adverse events can occur in a minority of patients. The use of abiraterone acetate without prednisone should be balanced with the potential for toxicity and requires close monitoring.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Follow-Up Studies; Glucocorticoids; Humans; Male; Middle Aged; Prognosis; Prostatic Neoplasms, Castration-Resistant

Abiraterone acetate plus prednisone (AA+P), when added to androgen deprivation therapy (ADT), demonstrated significant improvements in overall survival and disease progression over dual placebos added to ADT in the LATITUDE clinical trial (NCT01715285). The objective of this study was to assess event-driven medical resource utilization (MRU) of ADT plus AA+P (ADT+AA+P) versus ADT plus dual placebos (ADT+placebos) in LATITUDE.. Event-driven MRU data from LATITUDE while patients were on treatment were used for analyses. Types of MRU included overnight hospitalizations and length of stay (LOS), emergency room (ER) visits, radiotherapy, surgery, imaging, and specialist and general practitioner (GP) visits. Rates by treatment (per 100 person-years) and rate ratios comparing ADT+AA+P with ADT+placebos were estimated with zero-inflated Poisson regression. The difference in the average hospital LOS between arms was assessed with repeated measures regression analyses. Reasons for hospitalization were explored. Sensitivity analyses were conducted to assess the robustness of the results.. A total of 1199 patients were enrolled in LATITUDE. Significantly lower rates of hospitalization (a 24% reduction), imaging (a 36% reduction), and radiotherapy (a 50% reduction) were observed with ADT+AA+P versus ADT+placebos. There was a nonsignificant trend of lower rates of specialist visits and surgery. The rates of ER and GP visits and the average LOS per hospitalization episode were similar across arms. The most common hospitalization reasons were genitourinary, musculoskeletal, and respiratory tract symptoms/disorders. The results remained consistent in a sensitivity analysis.. Adding AA+P to ADT does not increase MRU and leads to lower rates of hospitalization, imaging, and radiotherapy. This likely reflects the more favorable clinical outcomes with ADT+AA+P therapy.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Follow-Up Studies; Health Resources; Hospitalization; Humans; Male; Prednisone; Prognosis; Prostatic Neoplasms, Castration-Resistant; Survival Rate

Recent clinical trials have changed the treatment landscape for metastatic castration-sensitive prostate cancer. Ongoing and future studies using new therapeutic approaches hold the promise of further improving outcomes for patients with advanced prostate cancer.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Docetaxel; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Radiotherapy; Steroid Synthesis Inhibitors; Tubulin Modulators

There is evidence linking metformin to improved prostate cancer-related outcomes.. Twenty-five men with metastatic castration-resistant prostate cancer and prostate-specific antigen (PSA) progression while receiving treatment with abiraterone from 3 Swiss centers were included in this single-arm phase 2 trial between November 2013 and September 2016. Metformin was added to abiraterone continuously at 1000 mg twice daily in uninterrupted 4-week cycles. The primary end point was the absence of disease progression at 12 weeks (PFS12). The Fleming single-stage design was applied. With a 5% significance level and 80% power, 25 patients were required to test PFS12 ≤ 15% (H0) compared to ≥ 35% (H1). Secondary end points included toxicity and safety issues. The study was registered at ClinicalTrials.gov (NCT01677897).. The primary end point PFS12 was 12% (3 of 25 patients) (95% confidence interval, 3-31). Most patients had PSA progression, almost half had radiographic progression, but only 1 patient had symptomatic progression. Eleven (44%) of 25 patients had grade 1 and 2 patients each grade 2 (8%) or grade 3 (8%) gastrointestinal toxicity (nausea, diarrhea, loss of appetite). One patient discontinued treatment at week 5 because of intolerable grade 3 diarrhea.. The addition of metformin to abiraterone for patients with metastatic castration-resistant prostate cancer and PSA progression while receiving abiraterone therapy does not affect further progression and has no meaningful clinical benefit. A higher-than-expected gastrointestinal toxicity attributed to metformin was observed.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Administration Schedule; Humans; Male; Metformin; Pilot Projects; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Treatment Outcome

To evaluate the potential benefit of curative radiotherapy (RT) to the primary tumor in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone.. The clinical parameters of 106 mCRPC patients treated with abiraterone were retrospectively evaluated. Patients were either oligometastatic (≤5 metastases) at diagnosis or became oligometastatic after the systemic treatment was analyzed. Local RT to the primary tumor and pelvic lymphatics was delivered in 44 patients (41%), and 62 patients (59%) did not have RT to the primary tumor. After propensity match analysis, a total of 92 patients were analyzed.. Median follow-up time was 14.2 months (range: 2.3-54.9 months). Median overall survival (OS) was higher in patients treated with local RT to the primary tumor than in those treated without local RT with borderline significance (24.1 vs. 21.4 months; p = 0.08). Local RT to the prostate and pelvic lymphatics significantly diminished the local recurrence rate (16 patients, 31% vs. 2 patients, 5%; p = 0.003). In multivariate analysis, the prostate specific antigen (PSA) response ≥50% of the baseline obtained 3 weeks after abiraterone therapy was the only significant prognostic factor for better OS and progression-free survival (PFS). Patients treated with primary RT to the prostate had significantly less progression under abiraterone and a longer abiraterone period than those treated without local prostate RT.. Local prostate RT significantly improved OS and local control in mCRPC patients treated with abiraterone. The patients treated with primary RT had significantly less progression under abiraterone and a longer abiraterone period than those treated without local prostate RT.

Topics: Abiraterone Acetate; Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Combined Modality Therapy; Drug Administration Schedule; Follow-Up Studies; Humans; Lymphatic Irradiation; Male; Middle Aged; Neoplasm Staging; Prednisone; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radiotherapy Dosage; Radiotherapy, Adjuvant; Retrospective Studies

Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients.. We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries. Eligible patients were aged 18 years or older, and had histologically confirmed, progressive, chemotherapy-naive, asymptomatic or mildly symptomatic castration-resistant prostate cancer and bone metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 6 months, and adequate haematological, renal, and liver function. Participants were randomly assigned (1:1) according to a permuted block design (block size 4) via interactive response technology to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks. All patients were also scheduled to receive oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment. The primary endpoint was symptomatic skeletal event-free survival, which was assessed in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, number NCT02043678. Enrolment has been completed, and follow-up is ongoing.. Between March 30, 2014, and Aug 12, 2016, 806 patients were randomly assigned to receive radium-223 (n=401) or placebo (n=405) in addition to abiraterone acetate plus prednisone or prednisolone. The study was unblinded prematurely, on Nov 17, 2017, after more fractures and deaths were noted in the radium-223 group than in the placebo group (in an unplanned ad-hoc analysis), but all patients had completed radium-223 or placebo before this date. At the primary analysis (data cutoff Feb 15, 2018), 196 (49%) of 401 patients in radium-223 group had had at least one symptomatic skeletal event or died, compared with 190 (47%) of 405 patients in the placebo group (median follow-up 21·2 months [IQR 17·0-25·8]). Median symptomatic skeletal event-free survival was 22·3 months (95% CI 20·4-24·8) in the radium-223 group and 26·0 months (21·8-28·3) in the placebo group (hazard ratio 1·122 [95% CI 0·917-1·374]; p=0·2636). Fractures (any grade) occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. The most common grade 3-4 treatment-emergent adverse events were hypertension (43 [11%] patients in the radium-223 group vs 52 [13%] patients in the placebo group), fractures (36 [9%] vs 12 [3%]) and increased alanine aminotransferase concentrations (34 [9%] vs 28 [7%]). Serious treatment-emergent adverse events occurred in 160 (41%) patients in the radium-223 group and 155 (39%) in the placebo group. Treatment-related deaths occurred in two (1%) patients in the radium-223 group (acute myocardial infarction and interstitial lung disease) and one (<1%) in the placebo group (arrhythmia).. The addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo. Thus, we do not recommend use of this combination.. Bayer.

Topics: Abiraterone Acetate; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Double-Blind Method; Fractures, Bone; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Prednisolone; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Radium

Abiraterone increases survival in prostate cancer, but tumors resistant to abiraterone can exhibit a hormonally resistant, aggressive phenotype. We hypothesized that the therapeutic pressure of abiraterone is resulting in more clinically aggressive disease at progression, characterized by increased visceral metastases. Our objective was to determine whether abiraterone increased the risk of development of visceral metastases at the time of progression compared with placebo in a randomized phase III trial.. We performed a post hoc analysis of the COU-AA-302 trial of abiraterone plus prednisone vs placebo plus prednisone in patients with metastatic castration-resistant prostate cancer. The primary outcome was the development of visceral metastases. The cumulative incidences of visceral metastases were calculated by the Kaplan-Meier method and compared using log-rank testing. Multivariable Cox regression analysis assessed for the independent association of abiraterone with the development of visceral metastases.. Eighty-four of 1088 patients developed visceral metastases during study. Log-rank testing and Cox regression showed no difference in time to visceral metastases between groups (HR 1.01 [95% confidence interval (CI), 0.65-1.56]; P = .97). Abiraterone treatment was not associated with the development of visceral metastases in multivariable analysis (HR 0.89 [95% CI, 0.57-1.40]; P = .62). The study was limited by censoring of radiographic outcomes at the time of completion of primary study therapy; longer term risks were not assessed.. Abiraterone was not associated with increased risk of visceral metastatic disease at the time of progression compared with placebo.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Double-Blind Method; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Testosterone suppression is the standard treatment for advanced prostate cancer, and it is associated with side-effects that impair patients' quality of life, like sexual dysfunction, osteoporosis, weight gain, and increased cardiovascular risk. We hypothesized that abiraterone acetate with prednisone (AAP) and apalutamide, alone or in combination, can be an effective hormonal therapy also possibly decreasing castration-associated side effects.. Phase II, open-label, randomized, efficacy trial of abiraterone acetate plus prednisone (AAP) and Androgen Deprivation Therapy (ADT) versus apalutamide versus the combination of AAP (without ADT) and apalutamide. Key eligibility criteria are confirmed prostate adenocarcinoma; biochemical relapse after definitive treatment (PSA ≥ 4 ng/ml and doubling time less than 10 months, or PSA ≥ 20 ng/ml); newly diagnosed locally advanced or metastatic prostate cancer; asymptomatic to moderately symptomatic regarding bone symptoms. Patients with other histology besides adenocarcinoma or previous use of hormonal therapy or chemotherapy were excluded.. There is an urgent need to study and validate regimens such as new hormonal agents that may add benefit to castration with an acceptable safety profile. We aim to evaluate if apalutamide in monotherapy or in combination with AAP is an effective and safety hormonal treatment that can spare patients of androgen deprivation therapy.. This trial was registered in ClinicalTrials.gov on October 16, 2017, under Identifier: NCT02867020.

Topics: Abiraterone Acetate; Adenocarcinoma; Androgen Receptor Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Goserelin; Humans; Male; Patient Reported Outcome Measures; Prednisone; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Testosterone; Thiohydantoins; Treatment Outcome

Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer. Retrospective analyses suggest some cross-resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported.. To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following abiraterone acetate plus prednisone treatment.. Multicentre, single-arm, open-label study, enrolled patients with progressing mCRPC after ≥24 wk of abiraterone acetate plus prednisone treatment. All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required.. Patients received enzalutamide 160mg/d orally.. The primary endpoint was radiographic progression-free survival. Secondary endpoints were overall survival, prostate-specific antigen (PSA) response, and time-to-PSA progression. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints.. Overall, 214 patients received enzalutamide treatment, 145 of whom were chemotherapy-naïve. Median radiographic progression-free survival was 8.1 mo (95% confidence interval: 6.1-8.3); median overall survival had not been reached. Unconfirmed PSA response rate was 27% (48 of 181). Median time-to-PSA progression was 5.7 mo (95% confidence interval: 5.6-5.8). The most common treatment-emergent adverse events were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). No seizures were reported.. Enzalutamide showed antitumour activity in some patients with mCRPC who had previously progressed following ≥24 wk of abiraterone acetate plus prednisone treatment.. Patients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy, received enzalutamide. Although cross-resistance between the two agents was observed in a majority of patients, some still benefited from enzalutamide treatment.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease Progression; Drug Resistance, Neoplasm; Europe; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

In the COU-AA-302 study (NCT00887198), abiraterone acetate plus prednisone (AAP) significantly improved outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) versus prednisone alone. Baseline clinical parameters predicting that treatment response could help inform clinical decisions were explored.. To identify patients who derive the greatest clinical benefit from AAP treatment.. A total of 1088 mCRPC patients treated with either AAP or prednisone in the first-line setting in COU-AA-302 were included in this post hoc analysis.. Abiraterone acetate1000mg daily versus placebo, both plus prednisone 10mg daily.. Univariate and multivariable Cox regression analyses were performed, including clinical and pathological parameters for the primary end points overall survival (OS) and radiographic progression-free survival (rPFS), and secondary study end points. Tumor-associated baseline parameters independently impacting OS were applied to stratify patients according to possible treatment effects.. Baseline prostate-specific antigen (PSA), tumor-related pain as assessed by the Brief Pain Inventory-Short Form (BPI-SF), and Gleason score (GS) at primary diagnosis were identified as tumor-associated variables that independently impacted OS. AAP significantly improved outcomes versus prednisone in both group 1 (BPI-SF 0-1 and PSA <80 ng/ml and GS <8; p=0.006; hazard ratio [HR]: 0.61) and group 2 (BPI-SF 2-3 and/or PSA ≥80 ng/ml and/or GS ≥8; p=0.03; HR: 0.84). The differences observed for treatment effects between groups 1 and 2 for OS (HR: 0.61 vs 0.84), rPFS (HR: 0.41 vs 0.59), and time to chemotherapy (HR: 0.64 vs 0.71) were not statistically significant.. AAP significantly improved outcomes in mCRPC patients compared with prednisone alone regardless of baseline pain and PSA level, and GS at primary diagnosis with no significant differences between observed treatment effects in groups 1 and 2.. Treatment with abiraterone acetate and prednisone (compared with treatment with prednisone only) for metastatic castration-resistant prostate cancer increased survival in all patients in the study regardless of pain, prostate-specific antigen levels at the start of treatment, and Gleason score at primary diagnosis.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Humans; Male; Middle Aged; Neoplasm Grading; Pain; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Survival Analysis

Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known.. In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC.. At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/β-catenin pathway were more frequently mutated and negative regulators of Wnt/β-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01).. Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Cell Proliferation; Drug Resistance, Neoplasm; Genome-Wide Association Study; Humans; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Wnt Signaling Pathway

This multicenter, randomized, open-label, active-controlled study evaluated therapeutic equivalence, steady-state pharmacokinetics, and safety of a novel abiraterone acetate fine particle formulation (AAFP) 500mg plus methylprednisolone vs. the originator AA (OAA) 1000mg plus prednisone in men with metastatic castrate-resistant prostate cancer (mCRPC). The primary endpoint was a comparison of average of serum testosterone levels on treatment days 9 and 10 between groups.. Men with progressive mCRPC, receiving gonadotropin-releasing hormone agonist or antagonist therapy, and with a serum testosterone level of <50ng/dl were randomized 1:1 to either AAFP 500mg daily plus 4mg methylprednisolone orally twice daily (BID), or OAA 1000mg daily plus 5mg prednisone BID for 84 days. Serum testosterone, serum prostate-specific antigen (PSA), steady-state (trough) abiraterone pharmacokinetics, and safety were evaluated.. Fifty-three patients were enrolled (n = 24, AAFP; n = 29, OAA). Mean age was 75.1 years and 54.7% had Gleason>7. Over 90% of patients in each group achieved absolute testosterone levels of ≤1ng/dl during the study. The averaged absolute testosterone levels ≤0.1ng/dl were achieved in 25% of AAFP-treated patients and 17% of OAA-treated patients. A PSA-50 response was observed in>65% of patients in both groups on days 28, 56, and 84 (P = NS, all timepoints). Days 9 and 10 averaged rounded-up least squares (LS) mean (SE) serum testosterone levels were comparable (1.05ng/dl [0.04], AAFP; 1.02ng/dl [0.03], OAA; P = 0.4703 for LS mean difference). The geometric mean ratio between groups was 1.021 (90% CI: 0.965-1.081); the 90% CI fell within 80.0% to 125.0% equivalence limits. The LS mean differences in abiraterone trough plasma concentrations were not statistically significant at any visit. Adverse event frequency was comparable between arms (75.0%, AAFP; 82.8%, OAA). Musculoskeletal events were more common among OAA-treated patients (37.9% vs. 12.5%).. Therapeutic equivalence between AAFP 500mg daily and OAA 1000mg daily based on serum testosterone levels was confirmed in mCRPC patients. Both agents led to similar PSA-50 response rates. Abiraterone trough levels were similar between treatments. No new safety concerns were observed.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Gastrointestinal Diseases; Humans; Male; Methylprednisolone; Middle Aged; Neoplasm Metastasis; Particle Size; Prednisone; Prostatic Neoplasms, Castration-Resistant; Therapeutic Equivalency

Multiple castration-resistant prostate cancer (CRPC) therapies are approved by the United States Food and Drug Administration. Radium-223 dichloride (Ra-223) with abiraterone acetate plus prednisone have different mechanisms of action and distinct off-target side-effect profiles. We prospectively investigated their combined safety, tolerability, and patient-reported outcome measures.. eRADicAte, an investigator-initiated, phase II trial, studied 31 patients with metastatic CRPC, from 5 United States uro-oncology research sites. Patients completed 6 cycles of Ra-223 with concurrent abiraterone therapy. Quality of life and pain were assessed using the Functional Assessment of Cancer Therapy-Prostate and the Brief Pain Inventory-Short Form questionnaires and their subscales; we reported the number of subjects meeting standardized criteria for clinically meaningful improvements on each scale. Safety assessment included Eastern Cooperative Oncology Group performance status, laboratory changes, opioid use, radiographic responses, and adverse events (AEs).. Twenty of 31 (65%) experienced positive clinically meaningful improvement changes on the Functional Assessment of Cancer Therapy-Prostate, and 25 (81%) of 31 on the Prostate Cancer Subscale. Eighteen (58%) of 31 demonstrated reduced pain intensity and 12 (39%) of 31 demonstrated reduction of pain interference in their lives. At baseline, subjects averaged 11.6 ± 2.8 bone lesions; at the end of treatment, subjects averaged 5.6 ± 2.4 bone lesions (P = .0002). The most frequent AEs were diarrhea (17%), nausea (17%), and fatigue (14%). There were 6 serious AEs; 1 led to study withdrawal.. Patients experienced clinically meaningful improvements in quality of life and pain, without unexpected adverse toxicities. Phase III combination trials of Ra-223 with novel oral hormonal agents are ongoing to further evaluate radiographic progression and overall survival benefit.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Humans; Male; Middle Aged; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Radioisotopes; Radium; Treatment Outcome

To investigate whether the response to an androgen receptor-axis-targeted (ARAT) agent is associated with the efficacy of subsequent docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients.. This study included 114 consecutive mCRPC patients, comprising 54 and 60 patients who progressed with abiraterone acetate (AA) and enzalutamide (Enz), respectively, before the introduction of docetaxel. The impact of the response to either ARAT agent on the activity of docetaxel was assessed.. Following ARAT therapy, a prostate-specific antigen (PSA) response was observed in 73 of the 114 patients, of whom 33 and 40 received AA and Enz, respectively. In the 114 patients, PSA response to docetaxel was achieved in 48 (42.1%) patients, and median PSA progression-free survival (PFS) and overall survival (OS) with docetaxel were 7.2 and 17.5 months, respectively. No significant difference was noted in PSA response rate, PSA PFS or OS with docetaxel between responders and non-responders to a prior ARAT agent in the overall 114 patients, 54 receiving AA and 60 receiving Enz. Despite the absence of a significant impact of the response to a prior ARAT agent on PSA PFS or OS by univariate analysis, independent prognostic predictors were identified by multivariate analysis, as performance status (PS) for PSA PFS, and PS and visceral metastasis for OS.. Disease control by docetaxel may not be affected by the response to a prior ARAT agent. Therefore, a prior response to an ARAT agent should not influence the decision on the subsequent introduction of docetaxel for mCRPC patients.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Docetaxel; Humans; Male; Middle Aged; Molecular Targeted Therapy; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome

In the LATITUDE trial, addition of abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) improved overall survival compared with placebos plus ADT in patients with newly diagnosed, high-risk, metastatic castration-naive prostate cancer. Understanding the effects of treatments on patient-reported outcomes (PROs) and health-related quality of life (HRQOL) is important for treatment decisions; therefore we aimed to analyse the effects of ADT plus abiraterone acetate and prednisone versus ADT plus placebos on PROs and HRQOL in patients in the LATITUDE study.. In the multicentre, international, randomised, phase 3 LATITUDE trial, eligible patients were aged 18 years or older, had newly diagnosed, high-risk, metastatic castration-naive prostate cancer confirmed by bone scan (bone metastases) or by CT or MRI (visceral, soft tissue, or nodal metastases), and an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less. Patients from 235 clinical sites in 34 countries were randomly assigned (1:1) following a country-by-country scheme done by permuted block randomisation (with two blocks) and stratified by the presence of visceral metastasis and ECOG performance status to receive ADT plus 1000 mg oral abiraterone acetate and 5 mg oral prednisone once daily or ADT plus placebos. Selection of ADT, chemical or surgical, was at the investigator's discretion. The co-primary endpoints of the trial, overall survival and radiographic progression-free survival, have been published. PRO data were collected directly on electronic tablet devices at the clinical sites during screening and before any other visit procedure on day 1 of cycles 1-3, monthly during cycles 4-13, and then every 2 months until the end of treatment, by use of the Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy Prostate scale (FACT-P), and the EuroQol (EQ-5D-5L) questionnaires. PRO analyses were an exploratory endpoint. Analyses were by intention-to-treat. Results from the first pre-planned interim analysis (Oct 31, 2016), are presented here. This ongoing study is registered with Clinicaltrials.gov, number NCT01715285.. Between Feb 12, 2013, and Dec 11, 2014, 1199 patients were randomly assigned: 597 to ADT plus abiraterone acetate and prednisone and 602 to ADT plus placebos. Median follow-up was 30·9 months (IQR 21·2-33·2) in the ADT plus abiraterone acetate and prednisone group versus 29·7 months (1·4-43·5; 16·1-31·3) in the ADT plus placebos group. Median time to worst pain intensity progression assessed by the BPI-SF score was not reached in either group (ADT plus abiraterone acetate and prednisone, not reached [95% CI not reached to not reached]; 25th percentile 11·07 months [95% CI 9·23-18·43]; ADT plus placebos group, not reached [95% CI not reached to not reached]; 25th percentile 5·62 [95% CI 4·63-7·39]; hazard ratio [HR] 0·63 [95% CI 0·52-0·77]; p<0·0001). Median time to worst fatigue intensity was not reached in either the ADT plus abiraterone acetate and prednisone group (not reached [95% CI not reached to not reached]; 25th percentile 18·4 months [95% CI 12·9-27·7]) or the ADT plus placebos group (not reached [95% CI not reached to not reached]; 25th percentile 6·5 months [95% CI 5·6-9·2]; HR 0·65 [95% CI 0·53-0·81], p=0·0001). Median time to deterioration of functional status assessed by the FACT-P total score scale was 12·9 months (95% CI 9·0-16·6) in the ADT plus abiraterone acetate and prednisone group versus 8·3 months (7·4-11·1) in the ADT plus placebos group (HR 0·85 [95% CI 0·74-0·99]; p=0·032).. The addition of abiraterone acetate plus prednisone to ADT in patients with newly diagnosed, high-risk metastatic castration-naive prostate cancer improved overall PROs by consistently showing a clinical benefit in the progression of pain, prostate cancer symptoms, fatigue, functional decline, and overall HRQOL.. Janssen Research & Development.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Internationality; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Patient Reported Outcome Measures; Prednisone; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Risk Assessment; Survival Analysis; Tomography, X-Ray Computed; Treatment Outcome

The CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trials showed that the addition of docetaxel (D) to androgen deprivation therapy (ADT) prolonged longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of upfront D on subsequent therapies is still unexplored. As abiraterone acetate (AA) and enzalutamide (E) are the most commonly used first-line treatment for metastatic castration-resistant prostate cancer (mCRPC), we aimed to assess whether they maintained their efficacy after ADT+D versus ADT alone.. A cohort of patients with mCRPC treated between 2014 and 2017 with first-line AA or E for mCRPC was identified from 3 hospitals' institutional review board-approved databases. Patients were classified by use of D for mHSPC. This time frame was chosen as ADT+D became a valid therapeutic option for mHSPC in 2014, and it inherently entailed a short follow-up time on AA/E. The endpoints included overall survival from ADT start, overall survival from AA/E start, and time to AA/E start from ADT start. Differences between groups were assessed using the log-rank test.. Of the 102 patients with mCRPC identified, 50 (49%) had previously received ADT alone, while 52 (51%) had ADT+D. No statistically significant difference in any of the evaluated outcomes was observed between the 2 cohorts. Yet, deaths in the ADT+D group were 12 versus 21 in the ADT alone, after a median follow-up of 24.4 and 29.8 months, respectively.. In a cohort of ADT/ADT+D-treated patients with mCRPC with short times to first-line AA/E and follow-up, the efficacy of AA/E is similar regardless of previous use of D.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Analysis; Treatment Outcome

We evaluated the use of abiraterone acetate (1,000 mg) plus prednisone (5 mg) in patients with high risk, nonmetastatic, castration resistant prostate cancer.. Patients considered at high risk for progression to metastatic disease (prostate specific antigen 10 ng/ml or greater, or prostate specific antigen doubling time 10 months or less) received abiraterone acetate plus prednisone daily in 28-day cycles. The primary study end point was the proportion of patients in whom a 50% or greater prostate specific antigen reduction was achieved during cycles 1 to 6. Secondary end points included time to prostate specific antigen progression, time to radiographic evidence of disease progression and safety.. Of the 131 enrolled patients 44 (34%) remained on treatment with a median followup of 40.0 months. Median age was 72 years (range 48 to 90). Of the patients 82.4% were white and 14.5% were black. Median screening prostate specific antigen was 11.9 ng/dl and median prostate specific antigen doubling time was 3.4 months. Prostate specific antigen was significantly reduced (p <0.0001) with a 50% or greater prostate specific antigen reduction in 86.9% of cases and a 90% or greater reduction in 59.8%. Median time to prostate specific antigen progression was 28.7 months (95% CI 21.2-38.2). Median time to radiographic evidence of disease progression was not reached but on sensitivity analysis in 15 patients it was estimated to be 41.4 months (95% CI 27.6-not estimable). Baseline testosterone 12.5 ng/dl or greater and a 90% or greater prostate specific antigen reduction at cycle 3 were associated with longer time to prostate specific antigen progression and radiographic evidence of disease progression. Outcomes in black patients were similar to those in other patients. Adverse events, grade 3 or greater adverse events and serious adverse events were reported in 96.2%, 61.1% and 43.5% of patients, respectively.. In patients with high risk, nonmetastatic, castration resistant prostate cancer treatment with abiraterone acetate plus prednisone demonstrated a significant 50% or greater prostate specific antigen reduction with encouraging results for the secondary end points, including the safety of 5 mg prednisone.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Humans; Kallikreins; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Prednisone; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

The optimal sequence of life-extending therapies in metastatic castration-resistant prostate cancer (mCRPC) is unknown.. To evaluate outcomes among mCRPC patients treated with docetaxel (DOC), cabazitaxel (CABA), and a novel androgen receptor-targeted agent (ART; abiraterone acetate or enzalutamide) according to three different sequences.. Data from 669 consecutive mCRPC patients were retrospectively collected between November 2012 and October 2016.. The primary endpoint was the prostate-specific antigen (PSA) response (decrease ≥50% from baseline) to each therapy. Secondary endpoints included best clinical benefit, time to PSA progression, radiological progression-free survival (rPFS), overall survival (OS), and toxicity.. A total of 158 patients received DOC→CABA→ART (group 1), 456 received DOC→ART→CABA (group 2), and 55 received ART→DOC→CABA (group 3). At baseline, PSA progression only and Gleason <8 were more common in group 3. PSA response on DOC was lower in group 3 than in other groups (p=0.02) and PSA response on CABA was higher in the second than in the third line (p=0.001). In Group 3, rPFS on ART (6.6 mo) and DOC (9.2 mo) was also shorter than in the other groups. OS calculated from the first life-extending therapy reached 34.8, 35.8, and 28.9 mo in groups 1, 2 and 3, respectively (p=0.007). Toxicity was comparable between the arms. The main limitations of the trial are its retrospective design and the low number of patients in group 3.. In this retrospective trial, sequencing of DOC, CABA, and one ART, was associated with median OS of up to 35.8 mo. CABA seemed to retain its activity regardless of treatment sequence. DOC activity after ART appeared to be reduced, but the data are insufficient to conclude that cross-resistance occurs.. The order of drugs administered to patients with metastatic castration-resistant prostate cancer could impact their efficacy, with cabazitaxel appearing to retain its activity whatever the therapeutic sequence.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Humans; Male; Middle Aged; Multivariate Analysis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

The combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored.. Androgen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance.. This phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy.. The combination of standard-dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on-target and off-target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug-Related Side Effects and Adverse Reactions; Humans; Imidazoles; Male; Middle Aged; Phosphoinositide-3 Kinase Inhibitors; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quinolines; Receptors, Androgen; Signal Transduction; TOR Serine-Threonine Kinases

Abiraterone acetate (AA) gives a significant improvement in survival for patients with metastatic castration-resistant prostate cancer (mCRPC) before and after chemotherapy and has a favorable effect on patients' health-related quality of life and pain. Only a few studies have investigated patient-reported outcomes (PROs) in AA treatment for mCRPC. The aim of this study was to investigate patients' satisfaction in men affected by mCRPC treated with AA.. This was a retrospective analysis of a database of consecutive chemonaive patients with progressive mCRPC. Patients were treated with AA until disease progression, death, or unacceptable toxicity. Evaluation was performed at baseline and every 4 weeks by means of physical examination and laboratory studies. Eastern Cooperative Oncology Group score, pain symptoms, treatment-related toxicity, prostate-specific antigen (PSA), and overall and progression-free survival were recorded. Satisfaction with treatment was investigated at 6 months by means of a 4-point arbitrary scale.. One-hundred twenty-eight patients were enrolled. Patients' satisfaction with treatment was "greatly improved" in 36.1% of patients and "improved" in 32.4% of them. Patients with higher satisfaction had lower baseline and final PSA values (P < .05), lower PSA levels at 12 weeks (P = .080), and less pain symptoms and lower Brief Pain Inventory scores (P = .001). Satisfaction with treatment was significantly correlated with baseline PSA level (P = .018), presence of pain (P = .007), duration of androgen deprivation therapy >12 months (P = .025), and number of hormonal manipulations (P = .051). Progression-free survival significantly correlated with patient satisfaction (P < .001).. AA is safe and well tolerated in chemonaive mCRPC patients, ensures good oncological and PROs. Patient's satisfaction is a predictor of progression-free survival.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Disease-Free Survival; Humans; Male; Patient Satisfaction; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Retrospective Studies; Treatment Outcome

The value of continuation of luteinizing hormone-releasing hormone (LHRH) therapy in castration-resistant prostate cancer (CRPC) remains controversial and clear evidence is lacking. Argumentation for cessation of LHRH therapy is the prolonged suppression of testosterone levels after the withdrawal of LHRH analogues and the fact that disease progression occurs despite castration levels of testosterone. Especially upon treatment with the life-prolonging cytochrome P450 17-alpha-hydroxylase (Cyp17)-inhibitor, abiraterone, which has the ability to further suppress testosterone serum levels over LHRH therapy alone, continuation of LHRH therapy seems to be negligible. However, the proven increase of luteinizing hormone levels after LHRH withdrawal, which is even further increased by abiraterone, may counteract the effects of abiraterone by the induction of enzymes of steroidogenesis. Therefore, cessation of LHRH therapy when starting treatment with abiraterone in CRPC may display an unpredictable hazard to the patients. This study will explore the role of continuation of LHRH therapy when starting treatment with abiraterone in patients with asymptomatic or mildly symptomatic, chemotherapy-naïve CPRC.. The trial will assess radiographic progression-free survival after 12 months of treatment with abiraterone/prednisone in patients who will be randomized to receive continuing LHRH therapy versus LHRH withdrawal at the time of starting abiraterone therapy.. This multicenter, prospective, randomized, exploratory phase-II trial will bring about new data regarding the efficacy and safety of abiraterone/prednisone treatment with or without continuation of LHRH therapy. In addition, further insight into the complex hormonal changes under treatment will be gained and the results of this trial may give rise to a larger phase-III trial to examine the possibility of withdrawing LHRH therapy in patients with CRPC.. ClinicalTrials.gov, ID: NCT02077634 . Registered on 9 December 2013.

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Germany; Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Metastasis; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Risk Factors; Steroid 17-alpha-Hydroxylase; Steroid Synthesis Inhibitors; Time Factors; Treatment Outcome

To evaluate the safety and efficacy of abiraterone acetate (AA) in the "real life" clinical practice for men with chemotherapy-naïve metastatic castration-resistant prostate.. A consecutive series of patients with mCRPC in 9 Italian tertiary centres treated with AA was collected. Demographics, clinical parameters, treatment outcomes and toxicity were recorded. The Brief Pain Inventory scale Q3 was tracked and patient treatment satisfaction was evaluated. Survival curves were estimated by the method of Kaplan-Meier and Cox regression and compared by the log-rank test statistic.. We included 145 patients (mean age 76.5y). All patients were on androgen deprivation therapy. Patients had prior radiotherapy, radical prostatectomy, both treatments or exclusive androgen deprivation therapy in 17%, 33%, 9% and 40%, respectively. 57% of the patients had a Gleason score higher more than 7 at diagnosis. 62% were asymptomatic patients. The median serum total PSA at AA start was 17 ng/mL (range 0,4-2100). The median exposure to AA was 10 months (range 1-35). The proportion of patients achieving a PSA decline ≥50% at 12 weeks was 49%. Distribution of patient satisfaction was 32% "greatly improved", 38% "improved", 24% "not changed", 5.5% "worsened". Grade 3 and 4 toxicity was recorded in 17/145 patients 11.7% (70% cardiovascular events, 30% critical elevation of AST/ALT levels). At the last follow-up, median progression free and overall survival were 17 and 26.5 months, respectively. Both outcomes significantly correlated with the presence of pain, patient satisfaction, PSA baseline and PSA decline.. The AA is effective and well tolerated in asymptomatic or slightly symptomatic mCRPC in a "real life" setting. The survival outcomes are influenced by the presence of pain, patient satisfaction, baseline PSA and PSA decline.. The study was retrospectively registered at ISRCTN as DOI: 10.1186/ISRCTN 52513758 in date April the 30th 2016.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Disease Progression; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms, Castration-Resistant; Risk Factors; Treatment Outcome

Recent analysis revealed strong associations between prostate-specific antigen (PSA) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) and supported PSA dynamics as bridging surrogacy endpoints for clinical benefit from treatment with abiraterone acetate plus prednisone. This analysis aimed to investigate the abiraterone exposure-PSA dynamics relationship in mCRPC.. Abiraterone pharmacokinetics-PSA models were constructed using data from the COU-AA-301 (chemotherapy-pretreated) and COU-AA-302 (chemotherapy-naïve) trials comparing abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily with prednisone alone in mCRPC. The drug effect-PSA dynamics relationship was modeled as a function of selected pharmacokinetic measures. The influences of baseline demographic variables, laboratory values, and disease status on PSA dynamics were assessed.. A tumor growth inhibition model best described PSA dynamics post-treatment with abiraterone acetate. Abiraterone acetate treatment in chemotherapy-pretreated and chemotherapy-naïve patients increased the PSA decay rate (k. The model appropriately described the exposure-response relationship between abiraterone and PSA dynamics in chemotherapy-pretreated and chemotherapy-naïve patients following oral administration of abiraterone acetate.

Topics: Abiraterone Acetate; Area Under Curve; Drug Therapy, Combination; Humans; L-Lactate Dehydrogenase; Male; Models, Biological; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Severity of Illness Index; Socioeconomic Factors; Testosterone

Topics: Abiraterone Acetate; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Humans; Imidazoles; Kaplan-Meier Estimate; Male; Middle Aged; Naphthalenes; Neoplastic Cells, Circulating; Prednisolone; Prognosis; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signalling axis and androgen receptor (AR) pathways exhibit reciprocal feedback regulation in phosphatase and tensin homologue (PTEN)-deficient metastatic castration-resistant prostate cancer (CRPC) in preclinical models. This phase Ib study evaluated the pan-PI3K inhibitor buparlisib (BKM120) and the dual pan-PI3K/ mammalian target of rapamycin (mTOR) inhibitor dactolisib (BEZ235) in combination with abiraterone acetate (AA) in patients with CRPC.. Patients with CRPC who had progressed on AA therapy received escalating doses of either buparlisib or dactolisib, along with fixed doses of AA (1000 mg once daily (qd)) and prednisone (5 mg twice daily (bid)). The primary objective was to define the maximum tolerated dose (MTD) and/or the recommended dose for expansion (RDE) of either buparlisib or dactolisib in combination with AA. Secondary objectives included safety, antitumour activity (Prostate Cancer Working Group 2 (PCWG2) criteria; 30% of prostate-specific antigen (PSA) decline at ≥week 12) and pharmacokinetic (PK) profile.. Based on the assessment of available pharmacokinetics, safety, and efficacy data, no further study is planned for either buparlisib or dactolisib in combination with AA in CRPC.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Asthenia; Chills; Diarrhea; Fever; Humans; Hyperglycemia; Imidazoles; Kallikreins; Male; Maximum Tolerated Dose; Middle Aged; Morpholines; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quinolines; Stomatitis; Vomiting

The duration of prior hormonal treatment can predict responses to subsequent therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).. To determine if prior endocrine therapy duration is an indicator of abiraterone acetate (AA) sensitivity.. Post-hoc exploratory analysis of randomised phase 3 studies examining post-docetaxel (COU-AA-301) or chemotherapy-naïve mCRPC (COU-AA-302) patients receiving AA. The treatment effect on overall survival (OS), radiographic progression-free survival (rPFS), and prostate-specific antigen (PSA) response analysed by quartile duration of prior gonadotropin-releasing hormone agonists (GnRHa) or androgen receptor (AR) antagonist.. Patients were randomised to AA (1000mg, orally once daily) plus prednisone (5mg, orally twice daily) or placebo plus prednisone. Prior endocrine therapy was GnRHa (COU-AA-301, n=1127 [94%]; COU-AA-302, n=1057 [97%], 45.1 mo or 36.7 mo median duration, respectively) and/or orchiectomy (COU-AA-301, n=78 [7%] COU-AA-302, n=44 [4%]); castrated patients received prior AR antagonists (COU-AA-301, n=1015 [85%]; COU-AA-302, n=1078 [99%], 15.7 mo or 16.1 mo median duration, respectively).. Cox model was used to obtain hazard ratio and associated 95% confidence interval with statistical inference by log rank statistic.. Clinical benefit with AA was observed for OS, rPFS, and PSA response for nearly all quartiles with GnRHa or AR antagonists in both COU-AA-301 and COU-AA-302. In COU-AA-301, patients with a longer duration of prior endocrine therapy tended to have greater AA OS, rPFS, and PSA response benefit, with lead-time chemotherapy bias potentially impacting COU-AA-301 results. Time to castration resistance was not captured. This analysis is limited as a post-hoc exploratory analysis.. In the COU-AA-301 and COU-AA-302 studies, AA produced clinical benefits regardless of prior endocrine therapy duration in patients with mCRPC.. Metastatic castration-resistant prostate cancer patients derived clinical benefits with abiraterone acetate regardless of prior endocrine therapy duration.

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Double-Blind Method; Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Metastasis; Orchiectomy; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retreatment; Survival Rate; Taxoids

The usefulness of Gleason score (<8 or ≥8) at initial diagnosis as a predictive marker of response to abiraterone acetate (AA) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) was explored retrospectively.. Initial diagnosis Gleason score was obtained in 1048 of 1195 (COU-AA-301, post-docetaxel) and 996 of 1088 (COU-AA-302, chemotherapy-naïve) patients treated with AA 1 g plus prednisone 5 mg twice daily by mouth or placebo plus prednisone. Efficacy end points included radiographic progression-free survival (rPFS) and overall survival (OS). Distributions and medians were estimated by Kaplan-Meier method and hazard ratio (HR) and 95% confidence interval (CI) by Cox model.. Baseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56-0.86), P = 0.0009 and Gleason score ≥8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48-0.72), P < 0.0001] and chemotherapy-naïve patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40-0.62), P < 0.0001 and Gleason score ≥8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49-0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate-specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups.. OS and rPFS trends demonstrate AA treatment benefit in patients with pre- or post-chemotherapy mCRPC regardless of Gleason score at initial diagnosis. The initial diagnostic Gleason score in patients with mCRPC should not be considered in the decision to treat with AA, as tumour metastases may no longer reflect the histology at the time of diagnosis.. COU-AA-301 (NCT00638690); COU-AA-302 (NCT00887198).

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androstenols; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Double-Blind Method; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant

Few prognostic models for overall survival (OS) are available for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with recently approved agents. We developed a prognostic index model using readily available clinical and laboratory factors from a phase III trial of abiraterone acetate (hereafter abiraterone) in combination with prednisone in post-docetaxel mCRPC.. Baseline data were available from 762 patients treated with abiraterone-prednisone. Factors were assessed for association with OS through a univariate Cox model and used in a multivariate Cox model with a stepwise procedure to identify those of significance. Data were validated using an independent, external, population-based cohort.. Six risk factors individually associated with poor prognosis were included in the final model: lactate dehydrogenase > upper limit of normal (ULN) [hazard ratio (HR) = 2.31], Eastern Cooperative Oncology Group performance status of 2 (HR = 2.19), presence of liver metastases (HR = 2.00), albumin ≤4 g/dl (HR = 1.54), alkaline phosphatase > ULN (HR = 1.38) and time from start of initial androgen-deprivation therapy to start of treatment ≤36 months (HR = 1.30). Patients were categorized into good (n = 369, 46%), intermediate (n = 321, 40%) and poor (n = 107, 13%) prognosis groups based on the number of risk factors and relative HRs. The C-index was 0.70 ± 0.014. The model was validated by the external dataset (n = 286).. This analysis identified six factors used to model survival in mCRPC and categorized patients into three distinct risk groups. Prognostic stratification with this model could assist clinical practice decisions for follow-up and monitoring, and may aid in clinical trial design.. NCT00638690.

Topics: Abiraterone Acetate; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Double-Blind Method; Humans; Male; Prednisone; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant

Coadministration of docetaxel and abiraterone acetate plus prednisone (AA + P) may benefit patients with metastatic castration-resistant prostate cancer (mCRPC) because of complementary mechanisms of action. COU-AA-206 was a phase 1b study to determine the safe dose combination of docetaxel and AA + P in three cohorts of chemotherapy-naïve mCRPC patients. Twenty-two patients received escalating doses of docetaxel plus AA + P. The primary endpoint was the proportion of patients with a dose-limiting toxicity (DLT) between weeks 2 and 7. The recommended phase 2 dose (RP2D) was the highest safe combination of docetaxel plus AA + P. Prostate-specific antigen (PSA) changes and intensive pharmacokinetic parameters for each drug were evaluated. Docetaxel 75mg/m. The combination of hormonal therapy and chemotherapy may improve outcomes in men with metastatic prostate cancer. This study demonstrates the ability to combine the hormonal therapy agent abiraterone acetate, plus prednisone, and the chemotherapy drug docetaxel with an acceptable side effect profile. A high rate of prostate-specific antigen decline was seen, but the study was small and additional research is needed before this becomes a standard approach.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Docetaxel; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

To evaluate the efficacy and safety of abiraterone acetate-prednisone versus placebo-prednisone in Asian metastatic castration-resistant prostate cancer patients who have failed docetaxel-based chemotherapy.. In this double-blind, phase 3 study from China, 214 patients were randomized (2:1) to abiraterone acetate 1000 mg once daily plus prednisone 5 mg twice daily and placebo plus prednisone 5 mg twice daily in 28-day treatment cycles.. Abiraterone acetate-prednisone treatment significantly decreased prostate-specific antigen progression risk by 49%, with longer median time to prostate-specific antigen progression of 5.55 months versus 2.76 months in the placebo-prednisone group (hazard ratio 0.506, P = 0.0001, primary end-point). There was a strong trend for improved overall survival in the abiraterone acetate-prednisone group, with a 40% decrease in the risk of death (hazard ratio 0.604, P = 0.0597); however, median survival was not reached in either group because of the short follow-up period (12.9 months) and limited number of observed death events. The prostate-specific antigen response rate was higher in the abiraterone-prednisone group (49.7%) than in the placebo-prednisone group (14.1%). A total of 37.1% patients in this group had pain progression events compared with 50.7% in the placebo-prednisone group. Abiraterone-prednisone significantly decreased the risk of pain progression by 50% (hazard ratio 0.496, P = 0.0014). The incidence of adverse events was similar between the two groups; the most common adverse events being anemia (25.9% for abiraterone-prednisone vs 22.5% for placebo-prednisone), hypokalemia (25.9% and 11.3%), bone pain (23.8% and 21.1%), hypertension (16.1% and 12.7%) and increased aspartate aminotransferase (14.7% and 15.5%), respectively.. Abiraterone-prednisone significantly delays disease and pain progression, and prostate-specific antigen, with a favorable benefit-risk ratio in Asian metastatic castration-resistant prostate cancer patients in the post-docetaxel setting.

Topics: Abiraterone Acetate; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; China; Disease-Free Survival; Docetaxel; Double-Blind Method; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Topics: Abiraterone Acetate; Disease Progression; Disease-Free Survival; Drug Therapy, Combination; Germany; Gonadotropin-Releasing Hormone; Humans; Male; Prostatic Neoplasms, Castration-Resistant

The optimal use of new therapies in metastatic castration-resistant prostate cancer (mCRPC) remains to be clarified. Prostate-specific antigen (PSA) response used as a pharmacodynamic end-point may help identify patients with early resistance to new androgen receptor-pathway inhibitors. We aimed to determine the clinical significance of early PSA response (EPR) during therapy with enzalutamide, abiraterone acetate (AA) and orteronel in mCRPC.. Data from patients recruited in clinical trials were studied. PSA values were obtained at baseline and 28 d after treatment initiation. EPR defined as a decline >50% from baseline was calculated according to the Prostate Cancer Working Group 2 criteria. The effects of clinical characteristics on radiographic progression-free survival (rPFS) and overall survival (OS) were examined using the Cox model.. EPR was assessed in 118 patients treated in clinical trials and was found to be associated with longer rPFS and OS (P < 0.0001 for both). Median rPFS was 13.9 and 5.6 months (hazard ratio [HR]:0.38, P < 0.001) for patients with and without an EPR, respectively. Median OS was 32.2 months in patients with an EPR and 15.9 months in patients without an EPR (HR: 0.4, P < 0.01). EPR remained prognostic for OS in multivariate analyses (HR: 0.5, p=0.009) that included validated pre-therapeutic prognostic factors for mCRPC. Prognostic values of EPR for rPFS and OS were confirmed in an independent cohort of 95 AA-treated non-trial patients.. EPR is an independent prognostic factor in patients with mCRPC treated with next-generation androgen pathway inhibitors and may be useful for the therapeutic management of these patients.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers, Tumor; Disease-Free Survival; Humans; Male; Middle Aged; Multivariate Analysis; Nitriles; Phenylthiohydantoin; Prognosis; Proportional Hazards Models; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

Previous studies have demonstrated an association between prostate-specific antigen (PSA) kinetics and predictive value for treatment outcomes. Abiraterone acetate (AA) is a newly approved cytochrome-P450C17 inhibitor for treatment of metastatic castration-resistant prostate cancer (mCRPC), and few studies have evaluated PSA kinetics using AA so far. Results of a study evaluating PSA kinetics in the beginning of AA and enzalutamide responded chemotherapy-treated patients suggested different trends between the drugs. PSA kinetics of AA-treated patients has been reported using large datasets; however, no studies which have fully evaluated PSA kinetics in the beginning treatment. The present study aimed to assess the PSA kinetics and relationship between the PSA kinetics and PSA progression in chemotherapy-naïve and chemotherapy-treated mCRPC patients receiving AA.. We used two Japanese phase II trial datasets: JPN-201, chemotherapy-naïve mCRPC (n = 48) and JPN-202, chemotherapy-treated mCRPC (n = 46). PSA kinetic parameters were calculated using actual PSA values measured every 4 weeks, and a subgroup analysis was performed to evaluate the influence of early PSA response on time to PSA progression (TTPP). In addition, we used a Cox proportional hazard model to investigate the influence of variables on TTPP.. PSA declined from week 4 but took more time to achieve nadir. PSA kinetic parameters were different between the datasets, mean time to PSA nadir was 5.3 ± 5.6 and 2.0 ± 3.4 months, and TTPP was 9.5 ± 7.4 and 3.8 ± 4.8 months in JPN-201 and JPN-202, respectively. In the subgroup analysis of week 4 PSA decline status, Kaplan-Meier curves for TTPP were similar between early responders and non-progression patients in JPN-201 (median, 9.2 vs. 6.5 months, respectively) but separated in JPN-202 (median, 3.7 vs. 1.9 months, respectively). According to univariate Cox regression analysis, achievement of PSA response (≥50 %) at week 12 was associated with TTPP in the both trials, but the hazard ratio of PSA decline (≥30 %) at week 4 was not significant in JPN-201.. Our results suggest that PSA kinetics were not comparable and early PSA response showed different association to TTPP according to prior history of chemotherapy.. The original trials are registered at ClinicalTrials.gov. The identifiers are; JNJ-212082-JPN-201 , registered 20 December 2012 and JNJ-212082-JPN-202 , registered 30January 2013.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Disease Progression; Humans; Japan; Male; Middle Aged; Prevalence; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Reproducibility of Results; Retrospective Studies; Risk Factors; Sensitivity and Specificity; Treatment Outcome

The safety and activity findings of abiraterone acetate plus prednisone treatment in black men with mCRPC were similar to results from previously conducted studies with largely white populations.Poor trial accrual continues to be a challenge in black men with mCRPC and further efforts are needed to address such underrepresentation.. Self-identified black men have higher incidence and mortality from prostate cancer in the United States compared with white men but are dramatically underrepresented in clinical trials exploring novel therapies for metastatic castration-resistant prostate cancer (mCRPC).. Black men with mCRPC were treated with abiraterone acetate (AA), 1,000 mg daily, and prednisone (P), 5 mg twice daily. The primary objective was to determine antitumor activity (defined by a ≥30% decline in prostate-specific antigen [PSA] level) and to correlate germline polymorphisms in androgen metabolism genes with antitumor activity. Secondary objectives included determining safety, post-treatment changes in measurable disease, and time to disease progression.. From April 2013 to March 2016, a total of 11 black men were enrolled and received AA plus P (AA+P); 7 of 10 evaluable patients were docetaxel naive. Post-treatment declines in PSA level of ≥30% were achieved in 90% of patients. The side effect profile was consistent with prior clinical trials exploring AA+P in mCRPC. Due to poor accrual, the study was closed prematurely with insufficient sample size for the planned pharmacogenetic analyses.. In this small prospective study terminated for poor accrual, the safety and activity of AA+P in black men with mCRPC was similar to that reported in prior studies exploring AA in largely white populations. Further efforts are needed to address underrepresentation of black men in mCRPC trials.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Black People; Humans; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

The aim of this study was to evaluate the safety profile of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) men with cardiovascular comorbidity, as little conclusive safety data are available in this patient subset.. A retrospective analysis of mCRPC patients with controlled cardiovascular comorbidities, receiving AA 1000 mg administered orally once daily and prednisone 5 mg twice daily, between April 2011 and July 2012, was performed. All clinical and instrumental variables and toxicity data were analyzed by descriptive statistics: mean, standard deviation, minimum and maximum values for continuous variables, and absolute and relative frequencies for categorical variables.. A total of 51 mCRPC patients were evaluated. Metastatic sites included the bone (74%), lungs, and liver (26%). All patients were previously treated with at least 2 lines of hormone and 1 docetaxel-based chemotherapy. Preexisting cardiac risk factors included hypertension (41%), cardiac ischemia (12%), arrhythmias (6%), dislipidemia (18%), and hyperglycemia (30%). No grade 3-4 adverse events were observed. Grade 1-2 adverse events included fluid retention (18%), asthenia (15%), and hypertension (16%). Median progression-free survival was 5.1 months (95% confidence interval, 0.5-12). Prostate specific antigen assessment revealed a good overall disease control rate (64%).. AA appears to be safe and well tolerated even in patients with cardiovascular comorbidities or with increased risk factors for cardiovascular diseases.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Cardiovascular Diseases; Comorbidity; Docetaxel; Follow-Up Studies; Humans; Male; Middle Aged; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

Gene fusions leading to androgen receptor-modulated ERG overexpression occur in up to 70% of metastatic castration-resistant prostate cancers (mCRPC). We assessed the association between ERG rearrangement status and clinical benefit from abiraterone acetate.. COU-AA-302 is a phase III trial comparing abiraterone acetate and prednisone versus prednisone in chemotherapy-naïve mCRPC. ERG status was evaluated by FISH on archival tumors. End points included radiographic progression-free survival (rPFS), time to PSA progression (TTPP), rate of ≥50% PSA decline from baseline, and overall survival (OS). Cox regression was used to evaluate association with time-to-event measures and Cochran-Mantel-Haenszel for PSA response.. ERG status was defined for 348 of 1,088 intention-to-treat patients. ERG was rearranged in 121 of 348 patients with confirmed ERG status (35%). Cancers with an ERG fusion secondary to deletion of 21q22 and increased copy number of fusion sequences (class 2+ Edel) had a greater improvement in rPFS after abiraterone acetate and prednisone [22 vs. 5.4 months; HR (95% confidence interval, CI), 0.31 (0.15-0.68); P = 0.0033] than cancers with no ERG fusion [16.7 vs. 8.3 months; 0.53 (0.38-0.74); P = 0.0002] or other classes of ERG rearrangement. There was also greater benefit in this subgroup for TTPP.. Both ERG-rearranged and wild-type cancers had a significant improvement in rPFS with abiraterone acetate and prednisone in the COU-AA-302 trial. However, our data suggest that 2+ Edel cancers, accounting for 15% of all mCRPC patients and previously associated with a worse outcome, derived the greatest benefit.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Disease-Free Survival; Double-Blind Method; Humans; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Male; Middle Aged; Prednisone; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Trans-Activators; Transcriptional Regulator ERG

Progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC.. rPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman's correlation.. A total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman's correlation coefficient between rPFS and OS was 0.72.. rPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Disease-Free Survival; Double-Blind Method; Humans; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radiography; Survival Rate; Treatment Outcome

The aim of this paper was to evaluate the activity and tolerability of weekly docetaxel (D) combined with weekly epirubicin (EPI) in patients with advanced castrate-resistant prostate cancer (CRPC) previously exposed to D and abiraterone acetate (AA). Locally advanced or metastatic CRPC patients with 0-2 performance status, who had progressed after D and AA therapy, were included in the study. Previous treatment with chemotherapy agent cabazitaxel was also admitted. Treatment consisted of D 30 mg/m(2) intravenously (i.v.) and EPI 30 mg/m(2) i.v., every week (D/EPI). Chemotherapy was administered until disease progression or unacceptable toxicity. In our institution, twenty-six patients received D/EPI: their median age was 72 years (range 59-83 years). Twenty-three (88.5%) patients had bone metastases. A decrease in PSA levels ≥50% was observed in seven patients (26.9%, 95% CI: 0.11-0.47); of these, five had achieved a ≥50% PSA response during prior first-line D and six had achieved a PSA response during prior AA Among the subjects who were symptomatic at baseline, pain was reduced in nine patients (38.1%) with a significant decrease in analgesic use. Median progression-free survival was 4.4 months (95% CI, 3-5.2), and median overall survival was 10.7 months (95% CI, 8.9-18.4). Treatment was well tolerated and no grade 4 toxicities were observed. Our findings suggest that weekly D/EPI is feasible and active in heavily pretreated advanced CRPC patients and seem to support the hypothesis that the addition of EPI to D may lead to overcome the resistance to D in a subgroup of patients.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Epirubicin; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Taxoids; Treatment Outcome

Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome measure.. Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level.. A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively.. A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androstenes; Biomarkers, Tumor; Endpoint Determination; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Prostatic Neoplasms, Castration-Resistant

We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/day of abiraterone acetate (AA).. The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy pretreated, n = 1,184) and COU-AA-302 (chemotherapy naïve, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model.. The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naïve and -pretreated patients. PSA kinetics [e.g., PSA nadir, PSA response rate (≥30%, 50%, and 90%), time to PSA progression, PSA doubling time (PSADT)] were highly associated with OS in both populations. The model-based posttreatment PSADT had the strongest association with OS (HR ∼0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic endpoints, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic endpoints. A strong correlation was also observed between PSA and radiographic progression-free survival.. The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naïve patients, thereby providing a rationale to consider PSA kinetics as surrogacy endpoints to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment.

Topics: Abiraterone Acetate; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Double-Blind Method; Drug Resistance, Neoplasm; Humans; Kaplan-Meier Estimate; Kinetics; Male; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

This phase II open-label study evaluated the effect of concurrent or sequential administration of abiraterone acetate plus prednisone (AA + P) on sipuleucel-T manufacture and immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients.. mCRPC patients received sipuleucel-T followed by AA + P 1 day (concurrent) or 10 weeks (sequential) after the first sipuleucel-T infusion. AA + P treatment continued for 26 weeks. The primary endpoint was cumulative antigen presenting cell (APC) activation, and secondary endpoints included cumulative APC number and total nucleated cell counts. Additional endpoints included in vivo peripheral immune responses to sipuleucel-T (T-cell responses, T-cell proliferation, humoral responses, and antigen spread) as well as safety.. Sixty-nine mCRPC patients were enrolled, with 35 and 34 patients randomized to the concurrent and sequential arms, respectively. Ex vivo APC activation was significantly greater at the second and third infusions compared with baseline in both arms (P < 0.05), indicative of an immunologic prime-boost effect. In both arms, sipuleucel-T product parameter profiles and peripheral immune responses were consistent with previously conducted sipuleucel-T phase III trials. Antigen spread was similarly observed in both arms and consistent with the other immunologic endpoints.. These data suggest that sipuleucel-T can be successfully manufactured during concurrent administration of AA + P without blunting immunologic effects or altering immune parameters that correlate with sipuleucel-T's clinical benefit. Combination of these agents was well tolerated, with no new safety signals emerging.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antigen-Presenting Cells; Antineoplastic Combined Chemotherapy Protocols; Humans; Lymphocyte Activation; Lymphocyte Count; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; T-Lymphocyte Subsets; Tissue Extracts; Treatment Outcome

Food effect on abiraterone pharmacokinetics and safety on abiraterone acetate coadministration with low-fat or high-fat meals was examined in healthy subjects and metastatic castration-resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to abiraterone acetate (single dose, 1000 mg) + low-fat meal, + high-fat meal, and fasted state. mCRPC patients received repeated doses (abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1-7) in a modified fasting state followed by abiraterone acetate plus prednisone within 0.5 hours post-low-fat (n = 6) or high-fat meal (n = 18; days 8-14). In healthy subjects, geometric mean (GM) abiraterone area under plasma concentration-time curve (AUC) increased ∼5- and ∼10-fold, respectively, with low-fat and high-fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, abiraterone AUC was ∼2-fold higher with a high-fat meal and similar with a low-fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high-fat/low-fat meals or fasted/modified fasting state. Short-term dosing with food did not alter abiraterone acetate safety.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Cytochrome P-450 Enzyme Inhibitors; Dietary Fats; Drug Therapy, Combination; Fasting; Female; Food-Drug Interactions; Healthy Volunteers; Humans; Male; Middle Aged; Prednisone; Prostatic Neoplasms, Castration-Resistant

Metastatic castration resistant prostate cancer primarily affects elderly men. In this post hoc analysis we investigated the safety and efficacy of abiraterone acetate in elderly (age 75 years or greater) and younger (less than 75 years) patient subgroups at the prespecified interim analysis (55% of total overall survival events) for the COU-AA-302 (Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer) trial.. Patients were stratified and randomized 1:1 to abiraterone acetate 1,000 mg plus prednisone/prednisolone 5 mg twice daily (abiraterone-prednisone) vs placebo plus prednisone/prednisolone 5 mg twice daily (prednisone alone). Co-primary end points were radiographic progression-free and overall survival. Median time to event and HR were estimated using the Kaplan-Meier method and a Cox model, respectively.. A total of 350 elderly patients treated with abiraterone-prednisone had significant improvements in overall and radiographic progression-free survival vs those with prednisone alone (HR 0.71, 95% CI 0.53-0.96 vs HR 0.63, 95% CI 0.48-0.83), similar to 738 younger patients (HR 0.81, 95% CI 0.63-1.03 vs HR 0.49, 95% CI 0.40-0.59). All secondary end points favored the abiraterone-prednisone arm for both age subgroups. Specific adverse events with abiraterone-prednisone were similar between the age subgroups. Elderly patients in both treatment arms had higher rates of fluid retention and cardiac disorders than younger patients, although rates of dose reduction or treatment interruptions due to adverse events were low in both age subgroups.. Abiraterone acetate demonstrated clinical benefit and was well tolerated in elderly and younger men with chemotherapy naïve, metastatic castration resistant prostate cancer. Thus, findings support it as a treatment option for elderly patients who may not tolerate other therapies with greater toxicity.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Follow-Up Studies; Glucocorticoids; Humans; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Visceral disease, non-nodal soft-tissue metastases predominantly involving the lung and liver, is a negative prognostic factor in patients with metastatic castration-resistant prostate cancer (mCRPC). An exploratory analysis of COU-AA-301 assessed whether abiraterone acetate (AA) improved overall survival (OS) in mCRPC patients with visceral disease progressing post docetaxel.. In COU-AA-301, post-docetaxel mCRPC patients were randomized 2:1 to AA 1000 mg (n=797) or placebo (n=398) once daily, each with prednisone 5 mg b.i.d. The primary end point was OS; secondary end points included radiographic progression-free survival (rPFS), PSA response rate and objective response rate (ORR). Treatment effects in visceral disease (n=352) and non-visceral disease (n=843) subsets were examined using final data (775 OS events).. AA plus prednisone produced similar absolute improvement in median OS in patients with (4.6 months) and without (4.8 months) visceral disease versus prednisone; hazard ratios (HRs) were 0.79 (95% confidence interval (CI): 0.60-1.05; P=0.102) and 0.69 (95% CI: 0.58-0.83; P<0.0001), respectively. Treatment with AA plus prednisone significantly and comparably improved secondary endpoint outcomes versus prednisone in both the subsets: the HRs for rPFS were 0.60 (95% CI: 0.46-0.78; P=0.0002) and 0.68 (95% CI: 0.58-0.80; P<0.0001) in visceral and non-visceral disease subsets, respectively. PSA response rates were 28% versus 7% in the visceral disease subsets and 30% versus 5% in the non-visceral disease subsets (both P<0.0001), and ORRs were 11% versus 0% (P=0.0058) and 19% versus 5% (P=0.0010), respectively. The incidence of grade 3/4 adverse events was similar between the subsets and between the treatment arms in each subset. Adverse events related to CYP17 blockade were increased in the AA arms and were similar in patients with or without visceral disease.. AA plus prednisone provides significant clinical benefit, including improvements in OS and secondary end points, in post-docetaxel mCRPC patients with or without baseline visceral disease. The presence of visceral disease does not preclude clinical benefit from abiraterone.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Risk Factors; Taxoids; Treatment Outcome; Viscera

Metastatic castration-resistant prostate cancer (mCRPC) is a disease that primarily affects older men. Abiraterone acetate (AA), a selective androgen biosynthesis inhibitor, in combination with low-dose prednisone (P) improved overall survival (OS) in a randomised trial in mCRPC progressing after docetaxel versus placebo (PL) plus P.. To examine the efficacy and safety of AA plus P versus PL plus P in subgroups of elderly (aged ≥ 75 yr) (n=331) and younger patients (<75 yr) (n=863).. We conducted a post hoc analysis of a randomised double-blind PL-controlled study in mCRPC patients progressing after docetaxel chemotherapy.. Patients were randomised 2:1 to AA (1000 mg) plus low-dose P (5mg twice daily) (n=797) or PL plus P (n=398).. Primary end point was OS. Secondary end points were time to prostate-specific antigen (PSA) progression (TTPP), radiographic progression-free survival (rPFS), and PSA response rate. Treatment differences were compared using the stratified log-rank test. The Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI). The key limitation was the post hoc analysis.. Elderly patients treated with AA plus P showed improved OS (HR: 0.64; 95% CI, 0.478-0.853; p=0.0022), TTPP (HR: 0.76; 95% CI, 0.503-1.155; p=0.1995), and rPFS (HR: 0.66; 95% CI, 0.506-0.859; p=0.0019), and higher PSA response rate with relative risk (HR: 4.15; 95% CI, 2.2-8.0]; p ≤ 0.0001) compared with patients treated with PL plus P. Grade 3/4 adverse events occurred in 62% of elderly patients and in 60% of patients aged <75 yr treated with AA plus P. Incidences of hypertension and hypokalaemia, although increased in the AA plus P arm, were similar in both age subgroups and readily managed.. AA improves OS and is well tolerated in both elderly patients and younger patients with mCRPC following docetaxel, hence providing an important treatment option for elderly patients who may not tolerate alternative therapies with greater toxicity.. ClinicalTrials.gov, identifier NCT00638690.

Topics: Abiraterone Acetate; Adult; Age Factors; Aged; Aged, 80 and over; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Double-Blind Method; Fatigue; Humans; Hypertension; Hypokalemia; Male; Middle Aged; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Survival Rate; Taxoids

We analyzed the potential of abiraterone acetate (henceforth abiraterone) to reduce androgen levels below lower limits of quantification (LLOQ) and explored the association with changes in PSA decline in metastatic castration-resistant prostate cancer (mCRPC) patients.. COU-AA-301 is a 2:1 randomized, double-blind, placebo-controlled study comparing abiraterone (1000 mg q.d.) plus low-dose prednisone (5 mg b.i.d.) with placebo plus prednisone in mCRPC patients post docetaxel. Serum testosterone, androstenedione and dehydroepiandrosterone sulfate from baseline to week 12 were measured by novel ultrasensitive two-dimensional liquid chromatography coupled to tandem mass spectrometry assays in a subset of subjects in each arm (abiraterone plus prednisone, n=80; prednisone, n=38). The association between PSA response (< or =50% baseline) and undetectable androgens (week 12 androgen level below LLOQ) was analyzed using logistic regression.. A significantly greater reduction in serum androgens was observed with abiraterone plus prednisone versus prednisone (all P < or = 0.0003), reaching undetectable levels for testosterone (47.2% versus 0%, respectively). A positive association was observed between achieving undetectable serum androgens and PSA decline (testosterone: odds ratio=1.54; 95% confidence interval: 0.546-4.347). Reduction of androgens to undetectable levels did not occur in all patients achieving a PSA response, and a PSA response did not occur in all patients achieving undetectable androgen levels.. Abiraterone plus prednisone significantly reduced serum androgens, as measured by ultrasensitive assays and was generally associated with PSA response. However, androgen decline did not uniformly predict PSA decline suggesting ligand-independent or other mechanisms for mCRPC progression.

Topics: Abiraterone Acetate; Androgens; Androstenes; Double-Blind Method; Humans; Kallikreins; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Testosterone; Treatment Outcome

Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy.. Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302.. Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1).. Patients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by mouth versus prednisone.. Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets α-spending function was used for OS. Adverse events were summarised descriptively.. With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p<0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66-0.95]; p=0.0151) but did not reach the prespecified statistical efficacy boundary (α-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p=0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports.. The updated IA of study COU-AA-302 in patients with mCRPC without prior chemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ≥24 mo.. Study COU-AA-302, ClinicalTrials.gov number, NCT00887198.. The updated results of this ongoing study showed that disease progression was delayed in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone, and there was a continued trend in prolongation of life compared with patients treated with prednisone alone. Treatment with abiraterone acetate and prednisone was well tolerated by patients who were treated for >2 yr.

Topics: Abiraterone Acetate; Aged; Androstenes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cytochrome P-450 Enzyme Inhibitors; Disease Progression; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prednisone; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Risk Factors; Steroid 17-alpha-Hydroxylase; Time Factors; Treatment Outcome

Docetaxel or AA are therapeutic options for mCRPC. We retrospectively analyzed clinical outcomes with subsequent docetaxel in patients with mCRPC after disease progression (DP) with AA to evaluate cross resistance between these therapies.. Patients with chemotherapy-naive mCRPC who were treated with AA in previously reported phase I to III trials, who had DP, and were subsequently treated (not on study) with docetaxel, were included. Acquired AA resistance was defined as: PSA decline > 50% from baseline or radiographically stable disease for ≥ 8 months, with subsequent DP. All other patients were defined as having primary AA resistance. Efficacy outcomes after docetaxel therapy were analyzed.. We identified 23 patients who were treated with docetaxel after DP with AA, including 14 (61%) with acquired and 9 (39%) with primary AA resistance. Median duration between discontinuation of AA and docetaxel initiation was 2.7 months (range, 0.2-14.7 months). Subsequent docetaxel therapy led to ≥ 30% PSA decline in 15 patients (65%) and ≥ 50% PSA decline in 11 patients (48%). Median OS from date of first docetaxel dose was 12.4 months (95% confidence interval, 8.2-19.6). Patients with previous primary versus acquired AA resistance had similar outcomes with subsequent docetaxel therapy.. In this retrospective analysis, the type of AA resistance did not appear to affect outcomes with subsequent docetaxel. The PSA response rates observed suggest a lack of cross-resistance between docetaxel and AA, but prospective studies are needed to evaluate for potential cross-resistance and optimize sequences of therapy in patients with mCRPC.

Topics: Abiraterone Acetate; Aged; Androstenes; Antineoplastic Agents; Disease Progression; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Steroid 17-alpha-Hydroxylase; Taxoids; Treatment Outcome

Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase-1, open-label and dose-escalation study. Chemotherapy-naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28-day treatment cycles. In the first cycle, AA monotherapy was given on days 1-7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut-off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median tmax 2-3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose-group experienced ≥50% prostate-specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well-tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov: NCT01186484.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstadienes; Androstenes; Androstenols; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase

Topics: Abiraterone Acetate; Adolescent; Adult; Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Female; Germany; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome; Young Adult

Abiraterone acetate has been approved in >70 countries for chemotherapy-naïve metastatic castration-resistant prostate cancer patients. Efficacy and safety of abiraterone acetate (1000 mg/once daily) with prednisolone (5 mg/twice daily) in chemotherapy-naïve Japanese patients with metastatic castration-resistant prostate cancer was evaluated.. Men, ≥20 years, with prostate-specific antigen levels of ≥5 ng/ml and evidence of progression were enrolled in this Phase 2, multicenter, open-label study. Primary efficacy endpoint was proportion of patients achieving a prostate-specific antigen decline of ≥50% from baseline (prostate-specific antigen response) after 12 week of treatment. Secondary efficacy endpoints and safety were assessed.. A confirmed prostate-specific antigen response was observed in 29/48 (60.4%) patients by week 12; lower limit of two-sided 90% confidence interval was >35% (threshold response rate), demonstrating efficacy of abiraterone acetate. Secondary efficacy endpoints: prostate-specific antigen response rate during treatment period: 62.5%; objective radiographic response, partial response: 4/18 (22.2%) patients; complete response: none; stable disease: 11/18 (61.1%) patients; median percent change in prostate-specific antigen level from baseline at Week 12: -66.62%. Median prostate-specific antigen response duration and progression-free survival were not reached, and median radiographic progression-free survival was 253 days. Of 31/48 (64.6%) patients experienced adverse events of special interest; most common was hepatic function abnormality (37.5%, Grade 3: 10.4%). One Grade 3 hypertension was the only mineralocorticoid adverse event >Grade 1/2.. Efficacy of abiraterone acetate plus prednisolone was demonstrated by decline in prostate-specific antigen levels with evidence of antitumor activity by radiography in Japanese patients with chemotherapy-naïve metastatic castration-resistant prostate cancer. Abiraterone acetate plus prednisolone had an acceptable safety profile.. NCT01756638.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Middle Aged; Neoplasm Metastasis; Prednisolone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

Patients previously treated with ketoconazole were excluded from phase III trials of abiraterone acetate due to potential overlapping mechanism of action. The purpose of this study was to determine the clinical utility of abiraterone and its impact on circulating androgens following ketoconazole.. Chemotherapy-naïve patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and prior ketoconazole therapy ≥28 days received abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. The primary endpoint was the proportion of patients with PSA response, defined as ≥30% PSA decline at 12 weeks. H0 = 0.30 versus H1 = 0.50 (α = 0.05, power = 0.83). Circulating androgen levels were measured using liquid chromatography tandem mass spectrometry.. Thirty-nine patients were included in the final analysis. Twenty (51%; 95% confidence interval, 36%-66%) patients had ≥30% PSA decline; the null hypothesis was rejected. Sixteen (41%) had ≥50% PSA decline. Median PFS (progression-free survival) was 16 weeks; median radiographic PFS (rPFS) was 36 weeks. Samples for measurement of baseline androgens were available in 37 patients. The PSA response proportion was 59% in 29 patients with DHEA ≥ limit of quantitation (LOQ), compared with 13% in 8 patients with DHEA < LOQ (P = 0.042). Median PFS was 6 and 16 weeks in DHEA < LOQ and DHEA ≥ LOQ patients, respectively (P = 0.017); median rPFS was 14 and 36 weeks in DHEA < LOQ and DHEA ≥ LOQ patients, respectively (P < 0.001).. Abiraterone demonstrates modest clinical efficacy in mCRPC patients previously treated with ketoconazole. Patients with DHEA ≥ LOQ were more likely to demonstrate PSA responses and longer PFS. Analysis of circulating androgens merits further investigation as a biomarker for response to androgen synthesis inhibitor therapy.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgens; Androstenes; Humans; Ketoconazole; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retreatment; Steroid Synthesis Inhibitors; Treatment Outcome

Abiraterone acetate plus prednisone significantly improves radiographic progression-free survival in asymptomatic or mildly symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer compared with prednisone alone. We describe analyses of data for patient-reported pain and functional status in a preplanned interim analysis of a phase 3 trial.. Between April 28, 2009, and June 23, 2010, patients with progressive, metastatic castration-resistant prostate cancer were enrolled into a multinational, double-blind, placebo-controlled trial. Patients were eligible if they were asymptomatic (score of 0 or 1 on item three of the Brief Pain Inventory Short Form [BPI-SF] questionnaire) or mildly symptomatic (score of 2 or 3) and had not previously received chemotherapy. Patients were randomly assigned (1:1) to receive oral abiraterone (1 g daily) plus prednisone (5 mg twice daily) or placebo plus prednisone in continuous 4-week cycles. Pain was assessed with the BPI-SF questionnaire, and health-related quality of life (HRQoL) with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. We analysed data with prespecified criteria for clinically meaningful pain progression and deterioration in HRQoL. All patients who underwent randomisation were included in analyses.. 1088 patients underwent randomisation: 546 were assigned to abiraterone plus prednisone and 542 to placebo plus prednisone. At the time of the second prespecified interim analysis, median follow-up was 22·2 months (IQR 20·2-24·8). Median time to progression of mean pain intensity was longer in patients assigned to abiraterone plus prednisone (26·7 months [95% CI 19·3-not estimable]) than in those assigned to placebo plus prednisone (18·4 months [14·9-not estimable]; hazard ratio [HR] 0·82, 95% CI 0·67-1·00; p=0·0490), as was median time to progression of pain interference with daily activities (10·3 months [95% CI 9·3-13·0] vs 7·4 months [6·4-8·6]; HR 0·79, 95% CI 0·67-0·93; p=0·005). Median time to progression of worst pain was also longer with abiraterone plus prednisone (26·7 months [95% CI 19·4-not estimable]) than with placebo plus prednisone (19·4 months [16·6-not estimable]), but the difference was not significant (HR 0·85, 95% CI 0·69-1·04; p=0·109). Median time to HRQoL deterioration was longer in patients assigned to abiraterone plus prednisone than in those assigned to placebo plus prednisone as assessed by the FACT-P total score (12·7 months [95% CI 11·1-14·0] vs 8·3 months [7·4-10·6]; HR 0·78, 95% CI 0·66-0·92; p=0·003) and by the score on its prostate-cancer-specific subscale (11·1 months [8·6-13·8] vs 5·8 months [5·5-8·3]; HR 0·70, 95% CI 0·60-0·83; p<0·0001).. Abiraterone plus prednisone delays patient-reported pain progression and HRQoL deterioration in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. These results provide further support for the efficacy of abiraterone in this population.

Topics: Abiraterone Acetate; Activities of Daily Living; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Australia; Canada; Cost of Illness; Disease Progression; Double-Blind Method; Drug Administration Schedule; Europe; Humans; Kaplan-Meier Estimate; Male; Pain; Pain Measurement; Prednisone; Proportional Hazards Models; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Surveys and Questionnaires; Time Factors; Treatment Outcome; United States

On December 10, 2012, the U.S. Food and Drug Administration granted full approval for a modified indication for abiraterone acetate (Zytiga tablets; Janssen Biotech, Inc.) in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). The approval was based on clinical trial COU-AA-302, which randomly allocated asymptomatic or mildly symptomatic patients with chemotherapy-naïve mCRPC and no visceral metastases to either abiraterone acetate plus prednisone (N = 546) or placebo plus prednisone (N = 542). The coprimary endpoints were radiographic progression-free survival (rPFS) and overall survival (OS). The median rPFS was 8.3 months in the placebo arm and had not yet been reached in the abiraterone acetate arm {HR, 0.43 [95% confidence interval (CI) 0.35-0.52]; P < 0.0001}. A prespecified interim analysis demonstrated an improvement in OS favoring the abiraterone acetate arm [HR, 0.79 (95% CI, 0.66-0.96)] but did not cross the O'Brien-Fleming boundary for statistical significance. Safety data confirmed the known adverse reaction profile of abiraterone acetate. Full approval was granted on the basis of a large magnitude of effect on rPFS, a favorable trend in OS, and internal consistency across multiple secondary endpoints and exploratory patient-reported pain data. This is the first drug approval for mCRPC to use rPFS as the primary endpoint. Importantly, this approval was granted in the context of a prior statistically significant OS benefit that formed the basis of the original April 28, 2011, approval of abiraterone acetate for patients with mCRPC who had received prior chemotherapy containing docetaxel.

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Drug Approval; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome; United States; United States Food and Drug Administration

Prostate cancer (PC) is the most common type of neoplasm in men and the fourth leading cause of mortality in Brazil. The prostate cancer refractory metastatic castration can be treated with abiraterone acetate (AA).. Its use has been associated with increased survival. However, there are also side effects associated with the use of this drug, such as severe electrolyte disturbances.. The objective is to report the clinical case of a patient with castration-resistant metastatic prostate cancer who developed ascending flaccid paralysis secondary to severe hypokalemia, probably due to hyperaldosteronism secondary to the use of Abiraterone Acetate, despite the use of Prednisone.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Hypokalemia; Male; Paralysis; Prednisone; Prostatic Neoplasms, Castration-Resistant

Comorbid diseases influence patient outcomes, yet little is known about how comorbidities interact with treatments for metastatic castrate-resistant prostate cancer (mCRPC). No head-to-head trials have compared the efficacy of abiraterone and enzalutamide - oral androgen-receptor targeted agents (ARTAs) for mCRPC. In patients with comorbid disease, outcomes with ARTAs may differ due to disparate mechanisms of action, adverse events, and drug interactions.. Retrospective observational study of US veterans initiating treatment for mCRPC with abiraterone or enzalutamide between September 2014 and June 2017. Treatment duration and overall survival (OS) was compared based on age and comorbid diseases. The association between ARTA and OS was assessed using Cox proportional hazards and propensity-score matched modeling while adjusting for potential confounders. Sensitivity analyses were performed based on patient age, comorbidities, and subsequent treatments for mCRPC.. Of 5822 veterans treated for mCRPC, 43.0% initially received enzalutamide and 57.0% abiraterone. Veterans initially treated with enzalutamide versus abiraterone were older (mean 75.8 vs. 75.0 years) with higher mean Charlson comorbidity index (4.4 vs. 4.1), and higher rates of cardiovascular disease or diabetes (74.2% vs. 70.6%). In the entire population, veterans initially treated with enzalutamide had longer median OS compared to those initially treated with abiraterone (24.2 vs. 22.1 months, p = 0.001). In veterans with cardiovascular disease or diabetes, median treatment duration with enzalutamide was longer (11.4 vs. 8.6 months, p < 0.001) with longer median OS compared to abiraterone (23.2 vs. 20.5 months, p < 0.001). In a propensity score matched cohort, enzalutamide was associated with decreased mortality compared to abiraterone (HR 0.90, 95% CI 0.84-0.96).. Veterans with cardiovascular disease or diabetes had longer treatment duration and OS with enzalutamide compared to abiraterone. Further study of ARTA selection may benefit men with metastatic castrate resistant prostate cancer and likely hormone sensitive prostate cancer, especially among patients with comorbid diseases.

Topics: Abiraterone Acetate; Cardiovascular Diseases; Diabetes Mellitus; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome; Veterans

The surgical timing after neoadjuvant androgen-deprivation therapy (ADT) plus abiraterone acetate (AA) for patients with locally advanced or metastatic prostate cancer (PCa) is unknown. We divided patients with locally advanced or metastatic PCa into three groups according to prostate-specific antigen (PSA) nadir after neoadjuvant ADT plus AA: group 1 (PSA ≤ 0.2 ng/ml), group 2 (0.2 < PSA ≤ 4.0 ng/ml), and group 3 (PSA > 4.0 ng/ml).The median PSA baseline levels in groups 1, 2, 3 were 118.42 (32.03-457.78), 143.48 (17.7-8100.16), and153.35 (46.44-423.31) ng/ml, respectively. The median times of progression to CRPC in groups 1, 2,and 3 were 30, 26, and 26 months, respectively. Compared to patients with PSA nadir >0.2 ng/ml, patients with PSA nadir <0.2 ng/ml presented with longer PFS (p = 0.048).Our results suggested that, in patients with locally advanced or metastatic PCa, the time to progression to CRPC was longer after radical prostatectomy when PSA decreased below 0.2 ng/ml using neoadjuvant ADT plus AA.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Humans; Male; Neoadjuvant Therapy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

The clinicopathologic data of 106 mCRPC cases receiving AA treatment were retrospectively analyzed. Logistic regression analysis was used to determine the independent predictors of biochemical response to AA treatment. Cox analyses were applied to investigate the independent prognostic factors for time to biochemical progression (TTBP) and radiological progression-free survival (rPFS). Survival analysis and ROC curve were also used.. Low PSMA-TV, low TLR were vital independent predictors of biochemical response to AA treatment and were associated with preferable prognosis in mCRPC patients. Combining ADT duration, PSMA-TV and TLR performed well in distinguishing AA responders from non-responders in mCRPC patients.

Topics: Abiraterone Acetate; Castration; Hormones; Humans; Male; Positron Emission Tomography Computed Tomography; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome; Tumor Burden

We assessed the impact of plasma trough concentrations of abiraterone (ABI) and its metabolite Δ4-abiraterone (D4A) and related polymorphisms on adverse events (AEs) in patients with metastatic prostate cancer who received abiraterone acetate (AA).. This prospective study enrolled patients with advanced prostate cancer treated with AA between 2016 and 2021. Plasma trough concentrations of ABI and D4A were measured using high-performance liquid chromatography. The impact of HSD3B1 rs1047303, SRD5A2 rs523349, and cytochrome P450 family 3A member 4 rs2242480 polymorphisms on plasma concentrations of ABI and D4A and the incidence of AEs were also assessed.. In 68 patients treated with AA, the median ABI and D4A concentrations were 18.1 and 0.94 ng/mL, respectively. The high plasma trough concentration of ABI (≥ 20.6 ng/mL) was significantly associated with the presence of any AE and its independent risk factor based on multivariable analysis (odds ratio, 7.20; 95% confidence interval (CI): 2.20-23.49). Additionally, a high plasma trough concentration of ABI was an independent risk factor of time to withdraw AA (hazard ratio, 4.89; 95% CI: 1.66-14.38). The risk alleles of three polymorphisms were not statistically associated with the ABI and D4A concentrations and the incidence of AEs.. The plasma trough concentration of ABI is associated with the presence of AEs and treatment failure after AA administration. ABI concentration monitoring may be useful in patients with prostate cancer who received AA.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Membrane Proteins; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

The neuroendocrine (NE) pathway cannot be ignored as a mechanism for castration-resistant prostate cancer (CRPC) progression. The neuromediator, gastrin-releasing peptide (GRP) may be involved in the aberrant activation of the normal androgen receptor (AR) and increased AR variants. This study focused on plasma levels of progastrin-releasing peptide (ProGRP) and examined the treatment outcomes with androgen receptor axis-targeted (ARAT) agents.. One hundred patients with metastatic CRPC were enrolled. Enzalutamide (ENZ) or abiraterone acetate/prednisone (AA/P) were administered to 50 patients each in a nonrandomized manner as a first-line or later choice. Plasma ProGRP levels were determined using a chemiluminescent enzyme immunoassay, and data were collected prospectively. The study endpoints were prostate-specific antigen (PSA) response and survival estimates.. In the ENZ series, ProGRP levels correlated with the maximum PSA change from baseline (high ProGRP: -34.5% vs. low ProGRP: -85.7% p = .033). PSA progression-free survival (PFS), radiographic/symptomatic (r/s) PFS, and overall survival (OS) in patients with high ProGRP were significantly worse than those in patients with low ProGRP (median PSA-PFS: 3.3 vs. 10.0 months, p = .001, r/s PFS: 5.0 vs. 15.0 months, p < 0.001, and OS 17.5 vs. 49.0 months, p < .001, respectively). In addition, ProGRP showed an independent predictive value for all survival estimates in multivariate analyses. In the AA/P series, ProGRP levels did not correlate with the PSA change or predict PSA-PFS and r/s PFS, but they maintained a significant difference in OS (19.0 vs. 48.0 months, p = .003).. Plasma ProGRP provides a consistent predictive value for OS in metastatic CRPC patients who underwent therapy with ARAT agents. Meanwhile, ProGRP showed different predictive profiles for PSA- and r/s PFS between ENZ and AA/P. These findings clinically suggest a mechanism for CRPC progression involving the NE pathway via the GRP. The underlying mechanism of different predictive profiles by the ARAT agent should be explored in future research.

Topics: Abiraterone Acetate; Antineoplastic Agents; Humans; Male; Peptides; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

Enzalutamide (ENZ) and abiraterone acetate with prednisone (AAP) represent novel hormonal therapies used in the treatment of metastatic castration-resistant prostate cancer (mCRPC). The aim of the study was to assess the long-term outcome of mCRPC patients treated with ENZ or AAP in real-life clinical practice.. The outcomes of 337 mCRPC patients treated with ENZ or AAP were retrospectively analysed.. Median radiographic progression-free (rPFS) and overall survival (OS) of patients treated in the first line (pre-chemotherapy) was 13.89 (95% CI=12.40-16.80) and 31.02 (95% CI=24.27-37.44) months vs. 10.97 (95% CI=8.97-14.82) and 26.57 (95% CI=15.97-33.92) months for those treated in the second line (post-chemotherapy). We found inferior survival for patients with synchronous metastases, high Gleason score (GS) and visceral metastases.. The efficacy of both ENZ and AAP in mCRPC patients is herein confirmed. Synchronous metastases, high GS and visceral metastases were identified as significant adverse prognostic factors.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Nitriles; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Topics: Abiraterone Acetate; Genes, BRCA1; Genes, BRCA2; Humans; Indoles; Male; Mutation; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

We aimed to develop and validate a plasma extracellular vesicle circular RNA (circRNA)-based signature that can predict overall survival (OS) in first-line abiraterone therapy for metastatic castration-resistant prostate cancer (mCRPC) patients.. In total, 582 mCRPC patients undergoing first-line abiraterone therapy from four institutions were sorted by three phases. In the discovery phase, 30 plasma samples from 30 case-matched patients with or without early progression were obtained to generate circRNA expression profiles using RNA sequencing. In the training phase, differentially expressed circRNAs were examined using digital droplet PCR in a training cohort (n = 203). The circRNA signature was constructed using a least absolute shrinkage and selection operator Cox regression to predict OS. In the validation phase, the prognostic ability of this signature was prospectively validated in two external cohorts (Cohort I, n = 183; Cohort II, n = 166).. We developed a five-circRNA signature, based on circCEP112, circFAM13A, circBRWD1, circVPS13C and circMACROD2, which successfully stratified patients into high-risk and low-risk groups. The prognostic ability of this signature was prospectively validated in two external cohorts (P < 0.0001, P < 0.0001). Patients with high-risk scores had shorter OS than patients with low-risk scores.. This five-circRNA signature is a reliable predictor of OS for mCRPC patients undergoing abiraterone.

Topics: Abiraterone Acetate; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; RNA, Circular; Treatment Outcome

Metastatic castration-resistant prostate cancer remains a challenging condition to treat. Among the available therapeutic options, the androgen receptor signaling inhibitors abiraterone acetate plus prednisone (AA) and enzalutamide (Enza), are currently the most used first-line therapies in clinical practice. However, validated clinical indicators of prognosis in this setting are still lacking. In this study, we aimed to evaluate a prognostic model based on the time of metastatic disease presentation (after prior local therapy [PLT] or de-novo [DN]) and disease burden (low volume [LV] or high-volume [HV]) at AA/Enza onset for mCRPC patients receiving either AA or Enza as first-line.. A cohort of consecutive patients who started AA or Enza as first-line treatment for mCRPC between January 1st, 2015, and April 1st, 2019 was identified from the clinical and electronic registries of the 9 American and European participating centers. Patients were classified into 4 cohorts by the time of metastatic disease presentation (PLT or DN) and volume of disease (LV or HV; per the E3805 trial, HV was defined as the presence of visceral metastases and/or at least 4 bone metastases of which at least 1 out the axial/pelvic skeleton) at AA/Enza onset. The endpoint was overall survival defined as the time from AA or Enza initiation, respectively, to death from any cause or censored at the last follow-up visit, whichever occurred first.. Of the 417 eligible patients identified, 157 (37.6%) had LV/PLT, 87 (20.9%) LV/DN, 64 (15.3%) HV/PLT, and 109 (26.1%) HV/DN. LV cohorts showed improved median overall survival (59.0 months; 95% CI, 51.0-66.9 months) vs. HV cohorts (27.5 months; 95% CI, 22.8-32.2 months; P = 0.0001), regardless of the time of metastatic presentation. In multivariate analysis, HV cohorts were confirmed associated with worse prognosis compared to those with LV (HV/PLT, HR = 1.87; p = 0.029; HV/DN, HR = 2.19; P = 0.002).. Our analysis suggests that the volume of disease could be a prognostic factor for patients starting AA or Enza as first-line treatment for metastatic castration-resistant prostate cancer, pending prospective clinical trial validation.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Nitriles; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

To investigate the predictive value of body composition parameters for biochemical response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) patients with prior chemohormonal therapy.. We retrospectively evaluated the clinicopathologic information of 132 mCRPC cases receiving AA treatment after chemohormonal therapy at hormone-sensitive stage from July 2018 to June 2021. All patients were divided into AA responders and non-responders according to the biochemical response to AA (prostate-specific antigen (PSA) reduction ≥50% than pretreatment). Multivariate Logistic analysis was used to determine the independent predictors and develop predictive model of biochemical response to AA. Cox regression analysis was utilized to investigate the prognostic factors for time to biochemical progression (TTBP), radiological progression-free survival (rPFS), failure-free survival (FFS), and overall survival (OS) after AA treatment.. There were 57 AA responders and 75 AA non-responders. Periprostatic fat area/prostate area (PPFA/PA) was decreased and skeletal muscle index (SMI) was increased in AA responders compared with AA non-responders. Multivariable logistic analysis demonstrated that ADT duration ≥12 months, bone metastasis only, high SMI and low PPFA/PA were independent predictors of biochemical response to AA treatment. The FFS, TTBP, rPFS, and OS of patients with lower SMI or higher PPFA/PA was decreased compared with that of patients with higher SMI or lower PPFA/PA, respectively. Combining SMI, PPFA/PA, ADT duration and metastatic sites performed well in differentiating AA responders from non-responders.. High SMI and low PPFA/PA could predict biochemical response to AA treatment and preferable prognosis in mCRPC patients with prior chemohormonal therapy at hormone-sensitive stage.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Hormones; Humans; Male; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Cardiovascular conditions are the most prevalent comorbidity among patients with prostate cancer, regardless of treatment. Additionally, cardiovascular risk has been shown to increase following exposure to certain treatments for advanced prostate cancer. There is conflicting evidence on risk of overall and specific cardiovascular outcomes among men treated for metastatic castrate resistant prostate cancer (CRPC). We, therefore, sought to compare incidence of serious cardiovascular events among CRPC patients treated with abiraterone acetate plus predniso(lo)ne (AAP) and enzalutamide (ENZ), the two most widely used CRPC therapies.. Using US administrative claims data, we selected CRPC patients newly exposed to either treatment after August 31, 2012, with prior androgen deprivation therapy (ADT). We assessed incidence of hospitalization for heart failure (HHF), ischemic stroke, and acute myocardial infarction (AMI) during the period 30-days after AAP or ENZ initiation to discontinuation, outcome occurrence, death, or disenrollment. We matched treatment groups on propensity-scores (PSs) to control for observed confounding to estimate the average treatment effect among the treated (AAP) using conditional Cox proportional hazards models. To account for residual bias, we calibrated our estimates against a distribution of effect estimates from 124 negative-control outcomes.. The HHF analysis included 2322 (45.1%) AAP initiators and 2827 (54.9%) ENZ initiators. In this analysis, the median follow-up times among AAP and ENZ initiators (after PS matching) were 144 and 122 days, respectively. The empirically calibrated hazard ratio (HR) estimate for HHF was 2.56 (95% confidence interval [CI]: 1.32, 4.94). Corresponding HRs for AMI and ischemic stroke were 1.94 (95% CI: 0.90, 4.18) and 1.25 (95% CI: 0.54, 2.85), respectively.. Our study sought to quantify risk of HHF, AMI and ischemic stroke among CRPC patients initiating AAP relative to ENZ within a national administrative claims database. Increased risk for HHF among AAP compared to ENZ users was observed. The difference in myocardial infarction did not attain statistical significance after controlling for residual bias, and no differences were noted in ischemic stroke between the two treatments. These findings confirm labeled warnings and precautions for AAP for HHF and contribute to the comparative real-world evidence on AAP relative to ENZ.

Topics: Abiraterone Acetate; Androgen Antagonists; Humans; Ischemic Stroke; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Despite the widespread availability of medication choices for metastatic castration-resistant prostate cancer (mCRPC), biomarkers to predict the efficacy of each mCRPC treatment have not yet been established. This study developed a prognostic nomogram and a calculator to predict the prognosis of patients with mCRPC who received abiraterone acetate (ABI) and/or enzalutamide (ENZ).. In total, 568 patients with mCRPC who underwent ABI and/or ENZ between 2012 and 2017 were enrolled. A prognostic nomogram based on the risk factors was developed using the Cox proportional hazards regression model and clinically important factors. The discriminatory ability of the nomogram was assessed according to the concordance index (C-index). A 5-fold cross-validation was repeated 2000 times to estimate the C-index, and the means of the estimated C-index for the training and validation sets were determined. A calculator based on this nomogram was then developed.. The median overall survival (OS) was 24.7 months. Multivariate analysis showed that the time to CRPC, pre-chemotherapy, baseline prostate-specific antigen, baseline alkaline phosphatase, and baseline lactate dehydrogenase levels were independent risk factors for OS (hazard ratio [HR]: 0.521, 1.681, 1.439, 1.827, and 12.123, p = 0.001, 0.001,  < 0.001, 0.019, and  < 0.001, respectively). The C-index was 0.72 in the training cohort and 0.71 in the validation cohort.. We developed a nomogram and calculator to predict OS in Japanese patients with mCRPC who received ABI and/or ENZ. Reproducible prognostic prediction calculators for mCRPC will facilitate greater accessibility for clinical use.

Topics: Abiraterone Acetate; Benzamides; Humans; Male; Nomograms; Prostatic Neoplasms, Castration-Resistant

Patients with metastatic castration-resistant prostate cancer (mCRPC) are divided into three groups based on their response to Abiraterone treatment: best responder, responder, and non-responder. In the latter two groups, successful outcomes may not be achieved due to the development of drug-resistant cells in the tumor environment during treatment. To overcome this challenge, a secondary drug can be used to control the population of drug-resistant cells, potentially leading to a longer period of disease inhibition. This paper proposes using a combination of Docetaxel and Abiraterone in some polytherapy methods to control both the overall cancer cell population and the drug-resistant subpopulation. To investigate the competition and evolution of mCRPC cancer phenotypes, as in previous studies, the Evolutionary Game Theory (EGT) has been used as a mathematical modeling of evolutionary biology concepts.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Topics: Abiraterone Acetate; Antineoplastic Agents; Drug Approval; Humans; Male; Prostatic Neoplasms, Castration-Resistant

Elevated serum chromogranin A (CGA) is associated with intrinsic or treatment-related neuroendocrine differentiation (NED) in men with metastatic castration-resistant prostate cancer (mCRPC). Fluctuations in serum CGA during treatment of mCRPC have had conflicting results. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with abiraterone acetate (AA) therapy.. Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial with uniform serum CGA processing performed before initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded), therefore 71 patients were analyzed. All patients underwent a composite response assessment at 12-weeks. Kaplan-Meier estimates and Cox Regression models were used to calculate the association with time-to-treatment failure analyses and overall survival.. An increase in chromogranin was associated with a lower risk of treatment failure (hazard ratio [HR]: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6-16.0) and an elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). An increase in CGA was not found to be associated with OS (HR: 0.71, 95% CI: 0.42-1.21, p = 0.207). An elevated baseline CGA/PSA ratio was not associated with OS (HR: 0.62, 95% CI: 0.37-1.03, p = 0.062). An increase in PSA after 12 weeks of treatment was associated with an increased risk of treatment failure (HR: 4.14, CI: 2.21-7.73, p = < 0.0001) and worse OS (HR: 2.93, CI: 1.57-4.45, p = < 0.0001).. We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in patients with mCRPC were associated with a favorable response to AA/P with no changes in survival. There may be limited clinical utility in serum CGA testing to evaluate for lethal NED as AA/P did not induce lethal NED in this cohort. This highlights that not all patients with an increasing CGA have a worse OS.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Chromogranin A; Chromogranins; Humans; Male; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Abiraterone Acetate (AA) is an important agent in the treatment of advanced prostate cancer. It was primarily approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) after failure of androgen deprivation therapy. There is still no available strong data regarding the impact of early decline of prostate-specific antigen (PSA) in the overall survival. The aim of this study was to evaluate the clinical efficacy of an early prostate-specific antigen response as a predictor of overall survival (OS) in metastatic castration-resistant prostate cancer when treated with Abiraterone Acetate.. A dual center, retrospective, cohort study on patients diagnosed with mCRPC treated with abiraterone between 2013 and 2020 was performed. Primary end-point was to demonstrate the efficacy of AA, with the analysis of PSA decline, and the correlation with overall survival.. The cohort analysis consisted of 84 patients with a median age of 71 ± 9 years. A PSA response of > 30% and > 50% at 60 and 90 days was associated with improved OS. Multivariate analysis revealed that a 60 day PSA decline of > 30% was predictive of overall survival. Median OS of diag-nosed mCRPC patients was 28 months. Docetaxel pre-treatment was not associated with longer OS. The median duration of drug exposure for patients submitted to AA was found to be 14 months.. Early PSA response rate can offer clinically meaningful information and can be considered a surrogate of longer OS. A > 30% or > 50% prostate-specific antigen decline at 60 and 90 days provided an important low-cost clinical tool to predict subsequent events in mCRPC patients treated with abiraterone.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Cohort Studies; Disease-Free Survival; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

We present long-term outcomes from 2 randomized studies [STAMP (with abiraterone, NCT01487863) and STRIDE (with enzalutamide, NCT01981122)] that were performed to study the impact of sequential or concurrent administration of androgen receptor-targeting agents (ARTAs) on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC).. Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan-Meier methodology was used to analyze survival.. Updated data reduced patient censoring in each study compared with the original analyses; the 95% confidence intervals (CIs) for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1-40.7) months for STAMP and 32.5 (26.0-45.1) months for STRIDE. There was no notable impact on median OS [HR, 0.727 (0.458-1.155); P = 0.177, reference = STRIDE]. OS with sequential administration was similar to concurrent administration [NDI update: HR, 0.963 (0.639-1.453); P = 0.845, reference = concurrent arm]. Sipuleucel-T potency, measured as antigen-presenting cell (APC) activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated versus baseline. No new safety signals were observed.. Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.

Topics: Abiraterone Acetate; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Tissue Extracts; Treatment Outcome

Deep prostate-specific antigen (PSA) response (≥90% reduction in PSA [PSA90]) is an important early response indicator of radiographic progression-free survival and overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC). This study compared PSA90 responses by 6 months between patients with mCSPC at first use of apalutamide or abiraterone acetate, both androgen receptor signaling inhibitors.. Clinical data from 77 community urology practices in the United States were analyzed. Patients with mCSPC were classified into treatment cohorts based on their first filled prescription (index date) for apalutamide or abiraterone acetate on or after September 17, 2019 (approval date of apalutamide for mCSPC). Patients were followed from the index date until the earliest of index treatment discontinuation, treatment switch, end of clinical activity, or end of data availability (September 17, 2021). Inverse probability of treatment weighting (IPTW) was used to ensure similarity in distribution of baseline characteristics between cohorts. PSA90 was defined as the earliest attainment of ≥90% reduction in PSA relative to baseline (most recent value within 13 weeks pre-index). Time to PSA90 between cohorts was compared by weighted Kaplan-Meier analysis and with Cox proportional hazards models.. A total of 364 patients treated with apalutamide and 147 treated with abiraterone acetate met the study criteria. Patient characteristics were well balanced after IPTW. By 6 months post-index, patients initiated on apalutamide were 53% more likely to achieve PSA90 than those initiated on abiraterone acetate (P = 0.016). Similar results were observed by 9 and 12 months post-index (both P ≤ 0.019). The median time to PSA90 was 3.5 months for the apalutamide cohort and not reached for the abiraterone acetate cohort.. In real-world patients with mCSPC, significantly more patients achieved PSA90 with apalutamide than with abiraterone acetate, and this response was achieved earlier with apalutamide.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Castration; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Visceral metastasis (VM) and a higher number of bone metastasis generally define high volume/risk in patients with metastatic castration-sensitive prostate cancer (mCSPC). Subgroup analysis of pivotal trials did not show a clear benefit of second-generation non-steroidal anti-androgens (NSAAs) in patients with VM. However, subgroup analysis of the trial assessing abiraterone acetate, a CYP 17 inhibitor, plus prednisone (AAP) showed an improved overall survival (OS) in patients with mCSPC with VM. We searched MEDLINE, Web of Science, and congress abstracts for the phase III randomized controlled trials of second-generation NSAAs and AAP in patients with mCSPC. In this pooled analysis, we included 6485 patients from the 6 phase III trials. The rate of patients with VM was 15.2%. Interestingly, in contrast to NSAAs, AAP seems to be effective in improving OS among patients with VM (hazard ratio, HR: 0.89, 95% CI, 0.72-1.11, P = .30 for second-generation NSAAs; HR: 0.58, 95% CI, 0.40-0.84, P = .004 for AAP). In contrast, both second-generation NSAAs (HR: 0.63, 95% CI, 0.57-0.70, P < .001) and AAP (HR: 0.68, 95% CI, 0.57-0.81, P < .001) improved OS in patients without VM. In this pooled analysis, we demonstrate that while AAP provided an OS improvement in patients with VM, second-generation NSAAs did not demonstrate a similar OS benefit in this population.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Castration; Humans; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

The availability of oral therapies for advanced prostate cancer allows urologists to continue to care for their patients who develop castration resistance. We compared the prescribing practices of urologists and medical oncologists in treating this patient population.. The Medicare Part D Prescribers data sets were utilized to identify urologists and medical oncologists who prescribed enzalutamide and/or abiraterone from 2013 to 2019. Each physician was assigned to one of 2 groups: enzalutamide prescriber (physicians that wrote more 30-day prescriptions for enzalutamide than abiraterone) or abiraterone prescriber (opposite). We ran a generalized linear regression to determine factors influencing prescribing preference.. There are dramatic prescribing differences between urologists and medical oncologists. A greater understanding of these differences is a health care imperative.

Topics: Abiraterone Acetate; Aged; Humans; Male; Medicare Part D; Oncologists; Prostatic Neoplasms, Castration-Resistant; United States; Urologists

This study aimed to highlight the comprehensive differences in adverse events between abiraterone and enzalutamide based on a big data data set.. We downloaded adverse event data sets of abiraterone and enzalutamide from the Food and Drug Administration Adverse Event Reporting System database. We used the Medical Dictionary for Regulatory Activities to treat each adverse event as a preferred term and grouped it into the System Organ Class. Logistic regression analyses were performed to compare abiraterone and enzalutamide.. In total, we extracted 59,680 data sets. After exclusion by criteria, we included 26,015 reports on enzalutamide and 7,507 on abiraterone. Enzalutamide and abiraterone presented different toxicity profiles in most System Organ Classes. Overall, the reporting odds ratio indicated a higher incidence rate of serious adverse events for abiraterone than enzalutamide.. In conclusion, our findings suggest that both drugs present a discrete and nonoverlapping toxicity profile that varies by System Organ Class and patient age. This data set confirms, for the most part, what has been reported in clinical trials as well as true real-world reports.

Topics: Abiraterone Acetate; Benzamides; Humans; Male; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Indazoles; Male; Piperidines; Prednisone; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Drug Approval; Humans; Male; Mutation; Prednisone; Prostatic Neoplasms, Castration-Resistant

Using large French retrospective study cohort of chemotherapy-naïve metastatic castration-resistant prostate cancer patients (mCRPC; n = 10,308) comparing survival between patients who initiated abiraterone (ABI; 64%) and those initiating enzalutamide (ENZ; 36%), the present objective was to describe treatment patterns in the 2 years following initiation.. Using the national health data system (SNDS) from 2014 to 2018, we first explored the number of treatment lines, and secondly, patterns of patient management using state sequence analysis; cluster analyses were performed on the 0 to 12 month and 13 to 24 month periods. Age, Charlson score, and duration of androgen deprivation therapy (ADT) were obtained for each cluster in the first year of follow-up.. Patients with only 1 treatment line accounted for 52%. In the 0 to 12 month sequence analysis, the main clusters among ABI/ENZ new users involved patients who continued the initial treatment (54% of 65% respectively) and discontinued active treatment (14.5% for both). Less than 2 years exposure to ADT prior to ABI/ENZ initiation was frequently observed for noncontrolled mCRPC, as shown in the death and switch from ABI/ENZ to docetaxel clusters. The clusters for a switch ABI/ENZ to ENZ/ABI involved 6% to 11% of the patients.. Our study suggested fairly similar patterns between ABI and ENZ initiation. The cluster of patients with active treatment discontinuation needs to be further investigated, as well as factors influencing therapeutic choice. Better understanding for the use of second-generation hormone therapy in mCRPC in real life, could improve its implementation by clinicians in the early stages of prostate cancer.

Topics: Abiraterone Acetate; Androgen Antagonists; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Prostate cancer (PCa) is one of the most common malignancies among men worldwide. Inevitably, all advanced PCa patients develop metastatic castration-resistant prostate cancer (mCRPC), an aggressive phase of the disease. Treating mCRPC is challenging, and prognostic tools are needed for disease management. MicroRNA (miRNA) deregulation has been reported in PCa, constituting potential non-invasive prognostic biomarkers. As such, this study aimed to evaluate the prognostic potential of nine miRNAs in the liquid biopsies (plasma) of mCRPC patients treated with second-generation androgen receptor axis-targeted (ARAT) agents, abiraterone acetate (AbA) and enzalutamide (ENZ). Low expression levels of miR-16-5p and miR-145-5p in mCRPC patients treated with AbA were significantly associated with lower progression-free survival (PFS). The two miRNAs were the only predictors of the risk of disease progression in AbA-stratified analyses. Low miR-20a-5p levels in mCRPC patients with Gleason scores of <8 were associated with worse overall survival (OS). The transcript seems to predict the risk of death regardless of the ARAT agent. According to the in silico analyses, miR-16-5p, miR-145-5p, and miR-20a-5p seem to be implicated in several processes, namely, cell cycle, proliferation, migration, survival, metabolism, and angiogenesis, suggesting an epigenetic mechanism related to treatment outcome. These miRNAs may represent attractive prognostic tools to be used in mCRPC management, as well as a step further in the identification of new potential therapeutic targets, to use in combination with ARAT for an improved treatment outcome. Despite the promising results, real-world validation is necessary.

Topics: Abiraterone Acetate; Cohort Studies; Humans; Male; MicroRNAs; Nitriles; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

This research work was aimed at evaluating the incidence and risk factors of adverse events (AEs) occurring in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials. These associations were assessed regarding the survival outcomes.. The study included 191 patients aged ≥18 years of confirmed metastatic castration-resistant prostate cancer (mCRPC) between March 2017 and April 2022. AE incidences were descriptively summarized from the whole cohort. Baseline characteristics, safety (treatment-emergent AEs and severe AEs), and efficacy [progression-free survival (PFS)] were analyzed. Multi-variable Cox proportional hazards models were employed to assess the factors linked with PFS.. AA is effective and tolerated in asymptomatic or slightly symptomatic mCRPC in "real-life" setting. The survival outcomes are influenced by multiple organ metastasis, hypertension, and radiotherapy.

Topics: Abiraterone Acetate; Adolescent; Adult; Humans; Hypertension; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

To investigate the survival outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line novel androgen receptor axis-targeted therapies (ARATs) and prognostic factors for patient survival.. This retrospective study obtained data from 202 patients who started abiraterone acetate or enzalutamide as first-line therapy for mCRPC between 2016 and 2021 from a single academic center. The primary endpoint was overall survival (OS) defined as the interval from the start of ARAT to death, loss to follow-up, or the end of the study period. The secondary endpoints were PSA decline, PSA nadir, and time to nadir (TTN) after ARATs. Kaplan-Meier survival analyses were applied for depicting OS. Cox proportional hazards model with inversed probability of treatment weighing-adjustment was used to validate the effect of patient, disease, and treatment response factors on OS.. Among 202 patients, 164 patients were treated with first-line ARATs alone and 38 patients received second-line chemotherapy. The median OS was not reached in patients with first-line ARATs alone and was 38.8 months in those with subsequent chemotherapy after failure from ARATs. OS was not different between the use of abiraterone and enzalutamide, though enzalutamide showed a higher rate of PSA decline ≧ 90% (56% versus 40%, p = 0.021) and longer TTN (5.5 versus 4.7 months, p = 0.019). Multivariable analysis showed that PSA nadir > 2 ng/mL [hazard ratio (HR) 7.04, p < 0.001] and TTN<7 months (HR 2.18, p = 0.012) were independently associated with shorter OS. Patients with both of these poor prognostic factors had worse OS compared to those who had 0-1 factors (HR 9.21, p < 0.001).. Patients with mCRPC who received first-line ARATs had better survival if they had a PSA nadir[Formula: see text]2 ng/mL or a TTN[Formula: see text]7 months. Further study is needed to determine if an early switch in therapy for those in whom neither is achieved may impact OS.

Topics: Abiraterone Acetate; Androgen Antagonists; Humans; Male; Nitriles; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Topics: Abiraterone Acetate; Humans; Male; Phenylthiohydantoin; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant

There is little evidence of abiraterone acetate (AA) plus prednisone for patients with non-metastatic castration-resistant prostate cancer (nmCRPC). In this study, we conducted a comparative analysis of real-world survival outcomes between AA plus prednisone and enzalutamide (Enz) in patients with nmCRPC, utilizing our consortium dataset.. The clinical records of 133 nmCRPC patients treated with first-line Enz or AA plus prednisone were analyzed. The primary endpoints of the study were overall survival (OS) and cancer-specific survival (CSS). Cumulative incidence function (CIF) using Fine and Gray models was also utilized to assess non-cancer-caused death considering the competing risk of cancer-caused death.. During a median follow-up of 36 months, 34 patients (25.6%) had deceased, with a median OS of 99 months in the entire cohort. There were no significant differences in comorbidities between the Enz and AA groups. Time to PSA progression (TTPP: HR 0.81, 95% CI 0.51-1.30, P = 0.375) and CSS (HR 1.32, 95% CI 0.55-3.44, P = 0.5141) were comparable between the two groups. However, intriguingly, there was a trend towards shorter OS in patients treated with AA plus prednisone compared to Enz (HR 0.57, 95% CI 0.29-1.12, P = 0.0978, median of 99 and 69 months in Enz and AA groups, respectively). CIF analysis revealed that nmCRPC patients treated with AA plus prednisone were more likely to result in non-cancer-caused death than those treated with Enz (HR 5.22, 95% CI 1.88-14.50, P = 0.0014).. Our real-world survival analysis suggests that while AA plus prednisone may demonstrate comparable treatment efficacy to Enz in the context of nmCRPC, there may be an increased risk of non-cancer-caused death. Physicians should take into consideration this information when making treatment decisions for patients with nmCRPC.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Phthalazines; Piperazines; Prednisone; Prostatic Neoplasms, Castration-Resistant

Regulatory authorities are recognizing the need for real-world evidence (RWE) as a complement to randomized controlled trials in the approval of drugs. However, RWE needs to be fit for regulatory purposes. There is an ongoing discussion regarding whether pre-publication of a protocol on appropriate repositories, e.g. ClinicalTrials.gov, would increase the quality of RWE or not. This paper illustrates that an observational study based on a pre-published protocol can entail the same level of detail as a protocol for a randomized experiment. The strategy is exemplified by designing a comparative effectiveness evaluation of abiraterone acetate against enzalutamide in clinical practice. These two cancer drugs are prescribed to patients with advanced prostate cancer. Two complementary designs, including pre-analysis plans, were published before data on outcomes and proxy-outcomes were obtained. The underlying assumptions are assessed and both analyses show an increased mortality risk from being prescribed abiraterone acetate compared to enzalutamide.

Topics: Abiraterone Acetate; Antineoplastic Agents; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Topics: Abiraterone Acetate; Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Pancreatitis; Prostatic Neoplasms, Castration-Resistant

Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice.. We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model.. Patients in the bicalutamide group were older, and more of them had poor performance status (≧2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p < 0.001). Median follow-up was 22.5 months for bicalutamide and 17 months for abiraterone (p < 0.001). Two-year OS and CSS for bicalutamide versus abiraterone was 77.8% versus 79.5% (p = 0.793) and 81.1% versus 82.5% (p = 0.698), respectively. Median time to CRPC was significantly longer in the abiraterone group than in the bicalutamide group (NA vs. 13 months, p < 0.001). In multivariate analysis, Gleason score ≧9, high alkaline phosphatase, high lactate dehydrogenase, liver metastasis, and bicalutamide were independent prognostic risk factors for time to CRPC. Abiraterone prolonged the time to CRPC in patients with each of these prognostic factors.. Despite limitations regarding the time-dependent bias, ADT with abiraterone acetate significantly prolonged the time to CRPC compared to bicalutamide in patients with high-risk mHSPC. However, further study with longer follow-up is needed.

Topics: Abiraterone Acetate; Androgen Antagonists; Anilides; Antineoplastic Combined Chemotherapy Protocols; Comparative Effectiveness Research; Humans; Japan; Liver Function Tests; Liver Neoplasms; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Nitriles; Nonsteroidal Anti-Androgens; Prednisolone; Prognosis; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Risk Assessment; Tosyl Compounds

Lay abstract Patients with metastatic castration-resistant prostate cancer are often first treated with novel hormonal therapy (NHT) using abiraterone or enzalutamide. To aid decisions about what treatment to use next, we reviewed information about patients who were treated with an alternative NHT (226 patients) or the nuclear medicine radium-223 (120 patients) after the first NHT. Most patients given radium-223 had cancer that had spread to their bones only, whereas many patients given an alternative NHT had cancer in their bones and other parts of their body. Around one in four patients given radium-223 and one in five given an alternative NHT had symptoms related to their bone metastases after starting treatment. Five in every ten patients given radium-223 received further therapy, including chemotherapy in 50% of these patients, while four in every ten patients given an alternative NHT received further therapy, including chemotherapy in 75%. On average, patients lived for almost a year after starting radium-223 or an alternative NHT.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Benzamides; Bone Neoplasms; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium; Retrospective Studies

Novel hormonal agents (NHAs) such as abiraterone acetate (ABI) and enzalutamide (ENZ) are frequently used in metastatic castration-resistant prostate cancer (mCRPC). Despite their overall tolerable risk profile, certain signals of cardiovascular toxicity were reported for these agents in clinical trials but little is known about their incidence in clinical practice. The objective was to assess the comparative cardiovascular safety of ABI and ENZ in patients with mCRPC in the real-world.. A retrospective population-based cohort was extracted from Quebec public healthcare administrative databases. First-time NHA users between 2011 and 2016 were selected. The primary outcome of interest was cardiovascular-related hospitalization (composite outcome that included acute coronary syndrome, cerebrovascular stroke, heart failure, arrhythmia and others). Inverse probability of treatment weighting (IPTW) with the propensity score was used to adjust for measured baseline characteristics including pre-existing cardiovascular disease.. The cohort comprises 2,183 patients, with 1,773 (81.2%) in the ABI group and 410 (18.8%) in the ENZ group. Crude incidence rates of cardiovascular-related hospitalization were of 9.8 events per 100 person-years (PYs) and of 7.1 events per 100 PYs for the ABI and ENZ groups, respectively. The ABI group was at greater risk of cardiovascular-related hospitalization compared to the ENZ group (IPTW-hazard ratio (HR) 1.82; 95% confidence interval (95%CI) 1.09-3.05). The risk of hospitalization for heart failure was greater in ABI (IPTW-HR 2.88; 95%CI 1.09-7.63).. Our findings suggest that ABI users may be at greater risk of cardiovascular-related hospitalization compared to ENZ users, in particular for heart failure. These results provide clinicians with additional insight on the cardiovascular risks of mCRPC patients treated with NHAs in the real-world and further large studies are required to corroborate these findings.

Topics: Abiraterone Acetate; Heart Failure; Humans; Male; Nitriles; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Combining abiraterone (Abi) with androgen deprivation therapy (ADT) improves overall survival, compared to ADT only, in patients with metastatic castration-sensitive prostate cancer (mCSPC). In Japan, bicalutamide (Bica) and ADT (combined androgen blockade: CAB) is frequently provided for mCSPC. Because these two treatments have not been compared, mCSPC patients who received either treatment were retrospectively analyzed.. Of 178 patients with LATITUDE high-risk mCSPC, 103 had received ADT plus upfront Abi (Abi group) and 75 had received ADT plus Bica (Bica group) in multiple institutions of the Tokai Urologic Oncology Research Seminar. Kaplan-Meir curves were used to retrospectively analyze survival and cancer recurrence. Univariate and multivariate Cox regression analyses identified potential prognostic factors for progression-free survival (PFS).. Significant differences in major clinicopathological characteristics between the two groups were not observed. The rate of castration-resistant development was higher in the Bica compared to Abi group (50.6 vs. 25.2%, p < 0.001). The median PFS in the Bica group was 13.6 months {95% confidence interval [CI] 9.2-22.2}; however, in the Abi group, PFS did not reach the median {95% CI 18.5-not assessed [NA]; p < 0.001}. Time to second progression for the Abi group was superior (p = 0.07). Univariate and multivariate analyses revealed Gleason pattern 5, high alkaline phosphatase levels, and conventional CAB using Bica as significant prognostic factors for short PFS.. In patients with LATITUDE high-risk mCSPC, upfront use of Abi combined with ADT resulted in favorable prognostic outcomes compared with conventional ADT with Bica.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Androstenes; Anilides; Antineoplastic Combined Chemotherapy Protocols; Humans; Japan; Male; Neoplasm Recurrence, Local; Nitriles; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Tosyl Compounds

Recently, hormonal therapy using abiraterone acetate, a second-generation androgen receptor axis-targeted agent, was reported to improve overall survival and progression-free survival in men with LATITUDE-high-risk metastatic castration-sensitive prostate cancer. This observational multicenter study aimed to assess the efficacy of upfront abiraterone acetate in Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer.. The present study included 112 Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer who received upfront abiraterone acetate at four institutions belonging to the Tokai Urologic Oncology Research Seminar group, between January 2018 and September 2020. Progression-free survival and overall survival were assessed, and Cox regression analyses were carried out to evaluate the prognostic significance of upfront abiraterone acetate for progression-free survival.. Within a median follow-up period of 13 months, the progression-free survival and overall survival rates were 76.8% and 89.3%, respectively. Both univariate and multivariable Cox regression analyses showed that the presence of Gleason pattern 5, performance status and hemoglobin were independent predictors of progression-free survival. The patients were subsequently divided into three groups as follows: group 1, 17 patients negative for these three independent progression-free survival predictors; group 2, 49 patients with one positive independent progression-free survival predictor; and group 3, 45 patients with two or three independent progression-free survival predictors. Progression-free survival was significantly different among these three groups (P < 0.001).. Upfront abiraterone acetate might provide satisfactory outcomes for Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer. Gleason pattern 5, performance status and hemoglobin are potential predictors of progression-free survival in Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer who received upfront abiraterone acetate.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Castration; Disease-Free Survival; Humans; Japan; Male; Progression-Free Survival; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Despite novel agents have been introduced to treat castration resistant prostate cancer (CRPC) during the last decade, up to one-third of CRPC patients face primary resistance to new generation compounds. Therefore, sensitive molecular tools are urgently needed for reliable treatment selection and response prediction. This study aimed to evaluate urinary miRNAs and blood circulating androgen receptor (AR) transcript level as a tool for noninvasive outcome prediction for CRPC patients undergoing abiraterone acetate (AA) therapy.. Prostate cancer-specific miR-148a, -365, -375, and -429 were analyzed in 129 urine samples collected from 100 CRPC patients before and during AA therapy via quantitative reverse transcription PCR. To test the prognostic value, urinary miRNA levels alone, as well as combined with AR level were associated with progression-free survival (PFS) and overall survival (OS).. Level of urinary miR-375 was the highest in CRPC in comparison to noncancerous controls, as well as in combination with miR-429 was predictive for short PFS in AA-treated patients (HR = 2.2, 95% CI: 1.1-4.2, p = 0.023). Especially high prognostic power of all analyzed miRNAs was observed in CRPC cases with high blood AR levels. For PFS prediction a tandem of miR-429 and high AR reached HR of 5.0 (95% CI: 2.2-11.8, p < 0.001), while for prediction of OS the best combination was demonstrated by miR-148a and AR with HR of 3.1 (95% CI: 1.4-7.1, p = 0.006).. Urinary miRNAs could be used as prognostic biomarkers for CRPC patients to predict response to AA therapy, especially for the cases with high blood AR levels.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Humans; Male; MicroRNAs; Middle Aged; Pilot Projects; Prognathism; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; RNA, Messenger; Treatment Outcome

New generation hormone therapies (NGHT) is the gold standard treatment for metastatic prostate cancers and/or castration-resistant tumors. Four molecules have been approved: enzalutamide, abiraterone acetate, apalutamide and darolutamide. These treatments are oral therapies taken on a daily basis, which raise issues of adherence to treatment, adverse effects and drug interactions. Therapeutic educational programs for patients represent an emerging care activity that allows patients to acquire skills to better live with their disease and treatment. As of today, no such specific program to new generation hormone therapy in prostate cancer has been developed in France, which was the goal of our current study. This was conducted in three steps: i) identification of patients' educational needs through an exchange with a focus group of patients, ii) gathering of expert opinions on useful information to be given to patients on NGHT via a questionnaire submitted to GETUG members and iii) implementation of the program per se. Qualitative analysis of exchanges with the focus group of patients led to the identification of 7 meaning categories. Expert opinions regarding useful information to deliver to patients identified 13 key items. Based on these preliminary data concerning patients' educational needs, we set up the first french program dedicated to metastatic prostate cancer patients undergoing NGHT that included three therapeutic education workshops: "Experience of the disease", "Management of the treatment" and "Physical activity and diet".

Topics: Abiraterone Acetate; Androgen Antagonists; France; Hormones; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant

Spironolactone when combined with abiraterone in metastatic castration-resistant prostate cancer (mCRPC) may theoretically exert androgenic properties, thereby compromising the therapeutic effectiveness of abiraterone.. Two patients with a medical history of cardiovascular disease and mCRPC combined spironolactone within the course of abiraterone regimen. The abiraterone-spironolactone interaction was identified using the Lexicomp® interaction tool (classified as risk C).. Spironolactone treatment was maintained as it was considered beneficial due to the cardiac condition. The prostate-specific antigen (PSA) levels started to rise when these two drugs were used together. Eventually, tumour progression was observed.. There is increasing evidence that spironolactone behaves as a selective androgen receptor modulator. Strategies to overcome abiraterone-spironolactone interaction could involve the use of eplerenone, although this drug is also controversial. The best strategy should imply a multidisciplinary evaluation by cardiologists and oncologists.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Spironolactone; Treatment Outcome

Topics: Abiraterone Acetate; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

Abiraterone acetate is an antiandrogen steroidal drug that is used to treat patients with metastatic prostate cancer. During the process development of abiraterone acetate, two process α and β-epoxy abiraterone acetate related impurities (2 and 3) were observed along with the final API. In the present work we describe the synthesis of these two known impurities using abiraterone acetate in the presence of hydrogen peroxide and acetic acid as oxidizing agent. The structure of these impurities fully characterized by NMR, Mass, CHN and HPLC analysis.

Topics: Abiraterone Acetate; Androgen Antagonists; Epoxy Compounds; Humans; Male; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials, Phase III as Topic; Humans; Male; Meta-Analysis as Topic; Nitriles; Phenylthiohydantoin; Prednisolone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Treatment Outcome

We designed this study to identify the prognostic value of baseline prognostic nutritional index (PNI) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate or enzalutamide.. 101 mCRPC patients were included. PNI was calculated using formula 10 x serum albumin value (gr/dL) + 0.005 × total lymphocyte count (per mm3). ROC analysis was used for determining prognostic PNI value.. The statistically significant cut-off value for PNI was 46.62. Initial PSA response and PSA kinetics (early PSA response and 30 %-50%-90% PSA response at any time) were much better in PNI > 46.62 group than the PNI ≤ 46.62 group (p < 0.01). In multivariate analysis, baseline PNI level >46.62 was an independent predictor of PSA-PFS (HR: 0.42, p < 0.01), radiologic PFS (HR: 0.53, p < 0.01), and OS (HR: 0.42, p < 0.01). In the PNI ≤ 46.62 group, median OS was 7.4 months (95% CI: 4.1-10.7) for the abiraterone acetate subgroup vs. 17.6 months (95% CI: 10.1-25.1) for enzalutamide subgroups (p < 0.01).. PNI is a useful, independent prognostic marker for mCRPC patients treated with either abiraterone acetate or enzalutamide. Using pre-treatment PNI may help clinicians in the prediction of survival and decision making based on abiraterone acetate or enzalutamide.

Topics: Abiraterone Acetate; Benzamides; Humans; Male; Nitriles; Nutrition Assessment; Phenylthiohydantoin; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

Limited real-world data exist on the effectiveness and safety of abiraterone acetate plus prednisone (abiraterone hereafter) in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) naive to chemotherapy. Most of the few available studies had a retrospective design and included a small number of patients. In the interim analysis of the ABItude study, abiraterone showed good clinical effectiveness and safety profile in the chemotherapy-naive setting over a median follow-up of 18 months.. We evaluated clinical and patient-reported outcomes (PROs) of chemotherapy-naive mCRPC patients treated with abiraterone as for clinical practice in the Italian, observational, prospective, multicentric ABItude study. mCRPC patients were enrolled at abiraterone start (February 2016-June 2017) and followed up for 3 years; clinical endpoints and PROs, including quality of life (QoL) and pain, were prospectively collected. Kaplan-Meier curves were estimated.. Of the 481 patients enrolled, 454 were assessable for final study analyses. At abiraterone start, the median age was 77 years, with 58.6% elderly patients and 69% having at least one comorbidity (57.5% cardiovascular diseases). Visceral metastases were present in 8.4% of patients. Over a median follow-up of 24.8 months, median progression-free survival (any progression reported by the investigators), time to abiraterone discontinuation, and overall survival were, respectively, 17.3 months [95% confidence interval (CI) 14.1-19.4 months], 16.0 months (95% CI 13.1-18.2 months), and 37.3 months (95% CI 36.5 months-not estimable); 64.2% of patients achieved ≥50% reduction in prostate-specific antigen. QoL assessed by Functional Assessment of Cancer Therapy-Prostate, the European Quality of Life 5 Dimensions 3 Level, and European Quality of Life Visual Analog Scale remained stable during treatment. Median time to pain progression according to Brief Pain Inventory data was 31.1 months (95% CI 24.8 months-not estimable). Sixty-two patients (13.1%) had at least one adverse drug reaction (ADR) and 8 (1.7%) one serious ADR.. With longer follow-up, abiraterone therapy remains safe, well tolerated, and active in a large unselected population.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Pain; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Retrospective Studies

Abiraterone acetate (AA) is a selective inhibitor of CYP17 α-hydroxylase, which is crucial for androgen biosynthesis. Apigenin (Api) is a natural plant-derived flavonoid with potent antiproliferative and antimigration effects.. We aimed to investigate the possible role of Api in combination with the androgen receptor inhibitor AA in the treatment of androgen-sensitive human prostate cancer LNCaP cells.. The cells were either exposed to 10 μM AA, 25 μM Api, or in combination for 48 hours, then the viability rate was determined by the MTT test, whilst apoptosis and cell cycle phases were assessed by image-based cytometry. The expression of selected mRNA and proteins were evaluated by RT-qPCR and Western blot, respectively.. The combination of AA and Api significantly inhibited LNCaP as well as androgen-insensitive PC3 cell survival in a manner more marked than observed with either single treatment. Co-administration of Api with AA triggered apoptosis. This effect was demonstrated by Hoechst staining, and up-regulation of Bax, cytochrome c, caspase -3, and - 8 and down-regulation of Bcl-2 expression confirmed the effect. AA and Api each individually arrested the cell cycle in the G1 phase, with dual applications, leading to no further increase in the effect produced. The expression of NF-κB p105/p50 and the phosphorylation of AKT markedly decreased after apigenin treatment, with combination treatment leading to a favourable effect in terms of further augmenting the reduction.. The co-administration of Api with AA strongly enhanced the efficacy of AA therapy in the treatment of prostate cancer cells. These data suggested that the combination of AA and Api would be a potential chemotherapeutic strategy against prostate cancer.

Topics: Abiraterone Acetate; Androgens; Apigenin; Apoptosis; bcl-2-Associated X Protein; Caspases; Castration; Cytochromes c; Flavonoids; Humans; Male; NF-kappa B; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; Receptors, Androgen; RNA, Messenger; Steroid 17-alpha-Hydroxylase

The overall survival (OS) of metastatic castration-resistant prostate cancer (mCRPC) patients has improved since 2011 with the use of novel hormonal agents (NHAs). The incidence of brain metastases (mets) has been reported to increase since 2004 with the use of docetaxel, but not the incidence of visceral mets. Our objective was to study whether the use of NHAs increases the risk of developing visceral or brain mets (VBMs).. mCRPC patients with mets limited to bone (bmCRPC), treated at Tours University Hospital between 2007 and 2015, were included retrospectively. The primary endpoint was to determine whether treatment with NHAs was associated with an increased incidence of VBMs. Secondary endpoints included the search for putative predictive factors to develop VBMs.. On 187 bmCRPC patients included, 65 developed VBMs. VBM incidence increased in bmCRPC patients alive after 2011, compared to patients who died before (39.7 vs. 24.6%, P = .04). Meanwhile, their median OS increased from 16.3 months to 28.5 months (P = .01). The longer was the treatment with NHAs, the lower was the risk of VBMs (HR = 0.96, 95% CI [0.94; 0.99]), whereas age < 70 years (HR = 3.33, 95% CI [1.50; 7.40]) and low PSA level at diagnosis (HR = 1.58, 95% CI [1.16; 2.15]) increased this risk.. Though retrospective, our results showed an increased incidence of VBMs in bmCRPC patients after 2011. However, this was not associated with NHA exposure duration. The role of NHA exposure remains unclear and needs further investigation.

Topics: Abiraterone Acetate; Aged; Androstenes; Benzamides; Brain Neoplasms; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Topics: Abiraterone Acetate; Humans; Male; Outcome Assessment, Health Care; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

To investigate the prognostic value and potential therapeutic target of the baseline serum hormones in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone.. This retrospective study was performed in patients with mCRPC receiving abiraterone acetate (AA) from July 2016 to September 2020. Patients who had serum hormone tests within 2 weeks before AA treatment were included. Univariate analysis and Cox regression were performed to evaluate the correlation of sex hormones with progression-free survival (PFS) and overall survival (OS). Prolactin (PRL) expression in the clinical specimens was evaluated by immunohistochemistry. Bone metastases were quantified by automated Bone Scan Index (aBSI).. The study included 61 patients with a median follow-up of 19.0 months. Patients with lower baseline PRL levels (median) responded better to AA than those with higher baseline PRL levels as indicated by prostate-specific antigen (PSA) reduction (PSA90, 66.7% vs. 25.8%, p = 0.001), PFS (19.6 vs. 7.9 months), and OS (52.8 vs. 19.2 months). Cox regression adjusted for clinical factors also confirmed that baseline PRL level was an independent predictive factor for PFS (hazard ratio = 1.096, p = 0.007). Prostatic PRL expression increased as the disease progressed. PRL expression was also detected in biopsy samples from bone metastasis but not in normal bone tissue, and the serum PRL levels were positively correlated with aBSIs (r = 0.28, p = 0.037).. Serum PRL levels are predictive of response to AA in patients with mCRPC. Serum PRL levels are positively correlated with the volume of metastatic bone disease.

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prolactin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

We assessed clinical outcomes in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with two upfront therapies.. The medical records of 301 patients with mCSPC treated with androgen deprivation therapy plus upfront abiraterone acetate (ABI) or docetaxel (DOC) between 2014 and 2021 were retrospectively reviewed. Propensity score matching (PSM) was performed to compare survival outcomes. Subgroup analyses of risk factors for second progression were conducted.. A total of 95 patients received upfront DOC, whereas 206 received upfront ABI. After PSM, the ABI group had a significantly better castration-resistant prostate cancer (CRPC)-free survival than the DOC group [hazard ratio (HR), 0.53; 95% confidence interval (CI), 0.34-0.82]. Second progression-free survival (PFS2) tended to be longer in the ABI group than in the DOC group, but the difference was not statistically significant (HR, 0.64; 95% CI, 0.33-1.22). No significant difference in overall survival (OS) was found between the two groups (HR, 0.92; 95% CI, 0.42-2.03). In the subgroup analysis, upfront ABI had significantly favorable PFS2 in patients aged ≥ 75 years compared with upfront DOC (p = 0.038). Four risk factors for second progression (primary Gleason 5, liver metastasis, high serum alkaline phosphatase level, and high serum lactate dehydrogenase level) successfully stratified patients into three risk groups.. Upfront ABI provided better CRPC-free survival than upfront DOC; however, no significant differences in PFS2 or OS were observed between the two groups. Personalized management based on prognostic risk factors may benefit patients with mCSPC treated with upfront intensified therapies.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Castration; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Risk Assessment; Treatment Outcome

Skeletal-related events (SREs) from bone metastases disease carry significant morbidity in men with metastatic castration resistant prostate cancer (mCRPC). The differential risk of SREs among patients receiving abiraterone acetate (AA) or enzalutamide (ENZ) is unknown.. To compare the risk of SREs among men with mCRPC receiving AA or ENZ, a retrospective cohort study using the SEER-Medicare Linked Database was conducted. Men with prostate cancer aged ≥65 years at first AA or ENZ prescription (index date) from 2011 to 2015 were identified. Patients were followed until the earliest occurrence of SRE, death, Medicare disenrollment, or December 31, 2016. The primary outcome was a composite endpoint of SRE (pathologic fracture, spinal cord compression, or surgery or radiation to bone) after the index date. Multivariable logistic regressions including key demographic and clinical covariates with death as a competing risk were conducted.. Overall, 5,856 patients were identified (4,207 received AA and 1,649 received ENZ). Median age was 76.5 years (IQR 71.4-82.3), 4,557 (77.8%) were White, 1,112 (19.2%) had recent chemotherapy, and 2,730 (46.6%) had recent zoledronic acid or denosumab. Eight-hundred and thirty-seven (14.3%) patients had ≥1 SRE after index date. In multivariable analyses, there was no difference in SRE risk based on AA and ENZ (HR=0.99 for ENZ, 95%CI 0.84-1.16, P=0.890). Denosumab was associated with lower SRE risk (HR=0.75, 95%CI 0.64-0.88, P=0.001).. In this large cohort of men with mCRPC, there was no difference in risk of SRE between AA and ENZ. Decision-making should be informed by prior therapies, comorbidities, toxicity profiles, and patient preferences. Denosumab has evidence of benefit in preventing SREs in this real-world population.

Topics: Abiraterone Acetate; Aged; Androstenes; Benzamides; Denosumab; Humans; Male; Medicare; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome; United States

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

To assess the prognostic effect of pan-immune inflammation value (PIV) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) or enzalutamide.. Patients with mCRPC treated with AA or enzalutamide between January 2010 and June 2021 were included in this study. The most recently examined complete blood count values in the 1-month period before treatment were used for calculating PIV. The relationship between overall survival (OS) and PIV was evaluated by multivariate analysis. By using PIV and lactate dehydrogenase (LDH) levels which had shown survival effect at multivariate analysis, PIV-LDH combined score was established.. A total of 114 patients were included in this study. At the median follow-up of 34.6 months (95% confidence interval [CI]: 32.4-36.8), the median OS was 21 months (95% CI: 17.6-21.3). The median OS in the low-PIV group was significantly higher than in the high-PIV group (34.4 months (95% CI: 21.3-47.5) vs. 14.3 months (95% CI: 10.0-18.7), p < 0.001). In the multivariate analysis for OS, high PIV (hazard ratio [HR]: 1.86, 95% CI: 1.11-3.13, p = 0.018) and LDH value 1.5 times the upper limit of normal and above (HR: 3.65 95%, CI: 1.86-7.16, p < 0.001) were associated with shorter OS. When survival analysis was performed according to the PIV-LDH combined score, the median OS was 34.4 months (95% CI: 22.2-46.6) in the low-risk group, 17.7 months (95% CI: 11.7-23.6) in the intermediate-risk group, and 8.4 months (95% CI: 5.1-11.7) in the high-risk group (p < 0.001). The C-index of the combined PIV-LDH score was higher than the C-index of PIV (0.65 vs. 0.61).. In this study, we demonstrated that PIV was an independent prognostic factor for OS in patients with mCRPC treated with AA or enzalutamide. Additionally, PIV-LDH combined score may be considered a promising composite peripheral blood-based biomarker to predict OS in those patients.

Topics: Abiraterone Acetate; Benzamides; Biomarkers; Humans; Inflammation; Lactate Dehydrogenases; Male; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

To conduct the direct comparison of abiraterone acetate and docetaxel for first-line treatment of metastatic castration-resistant prostate cancer (mCRPC) in real-life settings.. Data were extracted from the French nationwide claims database (SNDS) on all men aged ≥40 years starting first-line treatment with abiraterone acetate or docetaxel for mCRPC in 2014. A high-dimensional propensity score including 100 baseline characteristics was used to match patients of both groups and form two comparative cohorts. Three-year overall survival and treatment discontinuation-free survival were determined using Kaplan-Meier analysis.. In 2014, 2,444 patients started abiraterone for treatment of mCRPC and 1,214 started docetaxel. After trimming and matching, 716 patients were available in each group. Median overall survival tended to be longer in the abiraterone acetate cohort (23.8 months, 95% confidence interval = [21.5; 26.0]) than in the docetaxel cohort (20.3 [18.4; 21.6] months). Survival at 36 months was 34.6% for abiraterone acetate and 27.9% for docetaxel (. The findings underline the interest of oral abiraterone acetate over intravenous docetaxel as the first-line treatment option in mCRPC.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

The prognosis of high-risk metastatic hormone-naïve prostate cancer is poor, and real-world evidence of therapeutic options and sequences is lacking. The J-ROCK study aimed to evaluate the outcomes in a real-world setting in Japan.. Patients with high-risk metastatic hormone-naïve prostate cancer diagnosed after May 2019 were eligible. Based on their treatment within 3 months after diagnosis, patients were allocated to either cohort 1 (androgen deprivation therapy alone or combined androgen blockade with bicalutamide) or cohort 2 (androgen deprivation therapy with abiraterone acetate+prednisolone, docetaxel, enzalutamide, or apalutamide).. In this first interim analysis (cut-off January 2021), 410 patients were enrolled, including 163 patients in cohort 1 and 247 in cohort 2. The median follow-up period was 7.6 (range 0.1-20.5) months. A higher proportion of patients in cohort 2 (42.5%) achieved nadir prostate-specific antigen levels ≤0.2 ng/ml within a year, compared with cohort 1 (22.1%). Prostate-specific antigen-progression-free survival was also more favorable in cohort 2 (adjusted hazard ratio 0.629 [95% confidence interval 0.345-1.147]).. The higher proportion of cohort 2 suggest a paradigm shift has occurred in the real-world treatment of high-risk metastatic hormone-naïve prostate cancer in Japan. Some factors including prostate-specific antigen may affect treatment selection but need further observation. Most patients in cohort 2 received abiraterone acetate+prednisolone. The proportion of patients in cohort 1 receiving combined androgen blockade was lower than previously reported in Japan. This analysis suggest that more intensive therapy tends to prolong prostate-specific antigen-progression-free survival in patients with high-risk metastatic hormone-naïve prostate cancer.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Antineoplastic Combined Chemotherapy Protocols; Humans; Japan; Male; Prednisolone; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Registries; Treatment Outcome

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Gonadotropin-Releasing Hormone; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

Abiraterone acetate and enzalutamide are commonly employed in prostate cancer therapy in an interchangeable manner. These drugs are highly efficacious in androgen antagonism to improve patient outcomes, but they also carry noteworthy risk of adverse effects. Common toxicities vary amongst the two drugs and may have differential interactions with patient co-morbidities, but these patterns are unclear as co-morbidities typically serve as exclusion criteria in clinical trials. Hence, there is no existing guidance on how clinicians may tailor treatment based on patient-specific factors. Analysis of differential patient outcomes between these two drugs can inform future systematic reviews, new clinical studies, and clinical decision making.. The framework for this methodology was informed by the Joanna Briggs Institute methodology for scoping reviews. Title and abstract screening will be performed by two independent researchers to create an initial study inventory. This will be followed by full-text screening for study inclusion. Population-based studies describing patient outcomes, common toxicities, and associations with patient co-morbidities following abiraterone or enzalutamide therapy will be included. After data is extracted, it will be summarized for presentation.. The findings of this scoping review will be published in a peer-reviewed journal. The results will be used to inform future studies on patient-specific factors informing treatment choice between abiraterone and enzalutamide for castration-resistant prostate cancer. All data are from published openly accessible sources, and therefore, no ethical clearance is necessary. The protocol is also registered at https://doi.org/10.6084/m9.figshare.19149227.

Topics: Abiraterone Acetate; Androstenes; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Review Literature as Topic; Treatment Outcome

Metastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis. Abiraterone acetate (AA), enzalutamide, and chemotherapy are first-line treatments for patients with mCRPC. This study examined prognostic factors for AA response in the form of prostate-specific antigen (PSA) kinetics throughout androgen-deprivation therapy (ADT) in chemonaïve patients with mCRPC.. We retrospectively included data from 34 chemonaïve patients with mCRPC who had received AA at some point between January 2017 and December 2018. We separated patients into two study arms according to the decrease in PSA percentages after use of AA for 3 months. We correlated PSA kinetics parameters with response and compared the two study groups with respect to PSA kinetics.. The patients' median age was 77 years. In the total group of patients, 64% had a response to AA, whereas 35% did not. The ratio of the PSA level at nadir to the level during ADT was significantly higher in the AA-sensitive group (19.78 vs. 1.03, p=0.019).. Patients who experienced a dramatic change in PSA level during ADT were more likely to be resistant to AA after progression to mCRPC. Chemotherapy rather than AA might be more suitable as a first-line treatment for these patients.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Androgens; Androstenes; Humans; Kinetics; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study.. We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC).. At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4-4.5) or long-term (median 29 months; range 23.5-41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders.. Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K_AKT_MTOR pathways.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Aurora Kinase A; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

Despite advances and introduction of new therapies in the last decade, metastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis. The development of androgen axis-targeted therapies such as abiraterone acetate, enzalutamide and darolutamide can prolong survival in mCPRC; however, resistance remains a barrier to prolonged response, necessitating exploration into resistance mechanisms and locoregional therapies. Here, we describe a patient with mCRPC that was progressing on abiraterone acetate. He was also found to have primary hyperaldosteronism from a functional adrenal adenoma, and thus he had a partial adrenalectomy to remove this tumour. Pathology confirmed an aldosterone-producing adrenal adenoma. After his adrenalectomy, he had a sharp decline in both his PSA (prostate specific antigen) and testosterone levels, and he enjoyed a year-long period of remission after his adrenalectomy. We propose several explanations for his response, the most likely being that his adenoma was producing both aldosterone and androgens. This is a unique case of mCRPC responding to partial adrenalectomy from a functional adrenal adenoma, and it raises insights that warrant further investigation into underlying mechanisms of resistance to androgen-targeted therapies.

Topics: Abiraterone Acetate; Adrenalectomy; Aldosterone; Androgens; Androstenes; Humans; Male; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Testosterone; Treatment Outcome

BACKGROUND Prostate cancer growth is primarily driven by testosterone and 5a-dihydrotestosterone. Abiraterone is an irreversible inhibitor of CYP17, and CYP17 inhibition is a required step in testosterone biosynthesis. Previous studies have shown that abiraterone trough levels are predictive of prostate-specific antigen (PSA) response in metastatic castrate-resistant prostate cancer (mCRPC). It has not been demonstrated if this association exists for patients with metastatic hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to explore the correlation and association between abiraterone trough levels and PSA levels in patients with mHSPC. MATERIAL AND METHODS This was a single-center, prospective, observational study of patients with mHSPC being treated with abiraterone acetate (AA) 1000 mg once daily. Abiraterone trough levels (22-26 h after drug administration) were drawn at 1, 3, and 7 months after treatment initiation. RESULTS Thirteen patients with mHSPC were enrolled, and complete pharmacokinetic data were available for 8 patients. The mean trough levels at 1 month, 3 months, and 7 months were 34.49 ng/mL (3.36-240.46), 13.82 ng/mL (2.91-29.96), and 15.7 ng/mL (3.58-26.86), respectively. The correlation between the 1-month abiraterone trough level and 1-month PSA level was 0.29 (P=0.38), between 3-month abiraterone trough and 3-month PSA was -0.61 (P=0.08), and between 7-month abiraterone trough and 7-month PSA was -0.31 (P=0.54). CONCLUSIONS This study demonstrated a trend toward a negative correlation between 3-month abiraterone trough levels and PSA levels, but the correlation was not statistically significant. A study with a larger prospective sample size is needed to validate these findings.

Topics: Abiraterone Acetate; Androstenes; Dihydrotestosterone; Humans; Male; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Testosterone; Treatment Outcome

To assess whether the exposure-response relation for abiraterone is different in pre-chemotherapy patients compared to post-chemotherapy patients with metastatic castration-resistant prostate cancer (mCRPC).. Data were collected from three clinical studies in mCRPC patients treated with abiraterone acetate. Cox regression analysis was used to determine the relation between abiraterone exposure and survival (progression-free survival [PFS] and overall survival [OS]). An interaction term was used to test whether chemotherapy pretreatment was an effect modifier. To investigate the effect of the previously defined exposure threshold of 8.4 ng/mL on survival, Kaplan-Meier analysis was used.. In total, 98 mCRPC patients were included, of which 78 were pre-chemotherapy and 20 were post-chemotherapy patients. Chemotherapy pretreatment in mCRPC setting appears to be an effect modifier. In pre-chemotherapy patients, no significant association between abiraterone exposure and survival was observed (HR 0.68 [95% CI 0.42-1.10], P = .12 and HR 0.85 [95% CI 0.46-1.60], P = .61, PFS and OS, respectively) and no longer survival was seen for patients with an abiraterone exposure above the predefined threshold. In contrast, a significant association was seen in post-chemotherapy patients (HR 0.30 [95% CI 0.12-0.74], P = .01 and HR 0.38 [95% CI 0.18-0.82] P = .01, PFS and OS, respectively), with an increased survival when exposed above this threshold.. Chemotherapy pretreatment in mCRPC setting modifies the abiraterone exposure-response relation. No relation between abiraterone exposure and survival was seen for pre-chemotherapy patients. Therefore, potentially lower doses can be used in this setting to prevent overtreatment and reduce financial toxicity.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

This paper presents a study protocol for a comparative effectiveness evaluation of abiraterone acetate against enzalutamide in clinical practice, two cancer drugs given to patients suffering from advanced prostate cancer.. The protocol designs a comparative-effectiveness analysis of abiraterone acetate against enzalutamide. With the substantial number of covariates a two-step procedure is suggested in choosing relevant covariates in the matching design. In the first step, an exploratory factor analysis reduces the dimension of a large set of continuous covariates to nine factors. In the second step, we reduce the dimension of the covariates, interactions and second order terms for the continuous covariates using propensity score estimation. The final design makes use of a genetic matching algorithm. The study protocol provides a detailed statistical analysis plan of the analysis sample derived from the matching design. The analysis will make use of linear regression and robust inference adjusted for multisignificance testing.. As in a randomised experiment the focus is on the design of the assignment to treatment. This allows the publication of this preanalysis plan before having access to outcome data. This means that the p values will be correct if the maintained assumption of uncounfoundedness is valid. Given that is p-hacking is substantial problem in empirical research, this is a substantial strength of this study. However, while design yields, balance on the observed covariates one cannot discard the possibility that unobserved confounders are not balanced. For that reason, sensitivity tests for the maintained assumption of uncounfoundedness are presented.. The study was approved by the Regional Ethical Review Board in Uppsala, Sweden (Dnr 2017/482). Results will be published in a peer-reviewed journal and distributed to relevant stakeholders in healthcare.

Topics: Abiraterone Acetate; Benzamides; Humans; Longitudinal Studies; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Sweden; Treatment Outcome

Limited real-world data exist on treatment patterns and outcomes in patients with metastatic castration-sensitive prostate cancer (mCSPC).. A retrospective cohort study was conducted, using the Veterans Health Administration claims database (April 2013-March 2018). Among 369,734 prostate cancer patients, we selected all men who developed metastases within 90 days before or after medical/surgical castration and who received androgen deprivation therapy (ADT). Patients were categorized into four cohorts: ADT-only (± <90-day nonsteroidal anti-androgen [NSAA] use), ADT + NSAA, ADT + docetaxel, and ADT + abiraterone. Main outcomes were treatment patterns, time-to-progression to metastatic castration-resistant disease, and overall survival. Multivariable analysis and sensitivity analysis were conducted.. Of 1395 patients, 874 (63%) received ADT-only, 338 (24%) received ADT + NSAA, 108 (8%) received ADT + docetaxel, and 75 (5%) received ADT + abiraterone. Proportions on ADT-only and ADT + NSAA declined (from 66% to 60% and from 31% to 17%, respectively) over the study period, while proportions prescribed ADT + docetaxel or abiraterone increased from 3% to 9% and from 1% to 15%, respectively. Patients treated with ADT + NSAA had similar risks of castration-resistant disease (hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.87, 1.26) and overall mortality (HR 1.22; 95% CI: 0.97, 1.54) as ADT-only.. Most patients with mCSPC initiating ADT received ADT-only or ADT + NSAA, despite the emergence of docetaxel and novel hormonal therapies. Even in the most recent period (2017 to early 2018), only 24% of men received intensified therapy with agents known to prolong survival versus ADT-only. These data in real-world clinical practice suggest substantial room for improved outcomes in patients with mCSPC.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Analysis; United States; Veterans Health

Despite improvements in the diagnosis and treatment of cancers, the incidence of pituitary metastasis has increased. Prostate cancer metastasis to the pituitary, however, is rare, and these tumors usually grow rapidly. They are also more likely to be located in the posterior pituitary, and the presenting symptoms are often nonspecific, which makes early diagnosis challenging. The management of this condition is usually multidisciplinary, and requires careful assessment and decision making. We present a case of a patient who developed prostate cancer metastasis to the pituitary. In this report, we show that patients with prostate cancer on corticosteroid therapy who develop withdrawal symptoms or other endocrine symptoms should be assessed for pituitary and other brain metastasis. This case report also discusses the impact of switching from prednisone and abiraterone to dexamethasone and abiraterone. Our report shows that patients on abiraterone and prednisone whose PSA has increased, but who have no radiologic progression, may have their PSA controlled and thereby improved survival time when they are switched to abiraterone and dexamethasone.

Topics: Abiraterone Acetate; Adrenal Cortex Hormones; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Male; Pituitary Gland; Prednisone; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Prostate cancer is the most common cancer in men, accounting for 15% of all diagnosed cancers and is the sixth leading cause of cancerrelated deaths amongst men worldwide. Abiraterone and enzalutamide were the first two novel hormonal agents approved for the treatment of metastatic prostate cancer but there is a lack of quality evidence regarding which is associated with better outcomes and who would benefit the most with one or another of these drugs.. To evaluate the clinical outcomes of real-world patients submitted to treatment with novel hormonal agents, enzalutamide and abiraterone, for castration resistant metastatic prostate cancer in an academic center.. We retrospectively reviewed patients treated for castration-resistant prostate cancer with either abiraterone or enzulatamide between January 1, 2016 and December 31, 2019. The primary endpoints were biochemical response, biochemical progression, radiological progression, clinical deterioration (attributed to disease progression) and death.. Enzalutamide had a higher biochemical response rate than abiraterone in patients with mCRPC (77.1% vs 58.1%, p = 0.016). Achieving a biochemical response was associated with a lower risk of biochemical progression (OR: 0.248, p = 0.017) and death (OR: 0.302, p = 0.038).. Enzalutamide conferred higher biochemical response rate than abiraterone in patients with mCRPC. Despite the trend to better performance of other endpoints in the enzalutamide group, it did not achieve statistical significance. Well-designed prospective studies are needed to elucidate the comparative efficacies of these agents.

Topics: Abiraterone Acetate; Antineoplastic Agents; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Abiraterone and enzalutamide, androgen receptor pathway inhibitors (ARPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC), are at high risk of potential drug interactions (PDIs). We aimed to describe PDIs and their management, and triggered adverse events (AEs) in clinical practice.. We conducted a cross-sectional study in mCRPC patients who started treatment with abiraterone or enzalutamide in a university hospital between August 1st, 2016 and July 31st, 2020. Lexicomp® was used to identify and analyze PDIs, and the clinical records to assess their management and the occurrence of AEs.. We included 173 patients: 36.8% and 93.0% treated with abiraterone and enzalutamide, respectively, had at least 1 PDI. Globally, 6.3% of PDIs had X-risk (contraindication due to high probability of AE). Treatment was modified in 9.2% of patients and 9.8% suffered AEs due to PDIs. Factors associated with a higher risk of PDIs were polypharmacy (OR= 41.0, p  0.003) and treatment with enzalutamide (OR= 128.26, p < 0.001).. At least two-thirds of patients treated with ARPI suffered a PDI. Overall, abiraterone would have a more favorable PDI profile. Knowing these interaction profiles may be helpful to develop a more efficient therapeutic follow-up and to select the safest treatment.

Topics: Abiraterone Acetate; Androstenes; Benzamides; Cross-Sectional Studies; Drug Interactions; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

To evaluate the therapeutic efficacy of a steroid switch from prednisone to dexamethasone in Asians with metastatic castration-resistant prostate cancer (mCRPC) that progressed after docetaxel chemotherapy.. This study included postdocetaxel patients with mCRPC treated with abiraterone acetate combined with prednisone (AA + P) who had experienced prostate-specific antigen (PSA) progression. All patients underwent a steroid switch from prednisone (10 mg/day) to dexamethasone (1 mg/day). The PSA level and clinical symptoms were recorded. Moreover, follow-up was conducted until patients were either lost to follow-up or death.. This study included 11 patients from a single center in Taiwan. The median follow-up time starting from AA + P treatment was 19.47 months. Seven patients (63.64%) had >30% PSA decline, and 6 patients (54.55%) had >50% PSA decline. The median percentage of PSA decline was 83.6%. The median time until PSA progression after the steroid switch was 11.38 months. No adverse events greater than grade 3 were noted.. Steroid switching is a feasible and effective therapy in docetaxel-treated Asian patients with mCRPC.

Topics: Abiraterone Acetate; Antineoplastic Agents; Dexamethasone; Drug Substitution; Glucocorticoids; Humans; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

The aim of this study was to evaluate the efficacy of abiraterone in patients with castration-resistant metastatic prostate cancer.. We retrospectively analyzed 51 patients with mCRPC treated with abiraterone acetate from January 2014 to August 2018. Clinicopathological information, treatment modalities, treatment responses, and survival times were retrospectively reviewed.. A total of 51 patients who received abiraterone 1000 mg/day + prednisone 10 mg/day between January 2014 and August 2018 were included in the study. Of these patients, 33 (64.7%) had post-chemotherapy (CT) and 18 (35.3%) had CT-naive abiraterone receipt. Median overall survival (OS) was 17.3 months (range 9.3-33.1). Median OS was found to be 12.7 months (range 9.4-18.3) and 29.4 months (range 9.3-33.0) in the CT-naive and post-CT group, respectively (P = .236). Median radiographic PFS (rPFS) was 10.1 months (range 4.5-18.4). In the CT-naive group, rPFS was 10.1 months (IQR 6.0-14.7) and in the post-CT group, it was 9.7 months (range 4.0-18.4) (P = .808). PSA progression-free survival (PSA-PFS) was 9.1 months (range 4.6-13.1). In the CT-naive group, PSA-PFS was 7.4 months (range 4.6-13.4) and in post-CT, it was 9.1 months (range 4.8-13.1) (P = .843).. These results show that abiraterone acetate is an effective and reliable agent in real-life data.

Topics: Abiraterone Acetate; Castration; Data Analysis; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

We present the case of a 70-year-old patient affected by metastatic castration-resistant prostate cancer. He underwent radical prostatectomy in 2007 and subsequent adjuvant radiotherapy and hormonal therapy for 2 years. In 2011, he developed bilateral lung metastases, and therefore he received chemotherapy (eight cycles of docetaxel 75 mg/sqm every 3 weeks) with partial remission; rechallenge with the same drug was performed 7 months later due to recurrence of lung metastases. In August 2013, abiraterone acetate was started for progression of lung metastases. The patient received abiraterone for almost 5 years with stability of disease. During the 60th cycle of abiraterone, a diagnosis of acute myeloid leukemia was made.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Disease Progression; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Male; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Topics: Abiraterone Acetate; Humans; Ipilimumab; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Survivors

Topics: Abiraterone Acetate; Humans; Ipilimumab; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Survivors

To evaluate the possible major adverse cardiovascular events (MACE) associated with second-line hormonal therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).. We performed a population-based real-world cohort study of 4962 prostate cancer patients between 2014 and 2017 utilizing the Chang Gung Research Database of Taiwan. The second-line hormonal therapies included enzalutamide and abiraterone acetate. The outcomes of interest were MACE, including acute coronary syndrome (ACS), ischemic stroke (IS), and heart failure (HF) events that resulted in hospitalization. Cox proportional-hazards models with inverse probability of treatment weighting (IPTW) with propensity scores were used.. After IPTW, 288 patients were prescribed second-line hormonal therapy and 1575 received first-line androgen-deprivation therapy (ADT). Of all patients diagnosed with MACE, the event rates were 2.92% in the second-line hormonal group and 2.22% in the first-line ADT group. The mean follow-up period was 9.52 months for the second-line hormonal group. Patients who received second-line hormonal therapy exhibited a significantly increased risk for MACE (hazard ratio [HR]: 3.15; 95% confidence interval [CI]: 2.03-4.89), ACS (HR: 4.94; 95% CI: 2.36-10.33), and HF (HR: 2.83; 95% CI: 1.53-5.25), compared with the first-line ADT group, but a similar risk for IS was observed in both groups (HR: 1.70; 95% CI: 0.95-3.04).. The real-world evidence study revealed increased risks for MACE in mCRPC patients receiving second-line hormonal therapy.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Benzamides; Cardiovascular Diseases; Cohort Studies; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Risk Factors; Steroid Synthesis Inhibitors; Taiwan; Treatment Outcome

To quantify the association between dose reductions of abiraterone acetate plus prednisone (AAP) or enzalutamide and prostate-specific antigen (PSA) progression in patients with metastatic castration-resistant prostate cancer (mCRPC). Changes in medication-taking patterns of AAP or enzalutamide may arise due to clinical (e.g. toxicity) and non-clinical (e.g. patient compliance) reasons in men with mCRPC. However, it is unclear how this affects PSA progression.. Veterans Health Administration electronic health record database was used to identify Veterans diagnosed with prostate cancer who initiated AAP or enzalutamide (index) from April 2010 to December 2016. PSA progression was defined as the first rise in PSA of ≥2 ng/mL and ≥25% above nadir. The relative dose intensity (RDI) was defined as the ratio of the total dispensed dose over the last two months to the standard recommended dose and was updated monthly. Dose reduction was assessed using a threshold of RDI < 80%.. The cohort included 6069 Veterans aged 74.6 years on average. Mean follow-up was 12.3 months. PSA progression occurred in 62.7% of patients. About 63.6% of AAP- and 67.2% of enzalutamide-treated patients had ≥1 occurrence of RDI <80%. RDI <80% was associated with an 8.8% higher risk of PSA progression (hazard ratio [HR] = 1.088;. Dose reduction was observed in most patients and was associated with significantly higher risk of PSA progression in men with mCRPC. These results suggest future efforts to minimize dose reductions for non-clinical reasons are warranted and that patient adherence should be encouraged to limit the risk of PSA progression.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome; Veterans

To compare toxicity and all-cause mortality for mCRPC patients receiving first line oral systemic therapy prescribed by medical oncologists and urologists.. Population-based retrospective cohort study of chemotherapy-naïve men aged ≥66 years treated for mCRPC with first-line abiraterone or enzalutamide based on administrative health data (Ontario, Canada, 2012-2017). Primary outcomes were hospitalizations/ER visits for any cause or treatment-related toxicity during first-line mCRPC treatment. Secondary outcome was all-cause mortality. We calculated hazard ratios (HRs) comparing outcomes for different medical specialties using multivariable Cox proportional hazards models.. Among 3405 mCRPC patients, 2407 (70.7%) received abiraterone and 998 (29.3%) received enzalutamide. 1786 (52.5%) patients visited the ER or were hospitalized. Men treated by medical oncologists had an increased risk of hospitalization/ER visits (HR1.16, 95%CI 1.03-1.31; P = .02), toxicity-related visits (HR1.34, 95%CI 1.08-1.69; P = .01), and mortality (HR1.16, 95%CI 1.02-1.33; P = .02) compared to urologists. Limited information was available, beyond PSA adjustment and prior treatment, on patient disease burden.. We observed fewer hospital visits overall and for treatment-related toxicity for mCRPC patients who were prescribed first line abiraterone or enzalutamide by urologists compared to medical oncologists. These differences may result from higher prostate cancer disease burden in patients managed by medical oncologists, and/or other unmeasured differences in patient management between specialties.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Canada; Drug-Related Side Effects and Adverse Reactions; Hospitalization; Humans; Male; Medical Oncology; Neoplasm Metastasis; Neoplasm Staging; Nitriles; Oncologists; Outcome and Process Assessment, Health Care; Phenylthiohydantoin; Practice Patterns, Physicians'; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Urologists

Our retrospective study aims to evaluate the prognostic role of duration of response to androgen deprivation therapy (ADT) in metastatic castration resistant prostate cancer (mCRPC) patients treated with enzalutamide (E) or abiraterone acetate (AA).. Data about ADT start and duration were available in 255 (82%) of 311 patients treated with AA or E. Patients were divided in three groups according to ADT response (group 1 [G1]: <12 months; group 2 [G2]: 12-36 months; group 3 [G3]: >36 months). Outcome measures were progression-free survival (PFS) and overall survival (OS).. Patients with longer ADT response had better OS (median 17.3 months G1, 19.9 months G2, 31.6 months G3; HR G3 vs G1 0.41, 95% CI 0.25-0.64; p = 0.001) and better PFS (median 5.9 months G1, 8.8 months G2, 11.7 months G3; HR G3 vs G1 0.41, 95% CI 0.41-0.27; p < 0001). In docetaxel-naive patients, median OS was 18.8 in G1, 35.2 in G2, and not reached in G3 (HR G3 vs G1 0.33, 95% CI 0.14-0.78; p = 0.038), median PFS was 7 months G1, 9.3 months G2, and 20 months G3 (HR G3 vs G1 0.31, 95% CI 0.15-0.62; p = 0.003). In postdocetaxel patients, median OS was 13.1 months in G1, 17.2 months in G2, and 21.4 months in G3 (HR G3 vs G1 0.52, 95% CI 0.29-0.94; p = 0.082), while median PFS was 5.2 months in G1, 6.8 months in G2, and 8.3 months in G3 (HR G3 vs G1 0.54, 95% CI 0.32-0.91; p = 0.067).. Duration of ADT response is an independent prognostic factor of outcome with AA or E.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Follow-Up Studies; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Time Factors

Evaluation of the comparative effectiveness of enzalutamide and abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) is limited to meta-analyses of randomized trials that exclude patients with significant comorbidities. We evaluated overall survival (OS) in patients with chemotherapy-naive mCRPC treated with enzalutamide or abiraterone acetate (abiraterone) in a real-world single payer setting.. A retrospective analysis (4/1/2014-3/31/2018) of the Veterans Health Administration (VHA) database was conducted. Patients with mCRPC had ≥1 pharmacy claim for enzalutamide or abiraterone (first claim date = index date) following disease progression on surgical/medical castration, without chemotherapy <12 months prior to index date. Patients had continuous VHA enrollment for ≥12 months pre-index date and were followed until death, disenrollment, or end of study. Kaplan-Meier analysis and multivariable Cox proportional hazards regression models examined the OS treatment effect.. Patients with chemotherapy-naive mCRPC (N = 3174; enzalutamide, n = 1229; abiraterone, n = 1945) had mean ages of 74 and 73 years, respectively. Median follow-up was 18.27 and 19.07 months with enzalutamide and abiraterone, respectively. Enzalutamide-treated patients had longer median treatment duration than abiraterone-treated patients (9.93 vs 8.47 months, respectively, p = 0.0008). After baseline comorbidity adjustment, enzalutamide-treated patients had a 16% reduced risk of death (hazard ratio [HR] = 0.84; 95% CI, 0.76-0.94; p = 0.0012). For patients who remained on first line-therapy only, enzalutamide-treated patients had improved OS versus abiraterone-treated patients (HR = 0.71; 95% CI, 0.62-0.82). Enzalutamide-treated patients who crossed over to abiraterone had a comparable risk of death versus abiraterone-treated patients who crossed over to enzalutamide (HR = 1.10; 95% CI, 0.89-1.35). These results were confirmed by sensitivity analysis, which considered prognostic variables.. Retrospective analysis of the VHA database indicated that chemotherapy-naive patients with mCRPC initiating therapy with enzalutamide had improved survival versus abiraterone.

Topics: Abiraterone Acetate; Aged; Benzamides; Disease Progression; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Analysis; United States; Veterans

Circulating RNAs extracted from liquid biopsies represent a promising source of cancer- and therapy-related biomarkers. We screened whole blood from patients with metastatic castration-resistant prostate cancer (mCRPC) following their first-line treatment with abiraterone acetate and prednisone (AA-P) to identify circulating RNAs that may correlate with progression-free survival (PFS). In a prospective multicenter observational study, 53 patients with mCRPC were included after they started first-line AA-P treatment. Blood was drawn at baseline, 1, 3, and 6 months after treatment initiation. The levels of predefined circulating RNAs earlier identified as being upregulated in patients with mCRPC (e.g., microRNAs, long noncoding RNAs, and mRNAs), were analyzed. Uni- and multivariable Cox regression and Kaplan-Meier analyses were used to analyze the prognostic value of the various circulating RNAs for PFS along treatment. Detectable levels of kallikrein-related peptidase 3 (KLK3) mRNA at baseline were demonstrated to be an independent prognostic marker for PFS (201 vs 501 days, P = 0.00054). Three months after AA-P treatment initiation, KLK3 could not be detected in the blood of responding patients, but was still detectable in 56% of the patients with early progression. Our study confirmed that KLK3 mRNA detection in whole blood is an independent prognostic marker in mCRPC patients receiving AA-P treatment. Furthermore, the levels of circulating KLK3 mRNA in patients receiving AA-P treatment might reflect treatment response or early signs of progression.

Topics: Abiraterone Acetate; Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Case-Control Studies; Disease-Free Survival; Female; Humans; Kallikreins; Liquid Biopsy; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prognosis; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; RNA, Messenger; Treatment Outcome

Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy.. A 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline.. Cancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Cardiac Pacing, Artificial; Fluid Therapy; Heart Rate; Humans; Long QT Syndrome; Male; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors; Syncope; Torsades de Pointes; Treatment Outcome

Resistance to AR signaling inhibitors (ARSis) in a subset of metastatic castration-resistant prostate cancers (mCRPCs) occurs with the emergence of AR- neuroendocrine prostate cancer (NEPC) coupled with mutations/deletions in PTEN, TP53, and RB1 and the overexpression of DNMTs, EZH2, and/or SOX2. To resolve whether the lack of AR is the driving factor for the emergence of the NE phenotype, molecular, cell, and tumor biology analyses were performed on 23 xenografts derived from patients with PC, recapitulating the full spectrum of genetic alterations proposed to drive NE differentiation. Additionally, phenotypic response to CRISPR/Cas9-mediated AR KO in AR+ CRPC cells was evaluated. These analyses document that (a) ARSi-resistant NEPC developed without androgen deprivation treatment; (b) ARS in ARSi-resistant AR+/NE+ double-positive "amphicrine" mCRPCs did not suppress NE differentiation; (c) the lack of AR expression did not necessitate acquiring a NE phenotype, despite concomitant mutations/deletions in PTEN and TP53, and the loss of RB1 but occurred via emergence of an AR-/NE- double-negative PC (DNPC); (d) despite DNPC cells having homogeneous genetic driver mutations, they were phenotypically heterogeneous, expressing basal lineage markers alone or in combination with luminal lineage markers; and (e) AR loss was associated with AR promoter hypermethylation in NEPCs but not in DNPCs.

Topics: Abiraterone Acetate; Animals; Antineoplastic Agents; Benzamides; Carcinoma, Neuroendocrine; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Male; Mice; Neoplasm Transplantation; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; PTEN Phosphohydrolase; Receptors, Androgen; Retinoblastoma Binding Proteins; SOXB1 Transcription Factors; Thiohydantoins; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Combined Modality Therapy; Docetaxel; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals; Radium; Retrospective Studies; Survival Rate; Taxoids

Despite standard-of-care androgen-deprivation therapy and an increasing number of treatment options, the mortality rate for prostate cancer remains high. Progress to metastatic castration-resistant prostate cancer (mCRPC) necessitates additional treatments. Abiraterone acetate plus prednisone or prednisolone (AAP) prolongs survival in chemotherapy-naive and docetaxel-experienced patients.. To evaluate the real-world safety and efficacy of AAP as first-line and second-line [post-docetaxel only (AAP-PD)] treatment in patients with mCRPC.. The Prostate Cancer Registry (PCR) was a prospective, international, observational study of patients with mCRPC in routine clinical practice. Men aged ≥ 18 years with confirmed mCRPC were included. Baseline characteristics, safety (treatment-emergent adverse events, treatment-emergent severe adverse events), and efficacy [progression-free survival (PFS) and overall survival (OS)] were analyzed.. At baseline, patients who received first-line AAP (n = 754) were generally older than patients who received AAP-PD (n = 354); median age was 76 years and 70 years, respectively. However, the rate of visceral metastasis was higher in the AAP-PD cohort than in the AAP cohort (17.7% vs. 9.6%, respectively). Demographics and disease characteristics of patients with baseline cardiovascular disease were similar to those of the overall registry population. Efficacy outcomes were similar for all patients, regardless of the line of AAP therapy. For first-line AAP and AAP-PD, respectively, the median PFS was 8.9 and 5.8 months for all patients and 9.1 and 6.0 months for patients with cardiovascular comorbidities; median OS was 27.1 and 23.4 months for all patients, and 27.4 and 23.1 months for patients with cardiovascular comorbidities. There were no unexpected adverse events in any patient subgroup.. These real-world data complement the findings from randomized controlled trials, indicating that first- and second-line AAP is well tolerated and effective in patients with mCRPC, including those with underlying CV comorbidities.. NCT02236637, registered 8 September 2014.

Topics: Abiraterone Acetate; Aged; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Registries

Topics: Abiraterone Acetate; Biomarkers; Circulating Tumor DNA; Gene Conversion; Humans; Male; Prostatic Neoplasms, Castration-Resistant

Retrospective analyses of randomized trials suggest that Black men with metastatic castration-resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a prospective study of abiraterone acetate plus prednisone to explore outcomes by race.. This race-stratified, multicenter study estimated radiographic progression-free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate-specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome-wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self-identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients.. The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men.. Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side-effect rates than White men. This exploratory genome-wide analysis of TTP identified a possible candidate marker of ancestry-dependent treatment outcomes.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Male; Prednisone; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Abiraterone acetate plus prednisolone is approved to treat patients with castration-resistant prostate cancer. This study evaluated the safety and efficacy of abiraterone acetate plus prednisolone in castration-resistant prostate cancer patients with or without previous chemotherapy in a real-world setting in Japan.. This study was an observational, prospective, post-marketing surveillance. Castration-resistant prostate cancer patients, who initiated abiraterone acetate after its approval in Japan, were enrolled. Data were collected during an observation period of 12 months and a follow-up period of another 12 months. Adverse events and adverse drug reactions were evaluated for safety. Prostate-specific antigen levels and overall survival were evaluated for efficacy.. From 141 participating institutions, 497 patients were registered: 492 patients including 180 chemotherapy-naïve, 311 chemotherapy-experienced and one off-label-use patient received abiraterone and were evaluated for safety. Adverse events were observed in 225/492 patients (45.7%), adverse drug reactions in 131/492 patients (26.6%) and serious adverse drug reactions in 61/492 patients (12.4%). The most commonly observed adverse drug reaction was abnormal hepatic function (6.5%), followed by hypokalemia (3.0%) and decreased appetite (2.0%). At week 12, 110/432 patients (25.5%) achieved ≥50% decrease from baseline in prostate-specific antigen, and the proportion was higher in chemotherapy-naïve patients (56/161 patients; 34.8%) compared with chemotherapy-experienced patients (54/271 patients; 19.9%, P < 0.001). Survival rates at 24 months were 68.3% (295/432 patients), 73.9% (119/161 chemotherapy-naïve patients) and 64.9% (176/271 chemotherapy-experienced patients).. This large-scale, real-world, post-marketing surveillance study confirmed the safety and efficacy of abiraterone acetate plus prednisolone in Japanese castration-resistant prostate cancer patients with or without previous chemotherapy.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prednisolone; Product Surveillance, Postmarketing; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Studies describing treatment utilization for castration-resistant prostate cancer (CRPC) are limited. We aimed to describe the treatment utilization of a contemporary population-based CRPC cohort between 2006 and 2016.. We identified 1699 men with a PC diagnosis between 2005 and 2015, who developed CRPC between 2006 and 2015 in the Stockholm region of Sweden. Demographic information, stage and grade at PC diagnosis, stage at CRPC, prostate-specific antigen (PSA) nadir, PSA doubling time, treatment utilization rate within 1 year of CRPC diagnosis, reason for stopping therapy, treatment sequence trajectory, overall and PC specific survival was described.. Treatment for men with de novo metastatic disease (. Despite treatment availability, in this large real-world cohort we found treatment utilization to remain low.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Docetaxel; Humans; Male; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant

To compare enzalutamide (E) and abiraterone acetate (AA) in terms of efficacy, survival and to characterize prognostic factors affecting survival in metastatic castration-resistant prostate cancer (mCRPC) patients. A total of 250 patients treated with E or AA in 5 centers were included. The number of patients with no prostate specific antigen (PSA) decline was higher in the AA group than that in the E group, and the proportion of patients with a PSA decline of ≥ 50% was higher in the E group (p = 0.020). Radiological progression free survival (rPFS) and overall survival (OS) were significantly longer in the E group when compared to that in the AA group (p < 0.001 and p = 0.027, respectively). In the E group, rPFS was significantly longer than that in the AA group in both pre- and post-docetaxel settings (p = 0.010 and p = 0.003, respectively). OS was similar in the pre-docetaxel setting; but in the post-docetaxel setting, E group had a significantly longer OS than the AA group (p = 0.021). In the multivariate analysis performed in the whole patient group, we found that good prognostic factors for rPFS were E treatment, being ≥ 75 years and a PSA decline of ≥ 50% while there was no factor affecting OS. With longer OS and PFS, E seems to be more suitable for mCRPC patients in the post-docetaxel setting than AA.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Disease-Free Survival; Docetaxel; Humans; Kallikreins; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prognosis; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

The aim of the study was to evaluate the combined treatment with abiraterone acetate and prednisone (AA+P) in patients with castration-resistant prostate cancer (mCPRC), and to identify the survival prognostic factors.. Patients diagnosed with mCPRC not previously treated with chemotherapy and administered with AA+P were classified into two groups: those with lower and higher survival rates (at 30 months vs. 60 months).. A total of 53 patients were studied at the time of mCRPC diagnosis. Patients with the highest survival rate had suffered prostate cancer for >45 months. At the time of initial prostate cancer diagnosis, they belonged to the risk groups 1-4, had pain intensity measured according to the brief pain inventory (BPI) scale of 0-2, were treated with AA+P>16 months, and had the following tumour marker serum levels: LDH baseline ≤163 U/l, alkaline phosphatase at 6 months ≤56 U/l and PSA at 6 months ≤0.95 ng/ml.. Good response to treatment with AA+P for patients with mCRPC was demonstrated. Factors that contributed to the higher prognostic accuracy were time suffering from prostate cancer, the intensity of the pain measured by the BPI scale, the duration of AA+P treatment, and tumour marker levels.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prednisone; Prognosis; Prostatic Neoplasms, Castration-Resistant

Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown.. To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy.. This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019.. Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy.. The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used.. Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001).. In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Bone Density Conservation Agents; Bone Neoplasms; Cohort Studies; Humans; Kaplan-Meier Estimate; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Registries; Retrospective Studies

Real-world evidence suggest that next generation hormonal agents (NHAs) abiraterone and enzalutamide were preferred as first-line (1L) therapies for metastatic castration-resistant prostate cancer (mCRPC) in the United States (US) pre-2020, with chemotherapies, particularly docetaxel, being preferred in subsequent lines (2L+). This real-world study described patient characteristics, treatment patterns, time on treatment (ToT) and overall survival (OS) among patients with mCRPC treated with 2L and 3L docetaxel post-NHAs in the mCRPC setting.. Adults with confirmed adenocarcinoma mCRPC diagnosis and ≥1 month of follow-up post-diagnosis were selected from a US electronic health record-derived oncology de-identified database (01/2013-03/2019). Based on the observed line of therapy sequences post-mCRPC diagnosis, patients who received NHA therapy in 1L and docetaxel therapy in 2L were included in the 2L docetaxel cohort, and patients who received NHA therapy in both 1L and 2L and docetaxel therapy in 3L were included in the 3L docetaxel cohort. ToT and OS were evaluated using Kaplan-Meier analysis.. Among 5,213 patients with mCRPC, 278 and 166 were included in the 2L and the 3L docetaxel cohorts, respectively (median age: 73 years for both cohorts). ADT was the most used class of medication pre-mCRPC (>75%). For the 2L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L docetaxel (52.5%), while the median ToT and OS post-2L start were 4.1 and 10.5 months, respectively; for the 3L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L enzalutamide → 3L docetaxel (67.5%), while the median ToT and OS post-3L start were 3.8 and 8.7 months, respectively.. This real-world study provides novel data on patients treated with docetaxel post-NHAs in a mCRPC setting and highlights the critical unmet need for developing more effective treatment options in this population.

Topics: Abiraterone Acetate; Adult; Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Docetaxel (D) or secondary hormonal therapy (SHT) each combined with androgen deprivation therapy (ADT) represent possible treatment options in males with metastasized hormone-sensitive prostate cancer (mHSPC). Real-world data comparing different protocols are lacking yet. Thus, our objective was to compare the efficacy and safety of abiraterone acetate (AA)+ADT versus D+ADT in mHSPC.. In a retrospective multicenter analysis including males with mHSPC treated with either of the aforementioned protocols, overall survival (OS), progression-free survival 1 (PFS1), and progression-free survival 2 (PFS2) were assessed for both cohorts. Median time to event was tested by Kaplan-Meier method and log-rank test. The Cox-proportional hazards model was used for univariate and multivariate regression analyses.. Overall, 196 patients were included. The AA+ADT cohort had a longer PFS1 in the log-rank testing (23 vs. 13 mos., p < 0.001), a longer PFS2 (48 vs. 33 mos., p = 0.006), and longer OS (80 vs. 61 mos., p = 0.040). In the multivariate analyses AA+ADT outperformed D+ADT in terms of PFS1 (HR = 0.34, 95% CI = 0.183-0.623; p = 0.001) and PFS2 (HR = 0.33 95% CI = 0.128-0.827; p = 0.018), respectively, while OS and toxicity rate were similar between both groups.. AA+ADT is mainly associated with a similar efficacy and overall toxicity rate as D+ADT. Further prospective research is required for validation of the clinical value of the observed benefit of AA+ADT for progression-free end-points.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Middle Aged; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

To assess the efficacies and potential predictors of a corticosteroid switch in metastatic castration-resistant prostate cancer (mCRPC) patients with biochemical progression on abiraterone acetate plus prednisone (A + P).. Patients with mCRPC treated between April 2016 and August 2020, who experienced biochemical progression on A + P and then switched to A plus dexamethasone (D), were retrospectively identified. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were PSA response, overall survival (OS), and safety.. One hundred and thirty consecutive cases were enrolled. The median PFS and OS on A + D were 5.0 and 18.7 months, respectively. The best PSA decline of ≥50% (PSA50) and ≥ 30% (PSA30) were observed in 29.2 and 46.2% patients, respectively. Lower PSA at corticosteroid switch (≤ 20 ng/mL; median PFS, HR 0.63, p = 0.019; median OS, HR 0.38, p = 0.001) and longer mCRPC-free survival (≥ 18 months; median PFS, HR 0.61, p = 0.013; median OS, HR 0.51, p = 0.015) were identified as independent prognostic predictors associated with longer PFS and OS. A risk stratification tool was developed to select candidates for corticosteroid switch based on the independent prognostic predictors of PFS and OS.. A corticosteroid switch from prednisone to dexamethasone is effective for mCRPC which progressed on A + P treatment. Patients with lower PSA at corticosteroid switch and/or longer mCRPC-free survival may gain more benefits by the corticosteroid switch.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Dexamethasone; Disease Progression; Drug Substitution; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prednisone; Prognosis; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

It is hypothesised that cotargeting the androgen receptor (AR) and paracrine androgen biosynthesis with enzalutamide and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) will dissipate adaptive feedback loops observed with either agent alone.. To assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC).. This open-label, single-centre interventional study was conducted in bmCRPC patients.. Enzalutamide 160mg and abiraterone acetate 1000mg once daily; prednisone 5mg twice daily.. Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and C. Enzalutamide combined with abiraterone acetate has a manageable safety profile, without a meaningful DDI. Both agents are pharmacodynamically active with no feedback. Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC.. This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant

ERA 223, a phase III, international, multicenter, double-blind study published in

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium

Topics: Abiraterone Acetate; Humans; Lymphocytes; Male; Neutrophils; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

Several small studies have reviewed the efficacy of abiraterone acetate plus prednisolone (AAP) in clinical practice outside a trial setting. We report the largest cohort study of clinical outcomes in metastatic castrate-resistant prostate cancer (mCRPC) patients treated with AAP in a multicenter multiracial clinical setting.. A retrospective analysis on mCRPC patients treated at four tertiary hospitals in Singapore from 2012 to 2017 was conducted. Disease characteristics, treatment outcomes, and adverse events were retrieved from electronic medical records. Primary clinical end-point was overall survival (OS). A subset analysis of patients with various variables and OS curves were generated using the Kaplan-Meier method and compared using the log-rank test.. Out of 200 patients with mCRPC treated with AAP, 163 (81.5%) patients were chemo-naïve (CN) and 37 (18.5%) patients were postchemotherapy (PC), with the median age of 68 (34-87) and 65 (52-80) years, respectively. Median OS was 20.0 (95% CI, 18.3-22.9) and 10.5 months (95% CI, 1.1-40.5) for CN and PC cohorts, respectively. A subset analysis of 108 patients showed a significantly longer OS in patients who had prior ADT for more than 12 months in CN patients (P < 0.001). Incidences of G3/G4 events were around 6.6%; most common side effect being hypertension with an incidence of 2.4%.. Treatment of CN and PC patients with AAP was associated with a comparable OS and progression-free survival to the reported series. Patients who were responsive to prior ADT of 12 months or more were associated with an improved OS.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Drug Therapy, Combination; Humans; Male; Middle Aged; Prednisone; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Singapore; Survival Rate

There has been no established clinical evidence for using sequential treatment in castration-resistant prostate cancer (CRPC). Despite evident cross-resistance, androgen receptor axis-targeted agents (ARTAs), namely abiraterone (ABI) and enzalutamide (ENZ), are often used sequentially owing to less toxicity compared with chemotherapy.. A multicenter retrospective review of chemotherapy-naive patients with CRPC who had received ABI followed by ENZ (ABI-to-ENZ) or ENZ followed by ABI (ENZ-to-ABI) was conducted. Combined progression-free survival (PFS), overall survival (OS), and prostate-specific antigen (PSA) response (≥ 50% PSA decline) to each drug were compared between the 2 groups at the median follow-up of 36.0 months.. There were no significant differences in combined PFS (12.4 vs. 10.9 months; hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.72-1.23; P = .6594) or OS (28.3 vs 29.3 months; HR, 0.96; 95% CI, 0.66-1.38; P = .8314) between the ABI-to-ENZ and ENZ-to-ABI groups. PSA response rate was not significantly different in first-line ARTAs (48.9% vs. 58.4%; P = .153) but significantly higher in ENZ as a second-line ARTA (40.4% vs. 13.7%; P < .0001). Although multivariate analysis revealed that the ABI-to-ENZ sequence was associated with favorable PFS on second-line ARTA (HR, 0.65; 95% CI, 0.49-0.85; P = .0019), it was not associated with an increased combined PFS or OS.. With relatively longer follow-up, ARTA sequence did not affect clinical outcomes of CRPC treatment except for PSA response and PFS on a second-line ARTA. These findings will be useful information in clinical decision-making, particularly in chemotherapy-unfit patients with CRPC.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Receptor Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Flutamide; Follow-Up Studies; Humans; Kallikreins; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Tosyl Compounds

The sequential use of a number of new agents (NAs) have improved the overall survival (OS) of patients with metastatic castration-resistant prostate cancer whose disease progresses after docetaxel (DOC) treatment. The aim of this study was to assess the cumulative survival outcomes of different sequencing strategies by evaluating the individual data from published studies of patients treated with a post-DOC treatment sequence of 2 NAs.. The patients' individual data were analyzed to investigate whether different sequencing strategies lead to differences in OS.. We analyzed the data of 1099 evaluable patients. Among the patients treated with a second-line new hormone agent (NHA), median OS from the start of third-line treatment was significantly longer in the patients treated with cabazitaxel (CABA) than in those treated with abiraterone acetate or enzalutamide. Median cumulative OS (cumOS) from the start of second-line treatment was 21.1 months in the patients who received NHA then NHA, 22.1 months in those who received NHA then CABA, and 21.0 months in those who received CABA then NHA. Among the patients with a second-line progression-free survival of ≥6 months, median cumOS was significantly longer in patients who received CABA-including sequences than in those treated with NHA then NHA sequences (29.5 vs. 24.8 months; P = .03).. Our findings suggest that the sequential use of NAs with different mechanisms of action improves cumOS regardless of the order in which they are administered, thus supporting the hypothesis of cross-resistance between the 2 NHAs.

Topics: Abiraterone Acetate; Age Factors; Aged; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Docetaxel; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Neoplasm Grading; Nitriles; Observational Studies as Topic; Phenylthiohydantoin; Progression-Free Survival; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

Topics: Abiraterone Acetate; Benzamides; Cross-Over Studies; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy.. We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naive prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival.. The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, and 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio [HR], 0.84; P = .530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR, 0.82; P = .650), and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR, 1.58; P = .384).. The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.

Topics: Abiraterone Acetate; Aged; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Docetaxel; Follow-Up Studies; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Immune checkpoint inhibition has been shown to have limited efficacy in patients with metastatic prostate cancer. Prostate cancers that harbor certain homologous recombination (HR) DNA repair gene mutations, inactivating CDK12 mutations or have underlying mismatch repair deficiency may be effectively treated with immunotherapy. Combination therapy may improve clinical response rates to immune checkpoint blockade. We observed profound prostate-specific antigen (PSA) and/or objective responses to immune checkpoint blockade following prior treatment with bipolar androgen therapy (BAT) and enzalutamide.. We report three cases of patients with metastatic castration resistant prostate cancer (mCRPC) undergoing therapy with anti-PD-1 inhibitors. All patients underwent both somatic molecular testing and germline genetic testing.. Two of the three patients with mCRPC harbored an inactivating mutation in an HR DNA repair gene (BRCA2, ATM). No patient demonstrated mismatch repair deficiency, nor were CDK12 alterations present. All three patients had been treated with BAT and enzalutamide before immune checkpoint blockade, a paradoxical approach for the treatment of mCRPC developed by our group.. These cases of mCRPC suggest that immune checkpoint blockade may have therapeutic potential in patients with prostate cancer, especially following immune activation ("priming") using BAT and enzalutamide.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Frameshift Mutation; Germ-Line Mutation; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Poly(ADP-ribose) Polymerase Inhibitors; Programmed Cell Death 1 Receptor; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Testosterone

Reliable molecular diagnostic tools are still unavailable for making informed treatment decisions and monitoring the response in patients with castration resistant prostate cancer. We evaluated the significance of whole blood circulating androgen receptor transcripts of full length (AR-FL) and splice variants (AR-V1, AR-V3 and AR-V7) as biomarkers of abiraterone acetate treatment resistance in patients with castration resistant prostate cancer.. After retrospective analysis in 112 prostate specimens AR-FL, AR-V1, AR-V3 and AR-V7 were evaluated in 185 serial blood samples, prospectively collected from 102 patients with castration resistant prostate cancer before and during abiraterone acetate therapy via reverse transcription quantitative polymerase chain reaction.. AR-FL was present in all samples while AR-V1, AR-V3, AR-V7 and at least 1 of them was detected in 17%, 55%, 65% and 81% of castration resistant prostate cancer blood samples, respectively. The highest amount of AR-V1 was found in blood of patients whose response time was short and medium in comparison to extended. Patients with a higher level of AR-FL and/or AR-V1 had the shortest progression-free survival and overall survival (p <0.0001).. Blood circulating AR-FL or AR-V1 can serve as blood based biomarkers for identification of the primary resistance to abiraterone acetate and the tool to monitor de novo resistance development during abiraterone acetate treatment.

Topics: Abiraterone Acetate; Antineoplastic Agents; Biomarkers, Tumor; Case-Control Studies; Drug Resistance, Neoplasm; Follow-Up Studies; Humans; Male; Middle Aged; Multivariate Analysis; Progression-Free Survival; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; RNA

Prostate cancer (PC) is the second leading cause of cancer death among US men and accounts for considerable healthcare expenditures. We evaluated economic outcomes in men with chemotherapy-naïve metastatic castration-resistant PC (mCRPC) treated with enzalutamide or abiraterone acetate plus prednisone (abiraterone).. We performed a retrospective analysis on 3174 men (18 years or older) utilizing the Veterans Health Administration (VHA) database from 1 April 2014 to 31 March 2018. Men with mCRPC were included if they had at least one pharmacy claim for enzalutamide or abiraterone (first claim date = index date) following surgical or medical castration, had no chemotherapy treatment within 12 months prior to the index date, and had continuous VHA enrollment for at least 12 months pre- and post-index date. Men were followed until death, disenrollment, or end of study and were 1:1 propensity score matched (PSM). All-cause and PC-related resource use and costs per patient per month (PPPM) in the 12 months post index were compared between matched cohorts.. We identified 1229 men with mCRPC prescribed enzalutamide and 1945 prescribed abiraterone with mean ages of 74 and 73 years, respectively. After PSM, each cohort had 1160 patients. The enzalutamide cohort had fewer all-cause (2.51 vs 2.86; p < 0.0001) and PC-related outpatient visits (0.86 vs 1.03; p < 0.0001), with corresponding lower all-cause ($2588 vs $3115; p < 0.0001) and PC-related ($1356 vs $1775; p < 0.0001) PPPM outpatient costs compared with the abiraterone cohort. All-cause total costs (medical and pharmacy) PPPM ($8085 vs $9092; p = 0.0002) and PC-related total costs PPPM ($6321 vs $7280; p < 0.0001) were significantly lower in the enzalutamide cohort compared with the abiraterone cohort.. Enzalutamide-treated men with chemotherapy-naïve mCRPC had significantly lower resource utilization and healthcare costs compared with abiraterone-treated men.. Prostate cancer (PC) is the second leading cause of death among men with cancer in the USA. Healthcare costs associated with PC, including hospitalizations, outpatient visits, and medications prescribed to treat adverse effects, depend on the severity of the disease and intensity of treatment, but are generally very high. Enzalutamide and abiraterone acetate with prednisone (abiraterone) are both approved treatments for men with PC that does not respond to treatments that reduce the male hormone testosterone, known as castration-resistant PC (CRPC). These drugs are associated with varying treatment duration and different adverse effects, and therefore could result in differences in the use of healthcare resources and overall cost of treatment. Here we evaluated the healthcare resource utilization (HCRU), which was calculated as the average number of healthcare encounters, including inpatient stays, outpatient visits, and pharmacy visits, and length of inpatient stays, and treatment costs associated with use of enzalutamide or abiraterone by men with metastatic CRPC (mCRPC), who had not received prior chemotherapy in the Veterans Health Administration. We found that men with chemotherapy-naïve mCRPC treated with enzalutamide used less healthcare resources and incurred lower total healthcare costs than men treated with abiraterone. On average, all-cause total healthcare costs were $1007 per patient per month lower and PC-related total healthcare costs were $959 per patient per month lower for patients treated with enzalutamide than those treated with abiraterone. These results support the hypothesis that the long-term HCRU and costs of enzalutamide may be lower compared with abiraterone.

Topics: Abiraterone Acetate; Adult; Aged; Androstenes; Antineoplastic Agents, Hormonal; Benzamides; Cohort Studies; Drug Administration Schedule; Health Care Costs; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

Abiraterone acetate (abiraterone) combined with prednisone is a standard of care in metastatic castration-resistant prostate cancer. Recently, benefit in overall survival was reported in metastatic castration-sensitive prostate cancer also, and an extension of indication has been granted. Abiraterone is seldom associated with liver toxicity. The clinical management and the outcome of patients with transaminase increase while on abiraterone have not been described.. We identified 25 men with metastatic prostate cancer and liver function test disorders occurring while on abiraterone treatment from December 2009 to September 2017 in three oncology centres in France.. Forty-six liver disorder events occurred in 25 patients while on abiraterone treatment. The median age at liver function test increase was 67 (55-85) years. The incidence of aspartate aminotransférase (AST) (24 events) and that of alanine aminotransférase (ALT) (22 events) increases were similar. Liver toxicity was of grade 1, 2 and 3 (Common Terminology Criteria for Adverse Events. version 4) in 7 (32%), 6 (27%) and 9 (41%) patients for ALT, and in 12 (50%), 6 (25%) and 6 (25%) for AST, respectively. The median time from abiraterone initiation to the detection of liver toxicity was 7.1 (4-95) weeks. The median time from highest ALT/AST increase to normalisation was 6.2 [2-14] weeks. In 13 patients (52%), liver tests spontaneously returned to baseline values, while abiraterone was continued at full dose.. Liver function test increase is a rare event that typically occurs within the first two months on abiraterone. Most patients experience normalisation of the tests, either spontaneously or after dose reduction/discontinuation.

Topics: Abiraterone Acetate; Administration, Oral; Aged; Aged, 80 and over; Alanine Transaminase; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Bone Neoplasms; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Incidence; Liver Function Tests; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Prednisone; Prostatic Neoplasms, Castration-Resistant; Remission, Spontaneous

The combination of abiraterone acetate and prednisone (AA/P) is used to treat metastatic prostate cancer, but molecular predictors of treatment response are not well elucidated. We evaluated plasma circulating tumor DNA- (ctDNA-) based copy number alterations (CNAs) to determine treatment-related predictive and prognostic biomarkers for metastatic castration-resistant prostate cancer (mCRPC).. Serial plasma specimens were prospectively collected from 88 chemotherapy-naive mCRPC patients before and after 12 weeks of AA/P treatment. Sequencing-based CNA analyses were performed on 174 specimens. We evaluated CNA-associated 12-week responses for primary resistance, time to treatment change (TTTC) for secondary resistance, and overall survival for prognosis (P < 0.05). Associations with primary resistance were analyzed using the Fisher exact test. Kaplan-Meier survival curves and Cox regression analyses were used to determine the associations of CNAs with acquired resistance and overall survival.. ctDNA reduced by 3.89% in responders and increased by 0.94% in nonresponders (P = 0.0043). Thirty-one prostate cancer-related genes from whole genome CNAs were tested. AR and AR enhancer amplification were associated with primary resistance (P = 0.0039) and shorter TTTC (P = 0.0003). ZFHX3 deletion and PIK3CA amplification were associated with primary resistance (P = 0.026 and P = 0.017, respectively), shorter TTTC (P = 0.0008 and P = 0.0016, respectively), and poor survival (P = 0.0025 and P = 0.0022, respectively). CNA-based risk scores combining selected significant associations (AR, NKX3.1, and PIK3CA) at the univariate level with TTTC were predictive of secondary resistance (P = 0.0002). and established prognoses for survival based on CNAs in ZFHX3, RB1, PIK3CA, and OPHN1 (P = 0.002). Multigene risk scores were more predictive than individual genes or clinical risk factors (P < 0.05).. Plasma ctDNA CNAs and risk scores can predict mCRPC-state treatment and survival outcomes.

Topics: Abiraterone Acetate; Adult; Aged; Anti-Inflammatory Agents; Biomarkers, Tumor; Cell-Free Nucleic Acids; DNA Copy Number Variations; Humans; Kallikreins; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors; Survival Rate; Treatment Outcome

To evaluate the fracture risk and survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) who received sequentially abiraterone acetate (AA) and radium 223 [223Ra]RaCl. We retrospectively reviewed the records of mCRPC patients who received [223Ra]RaCl. We reviewed data of a consecutive series of 94 mCRPC patients. Most of the patients (85.1%) received [223Ra]RaCl. The findings of this study show that the treatment with [223Ra]RaCl

Topics: Abiraterone Acetate; Bone Neoplasms; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Radium; Retrospective Studies; Treatment Outcome

 Abiraterone acetate (AA) is a prodrug of abiraterone, which is an irreversible inhibitor of 17α-hydroxylase/C17, 20-lyase. Since 2011, abiraterone acetate has been available in combination with prednisone/prednisolone (AA + P) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) after pre-treatment with docetaxel, and since 2012 for the treatment of chemotherapy-naïve asymptomatic or mildly symptomatic mCRPC patients. A revision of the guidelines of the European Association of Urology in 2014 redefining castration resistance gave rise to the question of when the treatment of mCRPC with abiraterone acetate plus prednisone should be initiated after prior hormone treatment and how successful it would be. This led us to observe an early-onset AA + P therapy cohort (EC) and a late-onset therapy cohort (LC) of patients..  We designed a combined retrospective and prospective, multicentre, non-interventional two-cohort study to obtain data on the effectiveness and safety of an early-onset AA + P therapy in mCRPC patients in the clinical routine compared to a late therapy onset. The EC comprised patients who received AA + P immediately after castration resistance without a prior first-generation antiandrogen such as bicalutamide or flutamide. The LC included patients who, after castration resistance had occurred, started treatment with AA + P only after unsuccessful treatment with a first-generation antiandrogen. Patients with mCRPC who received AA + P therapy according to the physician's routine clinical practice decision were considered. The patients were consecutively included in the study on the basis of their medical records, with the treatment decision having been made independently of and before patient enrolment. Patients were documented or followed from the beginning of AA + P therapy until the start of a carcinoma-specific systemic follow-up therapy (retrospectively if before and prospectively if after start of data collection). Effectiveness analyses were done for all patients with at least two AA + P administrations and safety analyses for all treated patients..  Of the 159 patients included, 44 received early therapy and 105 received later therapy with AA + P. 10 patients could not be clearly assigned and were summarised in a third cohort (missed early-onset therapy assignment; MEC). 56/159 patients (35.2 %) were still alive at study start and 103/159 patients (64.8 %) had already deceased (31/44 [70.5 %] in EC, 64/105 [61.0 %] in LC, and 8/10 [80.0 %] in MEC). 24/159 patients (15.1 %) were documented both retrospectively and prospectively. The median duration of AA + P treatment was 11.3 months for EC, 12.0 months for LC, and 8.3 months for MEC patients. The median time to next systemic cancer therapy or death was 12.3 months for EC and 12.8 months for LC patients (p = 0.2820). The median time to the next systemic cancer therapy alone (i. e. without the event 'death') was 22.7 months for EC and 23.3 months for LC patients (p = 0.5995). Median overall survival (OS) was 22.3 months for EC and 39.2 months for LC patients (p = 0.0232). The incidence of serious adverse events (SAEs) was low. SAEs occurred in 3/44 EC (6.8 %), 4/105 LC (3.8 %), and 1/10 MEC patients (10.0 %). One SAE in EC and one in LC resulted in death..  In contrast to the new definition of castration resistance, AA + P was still more frequently used in daily clinical practice during the study observation period in patients treated with antiandrogens of the first generation after occurrence of castration resistance. Nevertheless, AA + P therapy appears to be effective and well tolerated during clinical routine in mCRPC patients. A comparison of the study results with earlier 'real-world' studies, however, has to take limiting factors into account. The observed difference in median overall survival might be explained by the imbalance of baseline characteristics between both cohorts with regard to number of patients, patients already deceased at start of documentation, patients with visceral metastases and patients with opioids at start of AA + P. For these reasons, patients in the EC initially might have had a poorer prognosis. A prospective randomised and controlled clinical trial would therefore be necessary to assess a possible difference in overall survival and response of the AA + P treatment with respect to therapy onset..  Abirateronacetat (AA) ist ein Prodrug von Abirateron, einem irreversiblen Inhibitor der 17α-Hydroxylase/C17, 20-lyase. Seit 2011 steht Abirateronacetat in Kombination mit Prednison/Prednisolon (AA + P) zur Therapie des metastasierenden, kastrationsresistenten Prostatakarzinoms (mCRPC) nach Vorbehandlung mit Docetaxel, und seit 2012 zur Behandlung von Chemotherapie-naiven asymptomatischen oder mild symptomatischen mCRPC-Patienten zur Verfügung. Basierend auf einer Überarbeitung der Richtlinien der European Association of Urology aus 2014 mit Neudefinition der Kastrationsresistenz, stellte sich die Frage, wann und mit welchem Erfolg die Therapie eines mCRPC mit Abirateronacetat plus Prednison nach vorheriger Hormonbehandlung eingeleitet werden soll. Dies führte zur Untersuchung der frühen und einer späteren AA + P-Therapiekohorte..  Wir konzipierten daher eine kombinierte retro- und prospektive, multizentrische, nicht-interventionelle Zwei-Kohorten-Studie, um Daten zur Wirksamkeit und Sicherheit einer frühen gegenüber einer später einsetzenden AA + P-Therapie bei mCRPC-Patienten in der klinischen Routine zu erhalten. In der frühen Kohorte wurden Patienten beobachtet, die AA + P direkt nach Auftreten der Kastrationsresistenz ohne vorheriges Antiandrogen der ersten Generation wie z. B. Bicalutamid oder Flutamid erhalten hatten. Die späte Kohorte umfasste Patienten, die nach Auftreten der Kastrationsresistenz erst im Anschluss an eine gescheiterte Therapie mit Erstgenerationsantiandrogen mit AA + P begonnen hatten.Es wurden Patienten mit mCRPC dokumentiert, die eine AA + P-Therapie gemäß Arztentscheidung im Behandlungsalltag erhielten. Die Patienten wurden auf der Grundlage ihrer Krankenakten konsekutiv in die Studie einbezogen, wobei die Behandlungsentscheidung unabhängig von und vor der Aufnahme des Patienten in die Studie getroffen worden war. Die Patienten wurden von Beginn der AA + P-Therapie an bis zum Start einer Karzinom-spezifischen systemischen Folgetherapie dokumentiert bzw. verfolgt (retrospektiv, wenn vor oder prospektiv, wenn nach Beginn der Datenerhebung). Wirksamkeitsanalysen wurden für alle Patienten mit mindestens zwei AA + P-Gaben und Sicherheitsanalysen für alle behandelten Patienten durchgeführt..  Von den 159 eingeschlossenen Patienten erhielten 44 Patienten eine frühe Therapie (FTh) und 105 Patienten eine spätere Therapie (STh) mit AA + P. 10 Patienten konnten nicht eindeutig zugeordnet werden und wurden in einer dritten Kohorte (fehlende Therapiezuordnung; FTZ) zusammengefasst. Während 56/159 Patienten (35,2 %) bei Studienbeginn noch lebten, waren 103/159 Patienten (64,8 %) bereits verstorben (31/44, 70,5 % in FTh, 64/105, 61,0 % in STh und 8/10, 80,0 % in FTZ). 24 /159 Patienten (15,1 %) wurden sowohl retro- als auch prospektiv dokumentiert.Die AA + P-Behandlung dauerte im Median 11,3 Monate für FTh-Patienten, 12,0 Monate für STh-Patienten und 8,3 Monate für FTZ-Patienten. Die mediane Zeit bis zur nächsten systemischen Karzinomtherapie oder bis zum Tod betrug 12,3 Monate für FTh- und 12,8 Monate für STh-Patienten (p = 0,2820). Bis zur nächsten systemischen Karzinomtherapie alleine (d. h. ohne Ereignis 'Tod') verging eine mediane Zeit von 22,7 Monaten für FTh- und 23,3 Monaten für STh-Patienten (p = 0,5995). Das mediane Gesamtüberleben (OS) betrug 22,3 Monate für FTh- und 39,2 Monate für STh-Patienten (p = 0,0232).Die Häufigkeit schwerwiegender unerwünschter Ereignisse (SUEs) war gering. SUEs traten bei 3 /44 FTh-Patienten (6,8 %), 4/105 STh-Patienten (3,8 %) und 1/10 FTZ-Patienten (10,0 %) auf. Jeweils ein SUE unter FTh und STh hatte den Tod zur Folge..  Entgegen der neuen Definition zur Kastrationsresistenz wurde während des Beobachtungszeitraums der Studie AA + P in der täglichen Praxis weiterhin häufiger bei Patienten angewendet, die nach Auftreten von Kastrationsresistenz zunächst mit Antiandrogenen der ersten Generation behandelt wurden. Eine AA + P-Therapie scheint aber in der klinischen Routine bei mCRPC-Patienten wirksam und gut tolerierbar zu sein. Beim Vergleich der Studienergebnisse mit früheren ‚Real-World‘-Studien sind aber limitierende Faktoren zu berücksichtigen. Der beobachtete Unterschied im Gesamtüberleben könnte auf die Unausgewogenheit der Basis-Charakteristika zwischen beiden Kohorten hinsichtlich Patientenanzahl, zu Dokumentationsbeginn bereits verstorbener Patienten, Patienten mit viszeralen Metastasen und Patienten mit Opioiden zu Beginn der Behandlung mit AA + P zurückzuführen sein. Aus diesen Gründen hatten FTh-Patienten möglicherweise bereits initial eine schlechtere Prognose. Eine prospektive randomisierte und kontrollierte klinische Studie wäre daher notwendig, um einen möglichen Unterschied im Überleben und Ansprechen der Behandlung in Bezug auf den Zeitpunkt des Therapiebeginns zu untersuchen.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Humans; Male; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Previous studies demonstrated a predictive value of prostate-specific antigen (PSA) kinetics for treatment outcome. Our retrospective study evaluates the prognostic role of early PSA drop in metastatic castration resistant prostate cancer (mCRPC) patients receiving abiraterone acetate (AA) or enzalutamide (E).. All mCRPC patients treated with AA or E at the San Luigi Hospital in Orbassano between 2010 and 2018 and at the Ordine Mauriziano Hospital in Turin between 2014 and 2018 were included in this retrospective study. Only patients with an early PSA (measured 28-60 days after the beginning of the treatment) were included in the analysis. Patients were divided in early responders and non-early responders according to early PSA response (drop≥50% from baseline). Univariate and multivariate analyses for progression free survival (PFS) and overall survival (OS) were performed.. Of 144 patients with early PSA value, 61 (42.4%) patients received E (docetaxel-naïve 42, post-docetaxel 19) and 83 (57.6%) received AA (docetaxel-naïve 44, post-docetaxel 39). Seventy-five (52.1%) patients achieved early PSA drop. In docetaxel-naïve setting (N.=86), median PFS was 14.9 (with early PSA drop) vs. 8.8 months (without early PSA drop, P=0.001). In post-docetaxel setting (N.=58) median PFS was 11.9 vs. 4.5 months (P<0.001). Globally, median PFS was 14.9 vs. 6.3 months in patients with and without early PSA drop, respectively (P<0.001). In docetaxel-naïve setting, patients with early PSA drop had a median OS of 39.5 vs. 18.8 months (P=0.12). In post-docetaxel setting median OS was 29.6 vs. 10.7 months (P=0.01). Comprehensively, median OS was 31.9 vs. 16.3 (P=0.002) in patients with and without early PSA drop, respectively. At multivariate analysis, early PSA drop confirmed an independent association with PFS (HR 0.21; 95% CI: 0.12-0.38, P<0.001) and OS (HR 0.25; 95% CI: 0.12-0.50, P<0.001).. mCRPC patients treated with AA or E, in docetaxel-naïve or post-docetaxel setting, with early PSA drop had significantly better OS and PFS.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Disease-Free Survival; Docetaxel; Humans; Kallikreins; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prognosis; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Castration; Humans; Kinetics; Male; Prednisone; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Humans; Male; Prostatic Neoplasms, Castration-Resistant

It is of much interest to understand the efficacy of abiraterone acetate (AA) in routine clinical practice. We assessed the clinical outcome of AA in patients with metastatic castration-resistant prostate cancer (mCRPC) and determined clinical factors associated with AA treatment duration in real-world setting. This real-world cohort consisted of 93 patients with mCRPC treated with AA in Thailand (58.1%) and Malaysia (41.9%). Primary endpoints were overall survival (OS) and biochemical progression-free survival (bPFS). Secondary endpoints were predictors associated with AA treatment duration evaluated with Cox proportional hazards regression. Around 74% were chemotherapy-naïve. The median AA treatment duration was 10 months (IQR 5.6-17.1). Malaysians had a relatively lower median OS and bPFS (OS 17.8 months; 95% CI 6.4-29.1, bPFS 10.4 months; 95% CI 8.8-12.0) compared to Thais (OS 27.0 months; 95% CI 11.3-42.7, bPFS 14.0 months; 95% CI 5.8-22.2), although it did not achieve statistical significance (P > .05). Patients with longer AA treatment duration (>10 months) had lower risk of death and longer bPFS, compared to those with shorter AA treatment duration (≤10 months) (hazard ratio [HR] 0.10, 95% CI 0.05-0.22 and HR 0.13, 95% CI 0.06-0.25, respectively). Multivariable analysis showed that PSA at AA initiation, presence of PSA response and chemotherapy-naive were independently associated with AA duration (P < .05). Abiraterone acetate is well-tolerated in the Southeast Asian cohort with comparable survival benefits to other Asian populations in real-world setting. Lower PSA levels at AA initiation, presence of PSA response, and chemotherapy-naive were significant in determining AA treatment duration.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Cohort Studies; Duration of Therapy; Humans; Kallikreins; Malaysia; Male; Middle Aged; Multivariate Analysis; Neoplasm Grading; Progression-Free Survival; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Thailand; Treatment Outcome

In men with castration-sensitive prostate cancer (CSPC), the HSD3B1 c.1245A>C variant has been reported to be associated with shorter responses to first-line androgen-deprivation therapy (ADT). Here, we evaluated the association between the inherited HSD3B1 c.1245A>C variant and outcomes from metastatic castration-resistant prostate cancer (mCRPC) after first-line treatment with abiraterone (Abi) or enzalutamide (Enza).. Patients with mCRPC (n = 266) were enrolled from two centers at the time of starting first-line Abi/Enza. Outcomes after Abi/Enza included best prostate-specific antigen (PSA) response, treatment duration, and overall survival (OS). Outcomes after first-line ADT were determined retrospectively, and included treatment duration and OS. As was prespecified, we compared patients with the homozygous variant HSD3B1 genotype (CC genotype) versus the combined group with the heterozygous (AC) and homozygous wild-type (AA) genotypes.. Among the 266 patients, 22 (8.3%) were homozygous for the HSD3B1 variant (CC). The CC genotype had no association with PSA response rate; the median Abi/Enza treatment duration was 7.1 months for the CC group and 10.3 months for the AA/AC group (log rank P = 0.34). Patients with the CC genotype had significantly worse OS, with median survival at 23.6 months for the CC group and 30.7 months for the AA/AC group (log rank P = 0.02). In multivariable analysis adjusting for age, Gleason score, PSA, prior chemotherapy, and M1 disease, the association between the CC genotype and OS remained significant (hazard ratio 1.78, 95% confidence interval 1.03-3.07, P = 0.04). Poor outcome after first-line ADT in the CC group was also observed when evaluating retrospective ADT duration data for the same combined cohort.. In this large two-center study evaluating the HSD3B1 c.1245 genotype and outcomes after first-line Abi/Enza, homozygous variant (CC) HSD3B1 genotype was associated with worse outcomes. Novel therapeutic strategies are needed to enable treatment selection based on this genetic marker.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Benzamides; Genotype; Germ Cells; Humans; Male; Multienzyme Complexes; Nitriles; Phenylthiohydantoin; Progesterone Reductase; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Steroid Isomerases; Treatment Outcome

Treatment with abiraterone acetate or enzalutamide is one of the approved approaches in men with metastatic castration-resistant prostate cancer (mCRPC) in the post-docetaxel setting. However, a significant fraction of patients do not respond to treatment, and we aimed to determine their characteristics. From April 2015 to May 2019, 71 patients with mCRPC were treated with abiraterone acetate (N = 34) or enzalutamide (N = 37) at our institution. Resistance to treatment was defined as radiological or scintigraphic progression within 3 months, as documented at the first control. After a median follow-up of 14.9 months, resistance was detected in 22 patients (31%). Many of the baseline characteristics differed between responders and nonresponders but did not serve as predictors with clinically acceptable certainty. To overcome this, the resistance score was defined as the number of positive out of the following six predictors: Most patients with resistance and a few responders had >3 positive predictors. Therefore, by using a cutoff of four positive predictors, the resistance score showed both a high sensitivity of 82% [57-96%; 95% confidence interval (CI)] and a specificity of 88% (74-96%; 95% CI). The proposed resistance score integrates the diagnostic performances of multiple predictors and may serve to decide which patients with mCRPC should be offered treatments other than hormonal therapy.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cohort Studies; Disease Progression; Docetaxel; Drug Resistance, Neoplasm; Humans; Kallikreins; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Abiraterone acetate (in combination with prednisone/prednisolone (abiraterone/P)), enzalutamide or docetaxel may all be used for the first-line treatment of asymptomatic or mildly symptomatic mCRPC. As treatment with docetaxel can result in the emergence of considerable adverse events, the less toxic substances abiraterone/P and enzalutamide are important alternatives. Apart from the safety and clinical effectiveness of these therapies, their optimal sequencing can play a significant role when choosing a mCRPC first-line therapy. Until recently, only retrospective trials were conducted, investigating the sequential use of abiraterone/P and enzalutamide in asymptomatic or mildly symptomatic mCRPC. However, the British Columbia Cancer Agency (BCCA) has now published results from a phase II randomised cross-over trial, which directly compared the safety and efficacy of abiraterone/P and enzalutamide in the first and second line.. Beim nicht oder mild symptomatischen metastasierten kastrationsresistenten Prostatakarzinom (mCRPC) können sowohl die modernen antihormonellen Wirkstoffe Abirateronacetat plus Prednison/Prednisolon (Abirateron/P) und Enzalutamid als auch eine Chemotherapie mit Docetaxel zum Einsatz kommen. Da die Behandlung mit Docetaxel teils ausgeprägte Nebenwirkungen haben kann, ist eine wichtige Therapiealternative die insgesamt besser verträgliche antihormonelle Therapie. Neben der Wirksamkeit und Verträglichkeit kann bei der Wahl der mCRPC-Erstlinientherapie zudem der Einfluss auf die Wirksamkeit von Folgetherapien eine wichtige Rolle spielen. Bisher lagen nur retrospektive Studien zum sequenziellen Einsatz von Abirateron/P und Enzalutamid bei dieser Indikation vor. In einer prospektiven, randomisierten Phase-II-Studie der British Columbia Cancer Agency (BCCA) wurden Abirateron/P und Enzalutamid nun erstmals bez. ihrer Wirksamkeit und Verträglichkeit in der Erstlinientherapie des nicht oder mild symptomatischen mCRPC sowie der Folgetherapie miteinander verglichen.

Topics: Abiraterone Acetate; Docetaxel; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

Abiraterone became a standard hormonal therapy for patients with metastatic castration-resistance prostate cancer (mCRPC). However, patients may experience primary resistance to treatment. To date, few predictive biomarkers of efficacy have been identified. Our aim was to investigate the association between the single nucleotide polymorphism (SNP) c.-362T>C in the CYP17A1 gene, and clinical outcome in mCRPC patients treated with abiraterone.. mCRPC patients candidate to receive abiraterone were enrolled in the present retrospective pharmacogenetic study. Based on a literature selection, CYP17A1 rs2486758 (c.-362T > C) was selected and analysed by real-time PCR on genomic DNA extracted from whole blood. Univariate analysis was performed to test the association between the SNP and treatment-related clinical outcomes.. Sixty mCRPC patients were enrolled in the present study. Patients carrying the mutant CYP17A1 c.-362CT/CC genotypes showed a shorter median progression-free survival (PFS) and prostate-specific antigen-PFS (PSA-PFS) compared to patients carrying the TT genotype (10.7 vs 14.2 months and 8 vs 16 months, respectively; p = 0.04). No association between the selected SNP and the overall survival was found.. These findings suggest an association between CYP17A1 c.-362T>C polymorphism and poorer clinical outcome with abiraterone for mCRPC patients. However, further validations on larger cohort of patients are needed to confirm its role as a predictive biomarker for abiraterone resistance.

Topics: Abiraterone Acetate; Adenocarcinoma; Aged; Aged, 80 and over; Biomarkers, Tumor; Disease Progression; Drug Resistance, Neoplasm; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Grading; Polymorphism, Single Nucleotide; Prognosis; Progression-Free Survival; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Steroid 17-alpha-Hydroxylase

Abiraterone acetate (AA) is an inhibitor of androgen biosynthesis, though this cannot fully explain its efficacy against androgen-independent prostate cancer. Here, we demonstrate that androgen deprivation therapy depletes androgen-utilizing Corynebacterium spp. in prostate cancer patients and that oral AA further enriches for the health-associated commensal, Akkermansia muciniphila. Functional inferencing elucidates a coinciding increase in bacterial biosynthesis of vitamin K2 (an inhibitor of androgen dependent and independent tumor growth). These results are highly reproducible in a host-free gut model, excluding the possibility of immune involvement. Further investigation reveals that AA is metabolized by bacteria in vitro and that breakdown components selectively impact growth. We conclude that A. muciniphila is a key regulator of AA-mediated restructuring of microbial communities, and that this species may affect treatment response in castrate-resistant cohorts. Ongoing initiatives aimed at modulating the colonic microbiota of cancer patients may consider targeted delivery of poorly absorbed selective bacterial growth agents.

Topics: Abiraterone Acetate; Akkermansia; Androgen Antagonists; Androgens; Bacteria; Feces; Gastrointestinal Microbiome; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; RNA, Ribosomal, 16S; Verrucomicrobia; Vitamin K 2

Inflammatory cytokine markers, including the neutrophil-to-lymphocyte ratio (NLR), monocyte-lymphocyte ratio, and platelet-to-lymphocyte ratio, play important roles as prognostic markers in several solid malignancies, including prostate cancer. We previously reported the NLR as a poor prognostic marker in bladder cancer, upper-urothelial carcinoma, adrenocortical carcinoma, penile cancer, and prostate cancer. This study examined the importance of the NLR as a prognostic marker for castration-resistant prostate cancer (CRPC) patients who received abiraterone acetate or enzalutamide.. A total of 805 prostate cancer patients developed in CRPC status were enrolled in this study. Of these patients, 449 received abiraterone acetate (ABI; 188 cases) or enzalutamide (ENZ; 261 cases) treatment, and the pre-treatment NLR values of these patients were obtained. We investigated the prognosis in those with higher and lower NLR values.. The median NLR was 2.90, and a receiver operating characteristics analysis suggested a candidate cut-off point of 3.02. The median overall survival (OS) was 17.3 months in the higher NLR group (≥3.02) and 27.3 months in the lower NLR group (< 3.02) (p < 0.0001). This trend was also observed in both the ABI and ENZ groups (ABI: 29.3 vs. 15.1 months; ENZ: NR vs. 19.5 months; p < 0.0001 and < 0.0001, respectively). A multivariate analysis revealed that a higher NLR was an independent risk factor. The NLR value was thus shown to be correlated with the prostate cancer progression.. A higher NLR was associated with a poorer OS for CRPC patients who received ABI or ENZ. The NLR was positively correlated with prostate cancer progression.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Lymphocytes; Male; Neutrophils; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant

The role of truncated androgen receptor splice variant-7 (AR-V7) in prostate cancer biology is an unresolved question. Is it simply a marker of resistance to 2nd-generation androgen receptor signaling inhibitors (ARSi) like abiraterone acetate (Abi) and enzalutamide (Enza) or a functional driver of lethal resistance via its ligand-independent transcriptional activity? To resolve this question, the correlation between resistance to ARSi and genetic chances and expression of full length AR (AR-FL) vs. AR-V7 were evaluated in a series of independent patient-derived xenografts (PDXs). While all PDXs lack PTEN expression, there is no consistent requirement for mutation in TP53, RB1, BRCA2, PIK3CA, or MSH2, or expression of SOX2 or ERG and ARSi resistance. Elevated expression of AR-FL alone is sufficient for Abi but not Enza resistance, even if AR-FL is gain-of-function (GOF) mutated. Enza resistance is consistently correlated with enhanced AR-V7 expression. In vitro and in vivo growth responses of Abi-/Enza-resistant LNCaP-95 cells in which CRISPR-Cas9 was used to knockout AR-FL or AR-V7 alone or in combination were evaluated. Combining these growth responses with RNAseq analysis demonstrates that both AR-FL- and AR-V7-dependent transcriptional complementation are needed for Abi/Enza resistance.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Animals; Benzamides; Biopsy; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Humans; Male; Mice; Middle Aged; Nitriles; Phenylthiohydantoin; Prostate; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; RNA Splicing; RNA-Seq; Xenograft Model Antitumor Assays

Since sipuleucel-T approval in 2010, the treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) now includes the androgen-receptor signaling pathway inhibitors (ASPIs) abiraterone acetate or enzalutamide. In 2013 and 2014, these oral agents were approved for use in men with metastatic prostate cancer who had minimal to no symptoms. We compared overall survival (OS) in men who received their first mCRPC treatment using the Medicare Fee-for-Service 100% administrative claims research dataset with patient-level linkage to the National Death Index.. This retrospective cohort analysis (January 2013 to December 2017) included men who were chemo-naïve at treatment start in 2014 and who had continuous Medicare Parts A, B, and D eligibility during the 3-year observation period. We compared: first-line sipuleucel-T vs. first-line ASPIs and any-line sipuleucel-T vs. any-line ASPIs (without sipuleucel-T). We used a multivariable regression model to help control for potentially confounding factors while assessing survival outcomes.. The model included 6044 eligible men (average age 75-78 years) with similar disease severity; > 80% were white. Median OS, presented as sipuleucel-T vs. ASPI, was 35.2 vs. 20.7 months (n, 906 vs. 5092; any-line cohort) and 34.9 vs. 21.0 months (n, 647 vs. 4810; first-line cohort). Model outcomes indicated sipuleucel-T was associated with significantly prolonged OS compared with ASPIs: adjusted hazard ratio, 0.59 (95% CI 0.527-0.651) and 0.56 (0.494-0.627) for the any-line and first-line cohorts, respectively.. This analysis suggests use of sipuleucel-T at any time was associated with improved OS compared with ASPI use alone. Of note, these analyses are intended as descriptive rather than definitive as this dataset contains limited data on key clinical factors. While selection bias is a risk in secondary claims data, this research provides important insight into real-world treatment outcomes.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Benzamides; Cohort Studies; Disease-Free Survival; Humans; Male; Medicare; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Tissue Extracts; Treatment Outcome; United States

Abiraterone acetate plus prednisone/prednisolone (AAP) and androgen deprivation therapy (ADT) was approved for the treatment of high-risk metastatic hormone-sensitive prostate cancer (mHSPC) in Japan in 2018. We investigated 22 patients with mHSPC showing ≥2 of 3 high-risk factors (Gleason score ≥8, ≥3 bone lesions or measurable visceral metastases) who received AAP plus ADT at our hospital between March 2018 and October 2019. We compared outcomes between the propensity-score matched AAP plus ADT group and the combined androgen blockade (CAB) group (19 matched pairs, 38 patients) to evaluate the efficacy and safety of AAP plus ADT. Prostate-specific antigen progression-free survival (PSA-PFS) was significantly longer in the AAP group than in the CAB group (not reached vs 15.1 months, p=0.014). Time to achievement of serum PSA ≤0.2 ng/ml and ≤0.1 ng/ml was shorter in the AAP group than in the CAB group (6.4 months vs not reached, p=0.001 and 11.0 months vs not reached, p=0.004, respectively). Although no significant intergroup difference was observed in the overall survival rates and PSA-PFS2 (PSAPFS on subsequent anticancer therapy) owing to the shorter follow-up in the AAP group, our data suggest that the clinical efficacy of AAP is betterthan that of CAB in patients with mHSPC.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Antineoplastic Combined Chemotherapy Protocols; Humans; Japan; Male; Prednisolone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Several randomized control trials (RCTs) have showed that adding either abiraterone acetate (AA) or docetaxel (D) to androgen-deprivation therapy (ADT) improves survival of metastatic castration-sensitive prostate cancer patients (mCSPC). Yet, the cost-effectiveness of these treatment options has not been fully compared under Hong Kong's setting. This cost-effectiveness analysis (CEA) serves as the first study in Hong Kong to compare the economic value of these two combinations ADT + AA vs. ADT + D.. A deterministic Markov model is used to project cost-effectiveness of each treatment until death. Survival curves for progression/death were extracted and digitized from the five RCTs (CHAARTED, LATITUDE, two STAMPEDE (2016/2017), and GETUG-AFU15). Clinically significant adverse events (AEs) were modeled; utility values were obtained from the literature. Primary outcomes were the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). We used the societal perspective from Hong Kong and considered three times of local gross domestic product per capita (GDPpc) as the willingness-to-pay (WTP) threshold (i.e., US$138,649). We estimated the break-even cost of AA in case ADT + AA is not a cost-effective strategy under this WTP threshold. While considering the standard AA dosage (1000 mg) as the main analysis, we also examined the potential impact of the low-dose AA (250 mg) strategy.. Integrating simulations with probabilistic sensitivity analysis, ADT + D returns 0.79 (median; 95% credible interval 0.56-0.97) QALY with an ICER of US$14,397/QALY ($7824-22,632) compared to ADT-alone. A head-to-head comparison indicates that ADT + AA further gains 0.79 (0.45-1.17) QALY but with an ICER of $361,439/QALY ($260,615-599,683) when compared to ADT + D. Considering three times of GDPpc as WTP threshold, ADT + D is more cost-effective in all simulations; while ADT + AA is more cost-effective than ADT + D only if the cost of AA is reduced by at least 63%. The low-dose AA (250 mg) strategy is potentially cost-effective when it generates equivalent efficacy as the standard dosage (1000 mg).. ADT + D is therefore shown to be a more cost-effective strategy than ADT + AA in metastatic castration-sensitive prostate cancer patients in developed economies. Addition of AA substantially improved QALY compared to D but at a significant cost.

Topics: Abiraterone Acetate; Cost-Benefit Analysis; Disease Management; Docetaxel; Drug Costs; Health Care Surveys; Hong Kong; Humans; Male; Markov Chains; Prostatic Neoplasms, Castration-Resistant; Quality-Adjusted Life Years; Treatment Outcome

Prostate cancer care in the Middle East is highly variable and access to specialist multidisciplinary management is limited. Academic tertiary referral centers offer cutting-edge diagnosis and treatment; however, in many parts of the region, patients are managed by non-specialists with limited resources. Due to many factors including lack of awareness and lack of prostate-specific antigen (PSA) screening, a high percentage of men present with locally advanced and metastatic prostate cancer at diagnosis. The aim of these recommendations is to assist clinicians in managing patients with different levels of access to diagnostic and treatment modalities.. The first Advanced Prostate Cancer Consensus Conference (APCCC) satellite meeting for the Middle East was held in Beirut, Lebanon, November 2017. During this meeting a consortium of urologists, medical oncologists, radiation oncologist and imaging specialists practicing in Lebanon, Syria, Iraq, Kuwait and Saudi Arabia voted on a selection of consensus questions. An additional workshop to formulate resource-stratified consensus recommendations was held in March 2019.. Variations in practice based on available resources have been proposed to form resource-stratified recommendations for imaging at diagnosis, initial management of localized prostate cancer requiring therapy, treatment of castration-sensitive/naïve advanced prostate cancer and treatment of castration-resistant prostate cancer.. This is the first regional consensus on prostate cancer management from the Middle East. The following recommendations will be useful to urologists and oncologists practicing in all areas with limited access to specialist multi-disciplinary teams, diagnostic modalities and treatment resources.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Biopsy, Large-Core Needle; Bone Neoplasms; Docetaxel; Endosonography; Health Resources; Health Services Accessibility; Humans; Iraq; Kallikreins; Kuwait; Lebanon; Lymph Node Excision; Magnetic Resonance Imaging; Male; Margins of Excision; Middle East; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radiotherapy, Adjuvant; Risk; Salvage Therapy; Saudi Arabia; Syria

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Metformin; Pilot Projects; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Bone Density; Bone Neoplasms; Double-Blind Method; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radium

Topics: Abiraterone Acetate; Benzamides; Cross-Over Studies; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

Abiraterone acetate (AA) plus prednisone is an approved treatment of advanced prostate cancer (PCa). Autophagy is linked to drug resistance in numerous types of cancers. We hypothesized, that upregulation of autophagy is one of the mechanisms by which PCa cells survive AA anti-tumor treatment and therefore evaluated the potential effect of a combination with autophagy inhibition.. Human PCa LNCaP cell lines were cultured in steroid-free medium and treated with AA. Autophagy was inhibited by 3-methyladenine, chloroquine and ATG5 siRNA knock-down. Cell viability and apoptosis was assessed by flow cytometry and fluorescence microscopy, and autophagy was monitored by immunohistochemistry, AUTOdot and Western blotting.. Western blot revealed upregulation of ATG5 and LC3 II with a reduction of p62 protein expression in AA-treated cells, indicating upregulation of autophagy. These data were supported by results obtained with immunocytochemistry and AUTOdot assays. Using flow cytometry, we showed that combining AA with autophagy inhibition significantly impaired cell viability (1.3-1.6-fold, p < 0.001) and increased apoptosis (1.4-1.5-fold, p < 0.001) compared to AA treatment alone.. AA activates autophagy as a cytoprotective mechanism in LNCaP prostate cancer cells and targeting of autophagy enhances the antitumor effect of the compound.

Topics: Abiraterone Acetate; Adenine; Antineoplastic Agents; Apoptosis; Autophagy; Autophagy-Related Protein 5; Cell Death; Cell Line, Tumor; Cell Survival; Chloroquine; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms, Castration-Resistant

New therapies with diverse mechanisms of action are available for metastatic castration-resistant prostate cancer (mCRPC). This study aims to evaluate the effectiveness, safety and cost of abiraterone acetate (AA) in patients with mCRPC.. Observational retrospective cohort study in which mCRPC patients who initiated AA between January 1, 2012 and December 31, 2017, were included. The patients were followed-up until death or March 31, 2018. Demographic, clinical and economic data were collected from the corporate electronic information systems. Survival distributions were estimated using the Kaplan-Meier method and compared using the log-rank test.. A total of 69 mCRPC patients were started on AA, of whom 18 (26.1%) received prior chemotherapy (post-CT) and 51 (73.9%) did not receive it (CT-naïve). A PSA decline of ≥ 50% was achieved in five (27.8%) post-CT and 32 (62.7%) CT-naïve patients (p = 0.011). Median time to PSA progression, progression-free survival (PFS) and overall survival (OS) were 4.4/7.9 months (p = 0.003), 5.1/7.5 months (p = 0.034) and 12.1/21.3 months (p = 0.119), respectively, for post-CT/CT-naïve patients. Treatment-related adverse events (AEs) occurred in 10 (55.6%) post-CT and 11 (21.6%) CT-naïve patients (p = 0.007). The most common AEs were hypokalaemia (11.6%), hypertension (8.7%) and fatigue (5.8%). The cost per median PFS month and per median OS month was €2818.4/€2784.3 and €1187.9/€980.4 for post-CT/CT-naïve patients, respectively.. CT-naïve patients treated with AA obtained a better clinical benefit in terms of effectiveness, safety and cost-effectiveness ratio than post-CT patients. The effectiveness outcomes were poorer than those reported previously in the clinical trial setting.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Cohort Studies; Disease-Free Survival; Humans; Kaplan-Meier Estimate; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

In the pre-chemotherapy (CT) and post-CT settings of metastatic castration-resistant prostate cancer (mCRPC), abiraterone acetate plus prednisone (AAP) significantly extended median overall survival and radiographic progression-free survival (PFS) compared with prednisone alone. Yet, few data are available on therapy efficacy in the subgroup with visceral metastases, who represent a small population with poor prognosis. The aim of this study was to describe the clinical experience of AAP in patients with mCRPC with liver and/or lung metastases in real-world setting. We retrospectively reviewed the clinical records of patients with mCRPC with liver and/or lung metastases treated at the National Cancer Institute 'Fondazione G. Pascale' from September 2011 to May 2017. Co-primary end points were overall survival and radiographic PFS. Survival estimates were computed using Kaplan-Meier method. Secondary end points were response rate and safety. Of 143 patients with mCRPC treated, 18.9% (N=27) had visceral metastases: 85.2% (N=23) of the lung, 11.1% (N=3) of the liver and 3.7% (N=1) of both. Median PFS was 13.1 months [95% confidence interval (CI): 4.8-NA] in the pre-CT setting (N=11, median follow-up: 12.9 months), and 10.5 months (95% CI: 4.4-16.6) in the post-CT setting (N=16, median follow-up: 17.2 months). Pre-CT and post-CT patients with lung metastases had a median PFS of 16.5 months (95% CI: 4.3-NA) and 11.4 months (95% CI: 4.2-17.0), respectively. AAP tolerability was consistent with that previously reported in patients with mCRPC, without new safety concerns. Our finding provides preliminary evidence that AAP in real-world setting is a potential effective and safe therapeutic option for patients with mCRPC with a more advanced disease associated with the presence of visceral metastases, in both the pre-CT and post-CT settings.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Follow-Up Studies; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate

Clinical studies have demonstrated the benefits of abiraterone acetate + prednisone (AAP) and enzalutamide (ENZ) in significantly improving survival among metastatic castration-resistant prostate cancer (mCRPC) patients. However, evidence regarding patient's real-world experience, particularly with respect to fatigue, treatment satisfaction and health-related quality of life (HRQoL) is limited. Interviews were initially conducted with patients (n = 38) and carers (n = 12) to elicit qualitative data regarding their experiences. Findings informed the design of a quantitative, multinational online survey of mCRPC patients (n = 152) receiving AAP or ENZ. Participants completed validated questionnaires assessing fatigue (Brief Fatigue Inventory), treatment satisfaction (Cancer Therapy Satisfaction Questionnaire) and HRQoL (EuroQol-5-Dimensions). Results indicated that patients were generally satisfied with these therapies, more specifically with reductions in prostate-specific antigen levels and extended survival. Fatigue was commonly linked to poor HRQoL and responses indicated that significantly fewer patients in the AAP group reported feeling usually tired or fatigued in the last week compared to the ENZ group (33% vs. 55%, p = 0.006 respectively). Findings highlight the benefit of AAP and ENZ in promoting the "quality" of extended survival. That fatigue was lower among patients receiving AAP may be important for informing treatment decisions. Further research is needed to gain deeper insights.

Topics: Abiraterone Acetate; Adenocarcinoma; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Fatigue; Health Status; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Patient Satisfaction; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Qualitative Research; Quality of Life

Topics: Abiraterone Acetate; Aged, 80 and over; Antineoplastic Agents; Bone Neoplasms; Contraindications, Drug; Disease Progression; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Mineralocorticoid Receptor Antagonists; Neoplasm Staging; Prostatic Neoplasms, Castration-Resistant; Spironolactone; Treatment Outcome; Withholding Treatment

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Humans; Male; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Disease-Free Survival; Genotype; Germ-Line Mutation; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Organic Anion Transporters; Polymorphism, Single Nucleotide; Prednisone; Prostate; Prostatic Neoplasms, Castration-Resistant

To evaluate the value of the serum neuroendocrine differentiation (NED) markers in helping to select the best treatment sequence of abiraterone acetate (AA) and docetaxel-prednisone (DP) in mCRPC.. Eighty-eight mCRPC patients were identified (42 in the DP-to-AA group and 46 in the AA-to-DP group). The serum levels of NED markers were measured before the first-line treatment in 88 patients and also before and after DP therapy in 38 patients. We determined their impact on OS, radiographic progression-free survival (rPFS), and PSA-PFS.. In men with an elevation of at least one NED marker (n = 46) before the first-line treatment, those who received AA and then DP had significantly better worse OS (21.7 months [95% CI 21.0-22.4] vs 19.9 months (95% CI 15.3-24.5); P = 0.023. In a multivariate Cox regression analysis, treatment sequencing selection (selecting DP-AA rather than AA-DP) independently predicted OS (HR 0.4, 95% CI 0.2-0.9, P = 0.035) in patients with an elevation of at least one NED marker. However, in the subgroup without NED marker elevation, there was no significant difference in clinical outcomes between AA-DP and DP-AA groups (all P > 0.05). In the group with continued NED marker evaluation during DP treatment, patients with higher baseline NED markers and obtaining PSA response to DP were more inclined to experience NED markers decline.. Elevated pretreatment serum NED markers might indicate mCRPC patients would get better clinical outcomes from DP-AA than AA-DP. In contrast, those without NED marker elevation had similar outcomes regardless of which agent was chosen first. mCRPC patients with elevated NED markers and chemotherapy response were more inclined to obtain NED markers decline during DP therapy, which could account for this phenomenon.

Topics: Abiraterone Acetate; Aged; Antigens, Differentiation; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Monitoring; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Patient Selection; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant

With the recent introduction of novel treatment options, real-world data from patients with metastatic castration-resistant prostate cancer (mCRPC) are required to better understand the impact on routine clinical practice. This study primarily aimed to describe the time to treatment failure (TTF) of mCRPC patients treated with abiraterone acetate plus prednisone or the corticosteroid of choice (AAP) in the pre-chemotherapy setting. Other relevant outcomes, clinical and treatment characteristics of these patients were also evaluated.. This retrospective, observational study collected data from chemotherapy-naïve mCRPC patients treated with AAP from four European countries. Kaplan-Meier curves were used to estimate TTF, progression-free survival (PFS), and time to first skeletal-related event. The impact of baseline characteristics on TTF and PFS was explored using univariate and multivariate Cox proportional hazard models. Log-rank test was used to assess the potential role of duration of response to ADT in predicting response to AAP treatment.. Data from 481 eligible patients (Belgium: 68; France: 61; Germany: 150; UK: 202) were analysed. At AAP initiation, the median age of patients was 75.0 years (interquartile range [IQR]: 69.0-81.0), and the median PSA was 56.2 ng/mL (IQR: 22.2-133.1), with over 50% of patients presenting an ECOG score of 0 or 1. Visceral metastases were present in 7.5% of patients; an exclusion criterion in the COU-AA-302 clinical trial. The median TTF with AAP was 10.0 months (95%CI: 9.2-11.1) and the median PFS was 10.8 months (95%CI: 9.6-11.8). Shorter TTF was significantly associated with higher ALP (> 119 units/L), higher PSA (> 56.2 ng/mL), or poorer ECOG PS scores at AAP initiation (p < 0.05). Patients with longer duration of response to ADT (≥12 months) presented longer TTF and longer time to progression (p < 0.0001).. This European real-world study provides valuable insights into the characteristics, treatment, and outcomes of chemotherapy-naïve patients with mCRPC who received AAP in routine clinical practice. Treatment effectiveness of AAP in the real-world is maintained despite patients having poorer clinical features at initiation than those observed in the COU-AA-302 trial population.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Comorbidity; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Prednisone; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Topics: Abiraterone Acetate; Humans; Male; Neoplasms, Second Primary; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radium

Results from the ERA 223 trial of abiraterone combined with radium-223 among men with chemotherapy-naïve castration-resistant prostate cancer and bone metastases show no improvement in survival free from symptomatic skeletal events. We hypothesize that this finding might be attributable to bone loss induced by the concomitantly administered prednisone.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Fractures, Bone; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium; Treatment Outcome

To explore adherence to oral hormone treatment in patients with metastatic prostate cancer (mCRPC) and to identify the factors that influence it.. A qualitative exploratory study was conducted at the National Cancer Institute of Rome. Patients aged >18 years with castration-resistant prostate cancer (mCRPC) and who were using oral hormone drugs were recruited. Semi-structured interviews were used for data collection, subsequently transcribed verbatim and analysed using Ritchie and Spencer's framework analysis.. The sample included 13 patients with a median age of 72 who were treated, on average, for seven months with abiraterone acetate (AA) (76.9%) and enzalutamide (ENZ) (23.1%). Five themes were identified: expression of the concept of adherence, favouring factors, obstacle factors, functional strategies and levels of adherence.. The patients express a good level of adherence, which they define in different ways-the helping relationship with the attending physician, the support of the family members and the few side effects of the drugs. For the future, it is recommended to perform a multicentre mixed method study to explain the levels of adherence and distress in women with breast cancer.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Humans; Male; Medication Adherence; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Qualitative Research; Treatment Outcome

Topics: Abiraterone Acetate; Double-Blind Method; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radium

To compare the prognostic outcomes between first-generation antiandrogen (FGA) and novel androgen-receptor-axis-targeted agent (ARATA) as first-line therapy in patients with non-metastatic castration-resistant prostate cancer (nmCRPC).. This study retrospectively included a total of 103 consecutive nmCRPC patients consisting of 47 (45.6%) and 56 (54.4%) who received FGA (bicalutamide or flutamide) and ARATA (abiraterone acetate or enzalutamide), respectively, as the first-line agent after the failure of primary androgen deprivation therapy (ADT).. There were no significant differences in the major clinicopathological parameters and previous therapeutic histories between the FGA and ARATA groups. During the observation period, 31 (66.0%) and 29 (51.8%) discontinued first-line therapy in the FGA and ARATA groups, respectively, and of these, 27 (87.1%) and 23 (79.3%) in the FGA and ARATA groups, respectively, were subsequently treated with approved agents as second-line therapy. The prostate-specific antigen (PSA) response rate in the FGA group was significantly lower than that in the ARATA group. Although no significant difference in overall survival was noted between the FGA and ARATA groups, there were significant differences in the PSA progression-free survival on first-line therapy and metastasis-free survival between the two groups, favoring the ARATA group compared with FGA group.. Collectively, these findings suggest that among nmCRPC patients who progressed following treatment with the primary ADT, the introduction of ARATA may result in the delay of disease progression compared with FGA.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Benzamides; Humans; Male; Middle Aged; Molecular Targeted Therapy; Nitriles; Phenylthiohydantoin; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; Treatment Outcome

Nearly 80% of advanced prostate cancer patients respond to initial androgen deprivation therapy (ADT). However, ADT does not prevent the progression of prostate cancer over the long term, and the disease eventually progresses to castration-resistant prostate cancer (CRPC). Prior to the development of enzalutamide (ENZ) and abiraterone acetate, docetaxel was the only established treatment with life-prolongation for CRPC. ENZ is a second-generation anti-androgen receptor drug that has contributed to improving the prognosis of CRPC. Several studies have reported factors predicting the efficacy of ENZ; however, there are no confirmed biomarkers. The neutrophil-to-lymphocyte ratio (NLR) is an easily calculated biomarker that is associated with the prognosis of several solid malignancies. However, there were few studies investigated NLR for ENZ in patients with mCRPC. We examined the usefulness of the NLR as a predictive tool for ENZ.. We retrospectively examined a total of 106 CRPC patients who were treated with ENZ until September 2016 in Yokohama City University Hospital, Yokohama City University Medical Center, and National Cancer Center Hospital East. ENZ was routinely started as a dose of 160 mg per day; the dosage was reduced in some patients due to side effects. Drug holiday for 1-2 weeks or dose reduction to 80-120mg was done and no patients discontinued ENZ treatment due to adverse effects. ENZ was stopped when cancer progression was detected based on PSA elevation, radiographic findings, and deterioration of the patient's performance status. The cut-off NLRs for overall survival (OS) and cancer-specific survival (CSS) were determined based on the receiver-operator curves. Kaplan-Meier curves were used to analyze the factors associated with OS or CSS and a log-rank test was performed. A multivariate analysis was also performed to analyze the factors associated with the prognosis.. We retrospectively reviewed 106 consecutive CRPC patients who were both treated with ENZ and were able to be counted before ENZ NLR. Cut-off point was 2.14 for both OS and CSS by receiver operator characteristic curve. The patients were then divided into the higher NLR group (≥2.14) and lower NLR group (<2.14). Multivariate analysis showed that NLR and predocetaxel chemotherapy were independent risk factors for both overall and cancer-specific survival.. The NLR might be a useful biomarker for predicting the prognosis of mCRPC patients who are treated with ENZ.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Agents; Benzamides; Disease Progression; Disease-Free Survival; Docetaxel; Humans; Lymphocytes; Male; Neutrophils; Nitriles; Phenylthiohydantoin; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Topics: Abiraterone Acetate; Androstenes; Artifacts; Clinical Laboratory Techniques; Humans; Immunoassay; Male; Prostatic Neoplasms, Castration-Resistant; Testosterone

Prostate cancer is the most common malignancy among men in the Western world. Treatment of this patient population, e.g. by (chemical) castration, is primarily focused on depletion of tumor-stimulating androgens, with testosterone being the major androgenic hormone. After initial therapy, prostate cancer may progress to metastatic castration-resistant prostate cancer. Anti-hormonal drugs abiraterone acetate and enzalutamide are commonly used to treat patients with this disease as both drugs reduce tumor growth and increase time to tumor progression. To evaluate the pharmacodynamic effects of anti-hormonal drugs in this patient population, we developed an LC-MS/MS method for the quantification of testosterone, dihydrotestosterone, androstenedione, cortisol and prednisone in human plasma. The validated assay ranges from 10-10,000 pg/mL for testosterone and androstenedione, 100-10,000 pg/mL for dihydrotestosterone, 50-5000 pg/mL for cortisol and 500-50,000 pg/mL for prednisone. Intra-assay and inter-assay variabilities were within ±15% of the nominal concentrations for quality control (QC) samples at low, medium and high concentrations and within ±20% at the lower limit of quantification (LLOQ), respectively. The applicability of the method was demonstrated in plasma from patients with metastatic castrated-resistant prostate cancer using either abiraterone acetate or enzalutamide.

Topics: Abiraterone Acetate; Androstenedione; Benzamides; Chromatography, Liquid; Dihydrotestosterone; Humans; Hydrocortisone; Male; Nitriles; Phenylthiohydantoin; Plasma; Prednisone; Prostatic Neoplasms, Castration-Resistant; Tandem Mass Spectrometry; Testosterone

Currently, there are no predictive markers of response to abiraterone. We calculated neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at baseline and at 4 and 12 weeks after initiation of abiraterone, and we evaluated prostate-specific antigen (PSA) response every 4 weeks in 102 metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone either pre- or postchemotherapy. With a median follow-up was 24.0 months (range: 0.3-54.9), median overall survival (OS) was 20.8 months. High-NLR patients who remained high or who returned to low NLR after 4 and 12 weeks showed significantly worse OS than patients with low baseline NLR. NLR and prostate-specific antigen response to abiraterone was a significant predictor of OS and progression-free survival (PFS) in metastatic castration-resistant prostate cancer patients treated with abiraterone delivered either pre- or postchemotherapy.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Blood Platelets; Follow-Up Studies; Humans; Lymphocytes; Male; Middle Aged; Neutrophils; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate

Intratumoral steroidogenesis and its potential relevance in castration-resistant prostate cancer (CRPC) and in cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1)-inhibitor treated hormone-naïve and patients with CRPC are not well established. In this study, we tested if substrates for de novo steroidogenesis accumulating during CYP17A1 inhibition may drive cell growth in relevant preclinical models.. PCa cell lines and their respective CRPC sublines were used to model CRPC in vitro. Precursor steroids pregnenolone (Preg) and progesterone (Prog) served as substrate for de novo steroid synthesis. TAK700 (orteronel), abiraterone, and small interfering RNA (siRNA) against CYP17A1 were used to block CYP17A1 enzyme activity. The antiandrogen RD162 was used to assess androgen receptor (AR) involvement. Cell growth was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. AR-target gene expression was quantified by reverse transcription polymerase chain reaction (RT-PCR). Nuclear import studies using cells with green fluorescent protein (GFP)-tagged AR were performed to assess the potential of precursor steroids to directly activate AR.. Preg and Prog stimulated cell proliferation and AR target gene expression in VCaP, DuCaP, LNCaP, and their respective CRPC sublines. The antiandrogen RD162, but not CYP17A1 inhibition with TAK700, abiraterone or siRNA, was able to block Preg- and Prog-induced proliferation. In contrast to TAK700, abiraterone also affected dihydrotestosterone-induced cell growth, indicating direct AR binding. Furthermore, Prog-induced AR translocation was not affected by treatment with TAK700 or abiraterone, while it was effectively blocked by the AR antagonist enzalutamide, further demonstrating the direct AR activation by Prog.. Activation of the AR by clinically relevant levels of Preg and Prog accumulating in abiraterone-treated patients may act as a driver for CRPC. These data provide a scientific rationale for combining CYP17A1 inhibitors with antiandrogens, particularly in patients with overexpressed or mutated-AR.

Topics: Abiraterone Acetate; Cell Growth Processes; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Male; Pregnenolone; Progesterone; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Steroid 17-alpha-Hydroxylase; Steroids

Abiraterone improves survival in metastatic castration-resistant prostate cancer (mCRPC) but may result in the development or worsening of comorbid conditions. We assessed the course of these conditions in patients receiving abiraterone in clinical practice and compared outcomes with those in clinical trials.. Medical records of patients with mCRPC who started abiraterone at an academic institution between 2012 and 2015 were reviewed for emergency department (ED) visits, hospitalizations, and the development and/or worsening of key comorbid conditions while on abiraterone. Patient characteristics and adverse events were compared with those from clinical trials.. In a cohort of 174 patients, 28% experienced either the development or worsening of a comorbid disease; 8% required an ED visit or hospitalization owing to known adverse effects of abiraterone. Increasing age (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.17), higher prostate-specific antigen at initiation of treatment (OR, 1.68; 95% CI, 1.18-2.47), preexisting uncontrolled hypertension (OR, 7.61; 95% CI, 1.22-38.70), congestive heart failure (OR, 7.61; 95% CI, 1.22-38.70), and cardiac arrhythmias (OR, 4.73; 95% CI, 1.39-15.12) were associated with increased odds of an ED visit or hospitalization owing to known adverse effects of abiraterone. The rate of discontinuation (6%) was similar to 1 phase III trial that demonstrated the drug's efficacy in chemotherapy-naive patients.. Few patients discontinued abiraterone owing to toxicity; however, the fact that over one-quarter of patients experienced the development or worsening of cardiovascular and metabolic diseases warrants development of team-based approaches to the management of these comorbid conditions.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Cardiovascular Diseases; Emergency Service, Hospital; Hospitalization; Humans; Hypertension; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androstenes; Double-Blind Method; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium

Topics: Abiraterone Acetate; Androstenes; Double-Blind Method; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium

To identify the impact of red cell distribution width (RDW) on treatment outcomes in patients with castration-resistant prostate cancer (CRPC) treated with androgen receptor axis-targeted agents (ARATs).. Baseline data were obtained from 153 patients with CRPC treated with ARATs. Patients were stratified according to the upper limit of the normal RDW range, measured within 1 month before starting treatment. Relationships between RDW levels and the best prostate-specific antigen (PSA) response, PSA progression-free survival, and overall survival were examined.. Forty-nine patients were treated with abiraterone acetate in combination with corticosteroid and 104 with enzalutamide. The median RDW was 13.7% (interquartile range, 13.0-14.9). High RDW was significantly associated with prior use of docetaxel (P < .001), presence of lymph node metastasis (P = .031), presence of visceral metastasis (P = .001), and low hemoglobin (P < .001), low albumin (P = .016), and high C-reactive protein levels (P = .02). In a multiple linear regression model, there was a statistically significant negative association between RDW levels and the best PSA response (P = .046). In addition, multivariate Cox regression analyses showed that high RDW was an independent predictor of both shorter PSA progression-free survival (hazard ratio = 1.84; 95% confidence interval, 1.04-3.27; P = .037) and overall survival (hazard ratio = 2.62; 95% confidence interval, 1.15-5.98; P = .022), showing statistical significance.. High RDW is an independent predictor of worse treatment outcomes in patients with CRPC treated with ARATs. RDW could be a readily available and inexpensive biomarker for predicting primary resistance to ARATs.

Topics: Abiraterone Acetate; Adrenal Cortex Hormones; Aged; Aged, 80 and over; Benzamides; Erythrocyte Indices; Humans; Male; Molecular Targeted Therapy; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Analysis; Treatment Outcome

This study examined the inter- and intra-patient variability in pharmacokinetics of AA and its metabolites abiraterone and Δ(4)-abiraterone (D4A), and potential contributing factors.. AA administered daily for ≥4 weeks concurrently with androgen deprivation therapy (ADT) for mCRPC were included. Pharmacokinetic evaluation was performed at two consecutive visits at least 4 weeks apart. Plasma samples were collected 24 h after last dose of AA to obtain drug trough level (DTL) of two active metabolites, abiraterone and D4A.. 39 plasma samples were obtained from 22 patients, with 17 patients had repeat DTL measurement. Considerable inter-patient variability in DTL was seen, with initial DTL for abiraterone ranging between 1.5 and 25.4 ng/ml (CV 61%) and for D4A between 0.2 and 2.5 ng/ml (CV 61%). Intra-patient variability in DTL for abiraterone varied between 0.85 and 336% and for D4A between 1.14 and 199%. There was no increase in AA exposure with use of dexamethasone (n = 5; DTL 13.9) compared with prednisone (n = 17; DTL 11.0 p = 0.5), dosing in fasted state (n = 13, DTL 12.1) compared to dosing in fed state (n = 9; DTL 11.1, p = 0.8), or chemotherapy-exposed (n = 10; DTL 8.9) compared to chemotherapy naïve (n = 12; DTL 14.0, p = 0.1).. Our cohort demonstrated high inter- and intra-patient variability in both abiraterone and D4A with fixed dosing of AA, with no effect from choice of corticosteroids, prior use of chemotherapy, or dosing in fasting state. Monitoring DTL of AA may be necessary to minimise risk of patients being under-dosed and earlier development of resistance.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Fasting; Humans; Longitudinal Studies; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

This study aimed to evaluate the therapeutic effect of enzalutamide (ENZ) or abiraterone acetate (ABI) on bone metastasis in castration-resistant prostate cancer (CRPC), using bone scan index (BSI).. Treatment outcomes for 31 patients who had undergone ENZ or ABI treatment were examined for CRPC with bone metastases. Cox proportional-hazards regression models were used to investigate the association between overall survival (OS) and clinical characteristics.. Median OS after ENZ or ABI treatment was 29 months. Considering the flare phenomenon, BSI in 17 (55%) patients decreased following treatment. In multivariate analysis, low baseline BSI value and a decrease in BSI following treatment were associated with longer OS (hazard ratio [HR]=8.009; p=0.35 and HR=7.025; p=0.045*, respectively).. Low BSI value before ENZ/ABI treatment and a decrease in BSI following ENZ or ABI treatment are independent predictors of longer OS. BSI could be useful for risk assessment of CRPC patients with bone metastases.

Topics: Abiraterone Acetate; Aged; Benzamides; Bone and Bones; Bone Neoplasms; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radionuclide Imaging

We report two elderly patients receiving peritoneal dialysis with castration-resistant prostate cancer (CRPC). Herein, we show that the patients were safely treated using abiraterone acetate (750 mg/day orally once daily) and prednisolone (5 mg/day orally once daily). Although the prostate-specific antigen (PSA) level increased in both cases, there was no manifestation of disease progression (clinical and radiographic) for 22 months in case 1 and 8 months in case 2. In case 2, the only adverse event was hypokalemia, which was treated using potassium preparations.

Topics: Abiraterone Acetate; Administration, Oral; Aged, 80 and over; Antineoplastic Agents; Castration; Humans; Hypokalemia; Male; Peritoneal Dialysis; Potassium; Prednisolone; Prostatic Neoplasms, Castration-Resistant; Time Factors; Treatment Outcome

Topics: Abiraterone Acetate; Aged; Androstenes; Feasibility Studies; Humans; Liver Transplantation; Male; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Topics: Abiraterone Acetate; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

There are few reports that verify the relationship between the therapeutic effects of flutamide and novel androgen receptor-targeted agents. We aimed to evaluate the benefits of flutamide as an alternative anti-androgen agent and its effects on the efficacy of novel androgen receptor-targeted agents.. Patients with castration-resistant prostate cancer on novel androgen receptor-targeted agents without prior docetaxel therapy were included. Changes in prostate-specific antigen (PSA) level were recorded.. Patients who responded well to flutamide (Flutamide effective) following initial maximum androgen blockade (MAB) showed significantly higher changes in serum PSA levels (p=0.039) and PSA-progression-free survival (PFS) rate (p=0.016) following enzalutamide therapy compared to those who did not respond well to flutamide. Multivariate analysis showed that the factor of Flutamide effective was significantly associated with a good PSA-PFS rate following enzalutamide therapy (HR=7.36, 95%CI=1.4-38.71, p=0.018).. Patients showing good response to flutamide following initial MAB may achieve a satisfactory PSA-PFS rate with subsequent enzalutamide therapy.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Docetaxel; Flutamide; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Treatment Outcome

Abiraterone (AA) and enzalutamide (ENZ) were introduced in Taiwan since 2012 for the treatment of patients with post-docetaxel metastatic castration-resistant prostate cancer (mCRPC). This study aims to retrospectively compare the efficacy of the two regimens.. The study cohort consisted of 77 mCRPC patients previously treated with docetaxel and subsequently with AA (n=63, the AA group) or ENZ (n=13, the ENZ group), all treated in our hospital. Clinical parameters of the two groups were compared to determine differences between pre-treatment variables and treatment outcomes.. Sixty-four patients received AA and 13 received ENZ, with a median 18.2 vs. 14.5 months follow-up (p=0.434). Prostate-specific antigen (PSA) response >50% was 31 (48.4%) in AA and 9 (69.2%) in ENZ (p=0.171), while PSA response >90% was 16 (25%) in AA and 5 (38.5%) in ENZ (p=0.32). The median progression-free survival (PFS) was 7.3 (95%CI=4.796-9.804) months in AA and 9.5 months (95%CI=5.743-13.257) in ENZ (p of log rank=0.766). The median overall survival (OS) from second-line hormone treatment was 30.2 months in AA group and 16.2 months in ENZ group (p of log rank=0.734). Neither the uni- nor the multi-variate COX-regression analysis distinguished any advantage of the two-drug regimen in terms of PFS or OS. Metastasis volume (HR=3.032, 95%CI=1.281-7.178, p=0.012) and nadir PSA (HR=1.000, 95%CI=1.000-1.001, p=0.010) were shown as independent risk factors for the survival of AA/ENZ-treated patients.. AA and ENZ had a similar efficacy in treating post-docetaxel mCRPC patients. Metastatic volume and nadir PSA were independent risk factors of these patients in predicting their disease-specific survival and overall survival.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Docetaxel; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Topics: Abiraterone Acetate; Bone Neoplasms; Double-Blind Method; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Radium

To describe the patterns of second-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel treatment in a Spanish population, to identify the factors associated with those patterns, and to compare the efficacy and safety of the treatments most frequently administered.. Observational, prospective study conducted in patients with histologically or cytologically confirmed prostate adenocarcinoma; documented metastatic castration-resistant disease; progression after first-line, docetaxel-based chemotherapy with or without other agents.. Of the 150 patients recruited into the study, 100 patients were prescribed abiraterone acetate plus prednisone (AAP), 44 patients received cabazitaxel plus prednisone (CP), and 6 patients received other treatments. Age (odds ratio [OR] 1.06, 95% [confidence interval] CI 1.01 to 1.11) and not elevated lactate dehydrogenase (LDH) levels (OR 0.33, 95% CI 0.14 to 0.76) were independently associated with the administration of AAP. Treatment with AAP was associated with significantly longer clinical/radiographic progression-free survival (hazard ratio [HR] 0.57, 95% CI 0.38 to 0.85) and overall survival (OS; HR 0.40, 95% CI 0.21 to 0.76) compared to CP, while no significant differences between the treatments were found regarding biochemical progression-free survival (PFS; HR 0.78 [95% CI 0.49 to 1.24]). However, in a post-hoc Cox regression analysis adjusted for potential confounders there were not differences between AAP and CP in any of the time-to-event outcomes, including overall survival. We observed no new safety signals related to either regimen.. Second-line AAP for patients with mCRPC is the most common treatment strategy after progression with a docetaxel-based regimen. When controlling for potential confounders, patients receiving this treatment showed no differences in PFS and OS in comparison to those receiving CP, although these latter results should be confirmed in randomized controlled trials.

Topics: Abiraterone Acetate; Adenocarcinoma; Age Factors; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Docetaxel; Humans; Kaplan-Meier Estimate; L-Lactate Dehydrogenase; Male; Middle Aged; Multivariate Analysis; Pain; Prednisone; Progression-Free Survival; Proportional Hazards Models; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Spain; Taxoids; Treatment Outcome

Although statin use has been associated with favorable effects in various solid malignancies, no conclusive evidence is available at present. Statins are safe and inexpensive, and may synergize with novel antiandrogen agents abiraterone via pharmacokinetic interactions and decrease substrate availability for de novo androgen biosynthesis.. To determine whether statin use affects survival in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone.. Medical records of patients with documented mCRPC between September 2011 and August 2016 were reviewed at multiple participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. A total of 187 patients receiving abiraterone for mCRPC between September 2011 and August 2016 were eligible for inclusion in this retrospective study.. Patients were assessed for overall survival (OS), statin use at the time of treatment initiation, prostate-specific antigen (PSA) variations, and other variables of interest. Univariable and multivariable analysis was used to explore the association of variables of interest with OS and PSA declines.. Statin use was a significant prognostic factor for longer OS in univariable (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.37-0.72; p<0.001) and multivariable analysis (HR 0.40, 95% CI 0.27-0.59; p<0.001) and was significantly associated with PSA declines (>50% decline at 12 wk: 72.1% in statin users vs 38.5% in non-users; p<0.001).. Our study suggests a prognostic impact of statin use in patients receiving abiraterone for mCRPC. The mechanism of this interaction warrants elucidation, but may include enhancement of the antitumor activity of abiraterone as well as cardioprotective effects.. We assessed the effects of statin use in patients with advanced prostate cancer receiving abiraterone. Patients treated with a statin plus abiraterone appeared to live longer than those treated with abiraterone only. Since no negative drug-drug interaction is known and statins are widely used and inexpensive, further studies assessing the use of abiraterone plus statins are warranted.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kallikreins; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Prognosis; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate

The testis-specific Y-encoded-like protein (TSPYL) gene family includes TSPYL1 to TSPYL6. We previously reported that TSPYL5 regulates cytochrome P450 (CYP) 19A1 expression. Here we show that TSPYLs, especially TSPYL 1, 2, and 4, can regulate the expression of many CYP genes, including CYP17A1, a key enzyme in androgen biosynthesis, and CYP3A4, an enzyme that catalyzes the metabolism of abiraterone, a CYP17 inhibitor. Furthermore, a common TSPYL1 single nucleotide polymorphism (SNP), rs3828743 (G/A) (Pro62Ser), abolishes TSPYL1's ability to suppress CYP3A4 expression, resulting in reduced abiraterone concentrations and increased cell proliferation. Data from a prospective clinical trial of 87 metastatic castration-resistant prostate cancer patients treated with abiraterone acetate/prednisone showed that the variant SNP genotype (A) was significantly associated with worse response and progression-free survival. In summary, TSPYL genes are novel CYP gene transcription regulators, and genetic alteration within these genes significantly influences response to drug therapy through transcriptional regulation of CYP450 genes.

Topics: Abiraterone Acetate; Cell Cycle Proteins; Cell Proliferation; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Dehydroepiandrosterone; DNA-Binding Proteins; Gene Expression Regulation; Gene Knockdown Techniques; Hep G2 Cells; Humans; Male; Neoplasm Metastasis; Nuclear Proteins; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; RNA, Messenger; Steroid 17-alpha-Hydroxylase; Treatment Outcome

Topics: Abiraterone Acetate; Benzamides; Europe; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Topics: Abiraterone Acetate; Humans; Male; Neoplasm Grading; Pain; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids

To investigate the overall survival (OS) of chemotherapy refractory patients with metastatic castration-resistant prostate cancer who were treated with abiraterone acetate + prednisolone (AA + P) beyond prostate specific antigen (PSA) and radiographic progression (PRP) until clinical progression in comparison to patients treated until PRP.. At our institute the AA + P treatment started in 2011 in an early-access protocol trial. In October 2012 AA became generally available. From April 2011 to November 2014, 116 patients received AA + P. The clinical trial patients (T; n = 56) were treated beyond PRP until clinical progression. In the nonclinical trial group (NT; n = 57) the treatment was covered until PRP. Three patients are still under treatment. The 2 groups were statistically homogeneous, except AA + P treatment duration. The primary objective was the OS and the secondary the PSA progression-free and radiographic progression-free survivals.. The median OS was significantly longer (P<0.0001) in the T group compared to the NT group: 21.9 (95% CI: 16.9-25) vs. 12.5 (9.3-14.1) months, respectively. In univariate analysis there were 11 parameters, which significantly affected OS, but in multivariate Cox analysis only alkaline phosphatase (AP) level at the start of treatment, systemic therapy after AA + P and cohort type (T or NT) proved to independently influence the OS. The progression-free survival curves of T and NT groups did not differ significantly.. In our retrospective analysis low levels of AP at the start of treatment, systemic therapy applied after AA + P and treatment beyond PRP proved to be independent factors of longer OS in metastatic castration-resistant prostate cancer.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Alkaline Phosphatase; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Humans; Male; Middle Aged; Neoplasm Metastasis; Outcome Assessment, Health Care; Prednisolone; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

Topics: Abiraterone Acetate; Androgens; Animals; Cell Line, Tumor; Core Binding Factor Alpha 1 Subunit; Cytochrome P-450 Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Knockout; Prostatic Neoplasms, Castration-Resistant; PTEN Phosphohydrolase; Signal Transduction; Steroid 17-alpha-Hydroxylase; Testosterone; Tumor Microenvironment; Xenograft Model Antitumor Assays

Patient-reported outcomes (PROs) are used to assess benefit-risk in drug development. The relationship between PROs and clinical outcomes is not well understood. We aim to elucidate the relationships between changes in PRO measures and clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC).. We investigated relationships between changes in self-reported fatigue, pain, functional well-being (FWB), physical well-being (PWB) and prostate cancer-specific symptoms with overall survival (OS) and radiographic progression-free survival (rPFS) after 6 and 12 months of treatment in COU-AA-301 (N = 1195) or COU-AA-302 (N = 1088). Eligible COU-AA-301 patients had progressed after docetaxel and had Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2. Eligible COU-AA-302 patients had no prior chemotherapy and ECOG PS 0 or 1. Patients were treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day) or prednisone alone daily. Association between self-reported fatigue, pain and functional status, and OS and/or rPFS, using pooled data regardless of treatment, was assessed. Cox proportional hazard regression modeled time to death or radiographic progression.. In COU-AA-301 patients, PRO improvements were associated with longer OS and longer time to radiographic progression versus worsening or stable PROs (P < 0.0001). In multivariate models, all except pain intensity remained associated with OS. Pain intensity, PWB and FWB improvements remained associated with rPFS. In COU-AA-302 patients, worsening PROs were associated with higher likelihood of radiographic progression (P ≤ 0.025) compared with improved or stable PROs. In multivariate models, worsening PWB remained associated with worse rPFS. The 12-month analysis confirmed the 6-month results.. PROs are significantly associated with clinically relevant time-to-event efficacy outcomes in clinical trials and may complement and help predict traditional clinical practice methods for monitoring patients for disease progression.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Disease-Free Survival; Double-Blind Method; Humans; Male; Middle Aged; Patient Reported Outcome Measures; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Surveys and Questionnaires; Treatment Outcome

Topics: Abiraterone Acetate; Androstenes; Cell Cycle; Cell Proliferation; Genome-Wide Association Study; Humans; Male; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Wnt Signaling Pathway

Two androgen receptor (AR)-targeted therapies, enzalutamide and abiraterone acetate plus prednisone (abiraterone), have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). Many patients respond to these agents, but both de novo and acquired resistance are common. The authors characterized resistant phenotypes that emerge after treatment with abiraterone or enzalutamide.. Patients who received abiraterone or enzalutamide in the course of routine clinical care were consented for serial blood collection. A proprietary system (CellSearch) was used to enumerate and enrich circulating tumor cells (CTCs). RNA-sequencing (RNA-seq) was performed on pools of up to 10 epithelial cell adhesion molecule (EpCAM)-positive/CD45-negative CTCs. The impact of gene expression changes observed in CTCs between patients who responded or were resistant to abiraterone/enzalutamide therapies was further explored in a model cell line system.. RNA-seq data from CTCs identified mutations commonly associated with CRPC as well as novel mutations, including several in the ligand-binding domain of AR that could facilitate escape from AR-targeted agents. Ingenuity pathway analysis of differentially regulated genes identified the transforming growth factor β (TGFβ) and cyclin D1 (CCND1) signaling pathways as significantly upregulated in drug-resistant CTCs. Transfection experiments using enzalutamide-sensitive and enzalutamide-resistant LNCaP cells confirmed the involvement of SMAD family member 3, a key mediator of the TGFβ pathway, and of CCND1 in resistance to enzalutamide treatment.. The current results indicate that RNA-seq of CTCs representing abiraterone and enzalutamide sensitive and resistant states can identify potential mechanisms of resistance. Therapies targeting the downstream signaling mediated by SMAD family member 3 (SMAD3) and CCND1, such as cyclin-dependent kinase 4/cyclin-dependent kinase 6 inhibitors, could provide new therapeutic options for the treatment of antiandrogen-resistant disease. Cancer 2018;124:1216-24. © 2017 American Cancer Society.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers, Tumor; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Resistance, Neoplasm; Humans; Male; Middle Aged; Neoplastic Cells, Circulating; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Signal Transduction; Smad3 Protein

The objective of the present study was to assess the oncologic outcomes of patients receiving second-line therapy against metastatic castration-resistant prostate cancer (mCRPC).. The present study included 222 consecutive mCRPC patients with progression during initial androgen receptor-axis-targeted agent (ARATA) therapy with either abiraterone acetate (AA) or enzalutamide (Enz). Of these 222 patients, 108 subsequently received an alternative ARATA (AA-to-Enz, n = 49; Enz-to-AA, n = 59) and 114 received docetaxel (DTX; AA-to-DTX, n = 54; Enz-to-DTX, n = 60).. The prostate-specific antigen (PSA) level in the 114 patients receiving DTX was significantly greater than that in the 108 patients receiving ARATA. However, no significant differences were found in the remaining parameters between the 2 groups. The PSA response rate, PSA progression-free survival (PFS), and overall survival (OS) during second-line therapy in the DTX group (n = 114) were significantly superior to those for the ARATA group (n = 108; PSA response rate, 42.1% vs. 21.3%; median PSA PFS, 7.2 vs. 4.2 months; median OS, 17.5 vs. 14.5 months). Similar trends were confirmed by comparing these outcomes among 4 therapy groups, with significant differences (PSA response rate, Enz-to-AA vs. AA-to-DTX and Enz-to-AA vs. Enz-to-DTX; PSA PFS, AA-to-Enz vs. Enz-to-AA, AA-to-Enz vs. AA-to-DTX, Enz-to-AA vs. AA-to-DTX, and Enz-to-AA vs. Enz-to-DTX; and OS, Enz-to-AA vs. AA-to-DTX and Enz-to-AA vs. Enz-to-DTX). Furthermore, the introduction of DTX was independently associated with improved PSA PFS, but not OS, on multivariate analysis.. Favorable oncologic outcomes can be expected with DTX treatment, rather than with alternative ARATA, for mCRPC patients after failure of an initial ARATA.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Docetaxel; Humans; Japan; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Treatment Outcome

With the advent of secondary androgen receptor (AR)-targeted therapies in metastatic castration resistant prostate cancer (PC), nonadenocarcinoma PCs are becoming more prevalent. Many of these cancers express neuroendocrine markers, which may provide biomarkers for emergence of this disease state. We aimed to quantify the expression of synaptophysin (Syp) on circulating tumor cells (CTCs) from serial samples of patients being treated with abiraterone acetate or enzalutamide.. CTCs were isolated from 44 patients with castration resistant PC before starting abiraterone or enzalutamide, at 4, 8, and 12 weeks on therapy, and at progression. Patients were stratified into 3 groups: de novo resistance, short response, and long response. CTCs were enumerated on the CellSearch platform and Syp expression was quantified using the open fluorescent channel on the platform. Correlative analyses were performed.. A baseline CTC count of 5 or greater was associated with a more rapid time to progression and increasing CTC counts correlated with emergence of drug resistance. Syp was readily detectable on the surface of CTCs, and baseline percentage CTC Syp expression was significantly associated with time to progression. Furthermore, in evaluable patients, percent CTC Syp expression increased with the emergence of drug resistance. We also found that prior exposure to AR-targeted therapies was inversely associated with progression free survival.. We have demonstrated that Syp can be quantified on CTCs and that Syp expression correlates with resistance to abiraterone and enzalutamide. Larger studies testing Syp as a biomarker of emergence of nonadenocarcinoma disease and as a marker of response to AR-targeted therapies are warranted.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Follow-Up Studies; Humans; Male; Middle Aged; Neoplastic Cells, Circulating; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Synaptophysin; Treatment Outcome

The aim of this study is to evaluate cardiotoxicity of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer patients (pts) with cardiovascular comorbidities or coronary artery disease (CAD) risk factors.. We prospectively analyzed pts receiving AA in order to evaluate correlations between cardiotoxicity onset and CAD risk factors or cardiovascular comorbidities.. Eighty-seven pts were enrolled, with median treatment duration of 9 months (1-44). At baseline, 84 pts (96%) had CAD risk factors. During treatment four pts (4; 6%) developed hypertension and 26 pts (30%) worsened the preexisting hypertension. Median left ventricular ejection fraction were 64 and 63% at baseline and after treatment, respectively.. AA appears to be safe in pts with cardiovascular comorbidities or CAD risk factors.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Cardiotoxicity; Cardiovascular Diseases; Comorbidity; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Risk Factors

Topics: Abiraterone Acetate; Humans; Male; Patient Reported Outcome Measures; Prednisone; Prostatic Neoplasms, Castration-Resistant; Quality of Life

Topics: Abiraterone Acetate; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

Decreased abiraterone exposure after introducing carbamazepine.. Abiraterone acetate and carbamazepine.. A 65-year-old man with metastatic castration resistant prostate cancer, was treated with abiraterone acetate and prednisolone, and received concomitant carbamazepine for treatment of facial neuropathy.. The interaction was confirmed by a decrease in abiraterone exposure >2-fold (area-under-the-curve and trough levels). After discontinuation of carbamazepine therapy, the abiraterone exposure normalized. No alternative causes were found that explain the decrease in abiraterone exposure.. Induction of CYP3A and potentially phase I metabolism (SULT2A1) by carbamazepine.. Clinicians and pharmacists should be aware of this clinically relevant interaction. The national drug-drug interaction checker does not warn for this interaction, whereas both the Lexicomp® and Micromedex® advice to avoid if possible or to increase the abiraterone dose frequency to twice daily. Carbamazepine should not be combined with abiraterone to avoid underexposure and suboptimal therapy. Therapeutic drug monitoring of abiraterone is useful to guide therapy when drug-drug interactions cannot be avoided.

Topics: Abiraterone Acetate; Aged; Analgesics, Non-Narcotic; Antineoplastic Agents; Carbamazepine; Cytochrome P-450 CYP3A Inducers; Drug Interactions; Facial Nerve Diseases; Humans; Male; Prednisolone; Prostatic Neoplasms, Castration-Resistant

In 2014, a landmark study was published demonstrating that the expression of androgen receptor splice variant (AR-V) 7 was a negative predictive biomarker for response to abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) patients. However, these results were not supported by the recently reported ARMOR3-SV phase III clinical trial, which employed an identical circulating tumour cell assay to assess AR-V7 expression. Therefore, the predictive utility of AR-V7 expression in mCRPC remains uncertain, as does any potential association between other AR-Vs and treatment response. To further investigate, we designed a highly sensitive and specific whole blood assay for detecting AR-V7 and AR-V9. We then examined for a correlation between baseline AR-V7/V9 status and treatment outcome in 37 mCRPC patients commencing abiraterone or enzalutamide. Of the patients, 24% (9/37) were AR-V-positive. Notably, prostate-specific antigen (PSA) response rates did not significantly differ between AR-V-positive (6/9) and AR-V-negative (18/28) patients (66% vs 64%, p=0.9). Likewise, median PSA progression-free survival was not significantly different between AR-V-positive and AR-V-negative patients (9.2 mo vs not reached; p=0.9). These data, which support the findings of the pivotal ARMOR3-SV clinical trial, suggest that baseline AR-V expression does not predict outcomes in mCRPC patients receiving abiraterone or enzalutamide.. Detection of androgen receptor splice variants (AR-Vs) in circulating tumour cells of advanced prostate cancer patients has been linked to resistance to abiraterone and enzalutamide. We designed a blood test to detect AR-Vs that can be performed more routinely than tests involving circulating tumour cells and found that patients with AR-Vs still benefit from these effective treatments.

Topics: Abiraterone Acetate; Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Predictive Value of Tests; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen

Topics: Abiraterone Acetate; Adenocarcinoma; Adrenal Cortex Hormones; Aged; Antineoplastic Agents, Hormonal; Bone Neoplasms; Chlorpheniramine; Desensitization, Immunologic; Dexamethasone; Drug Administration Schedule; Histamine Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Urticaria

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

Androgen deprivation therapy (ADT) has been the standard of care for the treatment of newly diagnosed metastatic prostate cancer for the past 70 years. Furthermore, adding docetaxel chemotherapy to ADT significantly improved patient survival, and thus became the new standard for patients with high volume disease. However, recent evidence has called this treatment strategy into question since a published study has shown that the drug abiraterone has a similar benefit to docetaxel in a similar patient population group but with less toxicity. The following article considers this key paper and its implications. Areas covered: In this key paper evaluation, the authors discuss the rational, trial design and results of the LATITUDE trial. Furthermore, the past and current standard of care of metastatic castrate-naïve prostate cancer (mCNPC) is discussed, while the authors also compare abiraterone and docetaxel in terms of benefit, safety profile, and affordability. Expert opinion: Abiraterone is highly effective and has an excellent safety profile for the treatment of metastatic castrate-naïve prostate cancer. It is the authors' opinion that it should now be considered the new standard of care.

Topics: Abiraterone Acetate; Androstenes; Anti-Inflammatory Agents; Docetaxel; Drug Therapy, Combination; Humans; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Taxoids

We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide.. We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay. We examined ≤50% prostate-specific antigen (PSA) responses, PSA progression-free survival (PSA-PFS), clinical and radiological progression-free survival (radiologic PSF), and overall survival (OS). We then assessed whether AR-V7 expression in CTC clusters identified after On-chip multi-imaging flow cytometry was related to disease progression and survival after first-line systemic therapy.. All abiraterone-treated or enzalutamide-treated patients received prior docetaxel. The median follow-up was 20.7 (range: 3.0-37.0) months in the abiraterone and enzalutamide cohorts, respectively. Forty-nine of the 98 men (50.0%) were CTC cluster (-), 23 of the 98 men (23.5%) were CTC cluster(+)/AR-V7(-), and 26 of the 98 men (26.5%) were CTC cluster(+)/AR-V7(+). CTC cluster(+)/AR-V7(+) patients were more likely to have EOD ≥3 at diagnosis (P = 0.003), pain (P = 0.023), higher alkaline phosphatase levels (P < 0.001), and visceral metastases (P < 0.001). On multivariable analysis, pretherapy CTC cluster(+), CTC cluster(+)/AR-V7(-), and ALP >UNL were independently associated with a poor PSA-PFS, radiographic PFS, and OS in abiraterone-treated patients and enzalutamide-treated patients.. The CTC clusters and AR-V7-positive CTC clusters detected were important for assessing the response to abiraterone or enzalutamide therapy and for predicting disease outcome.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Bone Neoplasms; Drug Resistance, Neoplasm; Humans; Male; Neoplastic Cells, Circulating; Nitriles; Phenylthiohydantoin; Predictive Value of Tests; Prognosis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

The HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, the HSD3B1 (1245C) variant was shown to predict shorter duration of response to androgen deprivation therapy with medical or surgical castration in the setting of castration-sensitive prostate cancer (CSPC). The HSD3B1 (1245C) variant also predicts longer duration of response to ketoconazole in men with castration-resistant prostate cancer (CRPC). We hypothesized that the HSD3B1 (1245C) variant predicts response to treatment with abiraterone acetate (AA) and can help personalize treatment in men with advanced prostate cancer.. Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed. The primary study end point was progression-free survival in first-line AA in men with metastatic CRPC. We performed prespecified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on progression-free survival on AA.. Seventy-six men with metastatic CRPC treated with first-line AA were included. In multivariate analysis, the HSD3B1 (1245C) variant did not predict response to first-line AA.. The HSD3B1 (1245C) variant does not predict response to first-line AA in metastatic CRPC. This finding could be due to the ability of AA metabolites to act as both agonist (3-keto-5α-abiraterone) and antagonist (Δ4-abiraterone) on androgen signaling.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Germ-Line Mutation; Humans; Male; Middle Aged; Multienzyme Complexes; Pharmacogenomic Variants; Point Mutation; Precision Medicine; Prednisone; Progesterone Reductase; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Steroid Isomerases

Abiraterone acetate (AA) is an androgen receptor axis inhibitor, indicated together with prednisone, for metastatic castration-resistant prostate cancer. Withdrawal syndrome for classical antiandrogen treatments is well known, but not so known for AA. Abiraterone withdrawal syndrome (AWS) could be related to simultaneous prednisone discontinuation or to an androgenic effect of AA metabolites.. A case is described of a patient with long-term AWS without prednisone discontinuation. The clinical and prostate-specific antigen (PSA) response allowed an 8-month delay in docetaxel treatment.. Prednisone did not play a role in AWS in this case. The long-term response allowed a delay in future treatment.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Substance Withdrawal Syndrome; Treatment Outcome

Topics: Abiraterone Acetate; Disease Progression; Humans; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Disease Progression; Humans; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

Primary prostate cancer can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we microdissected residual prostate cancer foci in radical prostatectomies from 18 men treated with neoadjuvant-intensive androgen deprivation therapy (leuprolide, abiraterone acetate, and prednisone) and analyzed them for resistance mechanisms. Transcriptome profiling showed reduced but persistent androgen receptor (AR) activity in residual tumors, with no increase in neuroendocrine differentiation. Proliferation correlated negatively with AR activity but positively with decreased RB1 expression, and whole-exome sequencing (WES) further showed enrichment for RB1 genomic loss. In 15 cases where 2 or 3 tumor foci were microdissected, WES confirmed a common clonal origin but identified multiple oncogenic alterations unique to each focus. These findings show that subclones with oncogenic alterations found in mCRPC are present in primary prostate cancer and are selected for by neoadjuvant-intense androgen deprivation therapy. In particular, this study indicates that subclonal RB1 loss may be more common than previously appreciated in intermediate- to high-risk primary prostate cancer and may be an early event, independent of neuroendocrine differentiation, in the development of mCRPC. Comprehensive molecular analyses of primary prostate cancer may detect aggressive subclones and possibly inform adjuvant strategies to prevent recurrence.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Aryl Hydrocarbon Hydroxylases; Biomarkers, Tumor; Carcinogenesis; Clonal Evolution; Cytochrome P450 Family 2; Drug Resistance, Neoplasm; Humans; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Prostatectomy; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Steroid 16-alpha-Hydroxylase

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androstenes; Drug Monitoring; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Enzalutamide and abiraterone acetate (plus prednisone) are new hormonal treatments for metastatic castration-resistant prostate cancer (mCRPC). This study compared treatment duration, healthcare resource utilization (HRU), and treatment costs for chemotherapy-naïve mCRPC patients treated with enzalutamide or abiraterone acetate in the USA.. Chemotherapy-naïve mCRPC patients initiating treatment with enzalutamide or abiraterone acetate were identified from administrative claims. Continuous enrollment ≥ 6 months before and ≥ 3 months after the index date (initiation date of enzalutamide or abiraterone acetate) was required. Treatment duration, all-cause and prostate cancer-related HRU, and costs were estimated during the post-index period. Multivariable analyses compared HRU and costs between cohorts, adjusting for baseline characteristics.. Overall, 920 chemotherapy-naïve patients initiated enzalutamide and 2310 initiated abiraterone acetate (median follow-up, 10.7 and 13.5 months, respectively). More enzalutamide-treated patients had corticosteroid-sensitive comorbidities at baseline. Treatment duration was longer with enzalutamide versus abiraterone acetate (median, 10.7 vs. 8.8 months; P = 0.008). Enzalutamide was associated with fewer all-cause inpatient admissions [adjusted incidence rate ratio (95% confidence interval) 0.87 (0.76, 0.99)], days of hospitalization [0.84 (0.70, 1.02)], and outpatient visits [0.94 (0.90, 0.98)], and fewer prostate cancer-related outpatient visits [0.92 (0.87, 0.96)] compared with abiraterone acetate. Enzalutamide was also associated with lower prostate cancer-related inpatient and emergency department costs [adjusted differences, $122 (P = 0.024) and $28 (P = 0.009), respectively].. Chemotherapy-naïve mCRPC patients treated with enzalutamide versus abiraterone acetate had longer treatment duration and incurred lower HRU and prostate cancer-related inpatient and emergency department costs.. Astellas Pharma Inc.

Topics: Abiraterone Acetate; Aged; Benzamides; Costs and Cost Analysis; Health Care Rationing; Hospitalization; Humans; Insurance Claim Review; Male; Middle Aged; Neoplasm Staging; Nitriles; Patient Acceptance of Health Care; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Time Factors; United States

The main purpose of this study was to evaluate the outcome of patients with prostate-specific antigen (PSA) progression after abiraterone acetate (AA) treatment for metastatic castration-resistant prostate cancer (mCRPC).. Between 2012 and 2017, 83 patients with clinically-confirmed mCRPC previously treated with docetaxel with/without cabazitaxel followed by AA were included in this retrospective study. All patients received 1,000 mg AA with 5 or 10 mg prednisolone. Among them, 59 were eligible for this study based on PSA progression during the clinical course. Patients were divided into two groups, AA responders and AA non-responders according to previous PSA response to AA treatment. Overall survival and treatment response to subsequent therapy were analyzed.. The median overall survival of the 59 patients after AA-treated PSA progression was 12 (95% confidence interval(CI)=7.6-16.4) months and was longer in the AA-responding group compared to the non-responding group (25 vs. 8 months, p<0.001). The survival time after PSA progression on AA was longer in the AA-responsive group despite not being statistically different (13 vs. 7 months, p=0.126). Patients with AA treatment who received subsequent therapies after PSA progression had better overall survival than those without (18 vs. 4 months, p=0.003). In addition, there was a trend for better chemotherapy response in AA non-responders than AA responders, 62.5% (5/8) vs. 12.5% (1/8) respectively.. In our small retrospective patient experience, effective sequential treatments for patients with mCRPC provided overall survival benefit. Previous treatment response can act as a clinical predictor for subsequent treatment.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Agents; Disease Progression; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Risk Factors; Time Factors; Treatment Failure; Up-Regulation

Treatment of metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly during the past decade, and the preferred combination and/or sequence of these treatments remains controversial. In this retrospective study, we explored clinical and pathologic factors that could predict response to consecutive treatment with enzalutamide (ENZA) after disease progression (PD) on abiraterone acetate and prednisone (AA/P).. Data were collected from 40 consecutive patients with mCRPC who were treated with ENZA without other interim therapy after progression on AA/P.. The median time from prostate cancer initial diagnosis to AA/P treatment was 6.2 (range, 0.9-16.3) years. The median prostate-specific antigen (PSA) progression-free survival (PSA-PFS) from treatment initiation was 8.5 months (95% confidence interval [CI], 7.1-10.1 months) and 2.3 months (95% CI, 1.8-3.4 months) on AA/P and ENZA, respectively. The median time to PD from treatment initiation was 9.7 months (95% CI, 7.1-12.4 months) and 3 months (95% CI, 2.3-4.1 months) on AA/P and ENZA, respectively. The correlations were weak between the best percent change in PSA on ENZA and time from diagnosis to AA/P initiation, best absolute or percentage change in PSA on AA/P, time to PSA progression or PD on AA/P. Patients with longer than the median duration of treatment with AA/P (11.73 months) had longer PSA-PFS on ENZA (median 2.8 vs. 1.9 months; P = .035).. In this retrospective analysis, we did not find any clinical or pathologic factors associated with response to ENZA administered consecutively after AA/P. Patients with longer than median AA/P treatment duration had longer PSA-PFS on ENZA. Further evaluations and validation are greatly needed.

Topics: Abiraterone Acetate; Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease Progression; Drug Resistance, Neoplasm; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Time Factors; Treatment Failure; Treatment Outcome

There is no definitive biomarker that predicts the effectiveness of abiraterone acetate. The objective of this study was to investigate whether dehydroepiandrosterone sulfate (DHEA-S) predicts the effectiveness of abiraterone acetate.. This study included a total of 28 consecutive patients. The optimal cutoff value of DHEA-S for predicting the PSA response was calculated by receiver operating characteristic (ROC) analysis. The Cox proportional hazards model was performed to determine the predictive factors for the susceptibility to abiraterone acetate.. Serum DHEA-S at baseline intercorrelated with the PSA response (correlation coefficient: -0.516). The optimal cutoff value of serum DHEA-S at baseline was 47.4 ug/dl in predicting >50% PSA decline. Serum PSA and serum DHEA-S at baseline were identified as significant factors for predicting PSA progression-free survival (p=0.010 and p=0.003, respectively).. Serum DHEA-S at baseline may be a biomarker for predicting the prognosis of CRPC patients treated with abiraterone acetate.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Dehydroepiandrosterone Sulfate; Follow-Up Studies; Humans; Male; Middle Aged; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate

To analyze drug adherence, overall survival (OS) and hospitalization rates of patients with castration-resistant prostate cancer (CRPC) treated with arbiraterone acetate (AA), enzalutamide (ENZ) and their sequence in a real-life setting.. The database of the largest public insurance company in Austria was analyzed. All CRPC patients with at least one prescription of AA and/or ENZ between September 2013 and August 2016 in the pre-chemotherapy and post-chemotherapy setting were extracted and matched to the Austrian death and hospital admission statistics. Drug adherence was estimated by the medication possession ratio (MPR).. Data of 457 patients (mean age: 74.4 ± 8.5 years) were analyzed. The mean MPR was 90% for AA, 85% for ENZ and 88% for the sequence therapy cohort. The median overall survival (OS) of the entire cohort was 21 months: 15 months for AA, 24 months for ENZ, 26 months for the sequence group, and 10 months for the sequence group after switching. In the post-chemotherapy setting, the median OS was 14 months in AA treatment (mean: 15.8 ± 0.9 months), 19 months in the ENZ treatment (mean: 17.2 ± 1.4 months) and 25 months in the sequence group (mean: 22.7 ± 0.8 months). Median OS in the pre-chemotherapy setting was 25 months (mean: 21.5 ± 1.1 months), 18 months in AA treatment group (mean: 18.9 ± 1.5 months) and 17 months in ENZ treatment group (mean: 18.2 ± 1.9 months). Only 43 (9.4%) patients were not hospitalized during the course of the study. On average patients spent 13% of their remaining life span in hospital care (median 8%, range: 1-34%).. This Austrian prescription database allows some insights into the outcome of CRPC patients treated with AA and ENZ and their sequence in a real-life setting. Drug adherence was satisfactory, OS was shorter for AA and ENZ as compared to the pivotal phase III trials.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Austria; Benzamides; Hospitalization; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Abiraterone acetate plus prednisone is a standard treatment option for mCRPC. The phase II SWITCH trial showed that further prostate-specific antigen (PSA) responses can be obtained in a subset of patients when prednisone was switched to dexamethasone at progression. Here, we discuss the potential underlying mechanisms, including the activation of glucocorticoid receptors (GR) in progressive mCRPC and the implications for clinical practice.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Glucocorticoids; Humans; Male; Pilot Projects; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

The aim of this retrospective study is to evaluate the activity and safety of a steroidal switch from prednisone to dexamethasone in patients with advanced, heavily pre-treated, castration-resistant prostate cancer (CRPC) who progressed on abiraterone acetate. Treatment consisted of oral daily abiraterone plus dexamethasone (0.5 mg once daily) administered until disease progression or unacceptable toxicity. Thirty-six patients were evaluated: all men underwent a prior treatment with enzalutamide. A PSA decrease ≥50% was observed in 11% of patients; median progression-free survival was 10.8 weeks (95% CI: 9.2-16), and median survival was 17.6 weeks (95% CI: 15.8-28.8). Better efficacy and survival were observed in the subgroup of patients treated with abiraterone acetate prior for a period >3 months; treatment was well tolerated, and no grade 3-4 toxicities were observed. Our findings did not suggest the use of steroid switch in all CRPC who were heavily pre-treated. However, the switch could be an option for patients who responded well to prior abiraterone acetate treatment.

Topics: Abiraterone Acetate; Adrenal Cortex Hormones; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Abiraterone acetate (AA), an androgen biosynthesis inhibitor, is now a standard of care for men with metastatic, castration-sensitive and castration-resistant prostate cancer (mCRPC). Data exploring real-world toxicity and outcomes are scarce.. Retrospective study on unselected patients with mCRPC on AA plus steroids.. 93 patients were included in the study. Median duration of treatment by AA was 7.5 months (95% CI 5.7-12) among the 58 patients pretreated with chemotherapy, versus 12.7 months ( 95% CI 8.2-35.9) among the 33 chemo-naive patients. Median survivals would reach 13.4 months (95% CI 10.2-19.1) and 36.4 months (95% CI 24.7-41.5) respectively. Rates of hypokalemia, peripheral edema, hypertension, cardiac failure, and overall survival assessments in patients with and without prior chemotherapy were similar to that previously reported in phase 3 randomized trials. The median survival time without adverse event of special interest was 7.5 months for hypokalemia and hypertension, and 5.3 months for liver-function test abnormalities (it was not reached for cardiac disorders).. Our findings provide further evidence for the survival benefits of AA with a low frequency of additional adverse events among unselected patients. In patients who have not developed hypokalemia or a transaminase increase within 7.5 and 5.3 months respectively, a lighter systematic monitoring may be considered.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Missouri; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

To evaluate the efficacy and safety of abiraterone acetate (AA) plus prednisone compared with prednisone alone in Asian patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), and to identify predictive factors.. We reviewed the medical records of 60 patients with chemotherapy-naive mCRPC at Renji Hospital who were treated with AA plus prednisone (n = 43) or prednisone alone (n = 17). All patients were assessed for prostate-specific antigen (PSA) response, PSA progression-free survival (PSA PFS), radiographic progression-free survival (rPFS), and overall survival (OS). The ability of several parameters to predict PSA PFS, rPFS, and OS was studied.. The median follow-up time was 14.0 months (range 7.0-18.5 months), at which time 19 death events had been reported: 11 in the AA + prednisone group and 8 in the prednisone group. The AA + prednisone group had significantly longer median PSA PFS (10.3 vs 3.0 months, P < 0.001), rPFS (13.9 vs 3.9 months, P < 0.001), and OS (23.3 vs 17.5 months, P = 0.016) than the prednisone-alone group. The most frequently reported grade 3 or 4 adverse event in both the AA + prednisone and prednisone-alone groups was elevated alanine aminotransferase level in 5 of 43 patients (11.6%) and 2 of 17 patients (11.8%), respectively. No adverse events led to discontinuation of therapy. In multivariate analysis, time from androgen deprivation therapy (ADT) to castration resistance of ≤18 months was a determinant of shorter OS (P = 0.007).. These results support the favourable safety and efficacy profile of AA for the treatment of Asian patients with chemotherapy-naive mCRPC. Longer duration of ADT response was significantly associated with longer survival.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Follow-Up Studies; Humans; Male; Middle Aged; Prednisone; Prognosis; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

In the COU-AA-302 trial, abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling-directed therapies following abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6-not estimable) for subsequent abiraterone acetate plus prednisone and 2.8 mo (range 1.8-not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with abiraterone acetate plus prednisone or enzalutamide for patients who progressed on abiraterone acetate is associated with limited clinical benefit.. This analysis showed limited clinical benefit for subsequent abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent abiraterone acetate plus prednisone or enzalutamide following initial therapy with abiraterone acetate plus prednisone.

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials, Phase III as Topic; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Multicenter Studies as Topic; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Signal Transduction; Steroid Synthesis Inhibitors; Time Factors; Treatment Outcome

Topics: Abiraterone Acetate; Disease-Free Survival; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Disease-Free Survival; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

Treatments and disease burden of metastatic castration-resistant prostate cancer (mCRPC) considerably affect a patient's quality of life. However, patient-reported symptom burden data are still largely insufficient. This study sought to compare the self-reported symptom burden of men with chemotherapy-naive (CN) mCRPC treated with abiraterone acetate (AA) or enzalutamide (EZ) in routine clinical practice.. Between 2011 and 2015, 189 CN-mCRPC patients who had received AA (n = 76) or EZ (n = 113) at the Princess Margaret Cancer Centre were included. The Edmonton Symptom Assessment System (ESAS) score, baseline demographic information, comorbidities, Eastern Cooperative Oncology Group performance status, laboratory data and narcotic analgesic use were recorded for each patient. The minimal clinically important difference was assessed using ±1 point change from baseline for each ESAS symptom. Mixed model for repeated measures (MMRM) was used to estimate and compare the longitudinal ESAS score changes from baseline in AA and EZ groups adjusted for age, baseline ESAS scores, treatment group, treatment duration and time.. The median (interquartile range) treatment duration with AA and EZ was 10 (6-16) and 12 (7-18) months, respectively (P = 0.19). Fatigue was rated the most distressing symptom at baseline and following treatment in both groups. There were no statistically significant differences in the proportion of patients with clinically meaningful symptom improvement or worsening after AA or EZ administration in any of the ESAS-based physical and psychological symptoms over time. In MMRM analyses, there were no significant differences in adjusted mean scores from baseline to 3, 6, 9 and 12 months for any of the ESAS items between AA and EZ groups.. Physical and psychological symptoms assessed by ESAS were comparable in CN-mCRPC men treated with AA or EZ in the real-world clinical setting. Further studies are warranted to confirm these findings.

Topics: Abiraterone Acetate; Aged; Benzamides; Disease-Free Survival; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Self Report

Topics: Abiraterone Acetate; Docetaxel; Humans; Male; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids

The originator abiraterone acetate (OAA) formulation is used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluated the bioavailability and bioequivalence of a novel formulation, abiraterone acetate fine particle (AAFP), versus OAA on a steady-state background of steroids.. Thirty-seven healthy male subjects were randomized in a crossover design to receive methylprednisolone (4 mg twice daily) or prednisone (5 mg twice daily) for 12 days in Period 1. On Day 11 of Period 1, subjects given methylprednisolone received a single dose of AAFP 500 mg, and subjects given prednisone received a single dose of OAA 1000 mg under fasted conditions. After a 2-week steroid washout period, subjects received the alternate treatments in Period 2.. There were no statistical differences regarding area under the curve (AUC) and maximum concentration (C. AAFP plus methylprednisolone provided abiraterone exposure that was comparable to OAA plus prednisone with respect to C

Topics: Abiraterone Acetate; Adolescent; Adult; Biological Availability; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Steroids; Young Adult

Recently neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have been reported to be inflammatory parameters that confer poorer outcome in metastatic castration-resistant prostate cancer (mCPRPC). However, these ratios have not been analyzed in patients treated with abiraterone acetate. We explored the relationship between different values of PLR and NLR and survival in mCPRCP treated with abiraterone and their possible relation with a prostate specific antigen (PSA) response.. We retrospectively analyzed 101 patients with mCRPC treated with abiraterone from January of 2012 to November of 2015 in two different hospitals. A cut-off value of 5 for NLR and 150 for PLR were used to compare survival by Kaplan-Meier method. Moreover, an association between these cut-off values and the PSA response was analyzed by a χ. In the case of NLR, the median DFS were 12, 1 months for NLR <5 and 7 months for NLR ≥5, p = 0.061. The median OS were 23.9 months for NLR <5 and 16.3 months for NLR ≥5, p = 0.046. In the case of PLR, the median DFS were 11.8 months for PLR <150 and 10.6 months for PLR ≥150, p = 0.549. The median OS were 27.4 months for PLR <150 and 15.9 months for PLR ≥150, p = 0.005. It was not observed a correlation between the different cut-off values of PLR or NLR and a PSA response ≥25% (p = 0.31).. It is shown a better prognostic relationship between PLR and NLR low values and OS that is statistically significant in mCPRC patients treated with abiraterone. Furthermore, it was not shown a relation between PLR and NLR values and PSA response.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Blood Platelets; Follow-Up Studies; Humans; Lymphocytes; Male; Middle Aged; Neutrophils; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate

Statins compete with DHEAS for influx through the SLCO2B1 transporter, which may prolong time to progression (TTP) on androgen deprivation therapy. Abiraterone acetate (AA) may also undergo SLCO-mediated transport. Based on preclinical findings showing antagonism, we hypothesized that statins may compete with AA for influx via SLCO2B1 and could negatively impact drug efficacy.. We queried two institutional clinical databases (Dana-Farber Cancer Institute [DFCI], Johns Hopkins University [JHU]) for CRPC patients treated with AA. Treatment duration was a surrogate for TTP. Associations between statin use and AA duration were estimated using the Kaplan-Meier method. Multivariable Cox regression modeling adjusted for known prognostic factors.. Of the 224 DFCI and 270 JHU patients included, the majority (96%) had metastatic disease. Nearly half (41% and 45%) were statin users. In the DFCI cohort, there was a trend toward longer AA duration in statin users: 14.2 versus 9.2 months (HR 0.79, 95%CI: 0.57-1.09, P = 0.14). There was no association between statin use and AA duration in the JHU cohort: 8.3 versus 8.0 months (HR 0.89, 95%CI: 0.69-1.16, P = 0.38) in the statin users versus non-users, except for a trend in patients that had not previously received docetaxel or enzalutamide (HR 0.79; 95%CI: 0.57-1.10).. Contrary to our initial hypothesis, there was a trend toward longer (rather than shorter) AA duration in statin users in the entire DFCI cohort and in the enzalutamide- and docetaxel-naïve JHU patients. Together, these results do not support the hypothesis that statins interfere with AA efficacy.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Biological Transport; Cell Line; Disease Progression; Docetaxel; Drug Synergism; Electronic Health Records; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Nitriles; Organic Anion Transporters; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Time Factors; United States

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Castration; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prednisolone; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids

To determine the influence of abiraterone Acetate (AA) on neuroendocrine differentiation (NED) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC).. We conducted an analysis in 115 chemotherapy-naïve mCRPC patients who would be treated with chemotherapy. The serum levels of chromogranin A (CgA), neurone-specific enolase (NSE) were measured in 67 mCRPC patients without AA treatment and 48 patients after the failure of AA treatment, in which these markers were also measured in 34 patients before and after 6 months of AA treatment. Comparative t-test was used to evaluate the serial changes of serum NED markers during AA treatment and univariate and multivariate analyses were performed to test the influence of AA treatment on NED.. Serum CgA were NSE were evaluated to be above the upper limit of normal (ULN) in 56 (48.7%) and 29 (25.2%) patients before chemotherapy. In 34 patients with serial evaluation, serum CgA level of 14 patients and NSE of 14 patients increased after the failure of AA treatment. There was no significant difference of NED markers (CgA or NSE variation (P = 0.243) between at baseline and after the failure of AA treatment. Compared with the CgA elevation group in the first 6 months of AA treatment and baseline supranormal CgA group, the CgA decline group, and baseline normal CgA group has a much longer median PSA PFS (14.34 vs 10.00 months, P < 0.001, and 14.23 vs 10.30 months, P = 0.02) and rPFS, respectively (18.33 vs 11.37 months, P < 0.001, and 17.10 vs 12.07 months, P = 0.03). In logistic univariate analysis, AA treatment and its duration were not independent factors influencing NED.. We hypothesized that AA might not significantly lead to progression of NED of mCRPC in general. Furthermore, we found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment. Serial CgA and NSE evaluation might help clinicians guide clinical treatment of mCRPC patients.

Topics: Abiraterone Acetate; Adenocarcinoma; Aged; Antineoplastic Agents; Biomarkers; China; Chromogranin A; Drug Monitoring; Humans; Male; Middle Aged; Neurosecretion; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

An important clinical question of great interest to clinicians is how to best sequence androgen receptor targeted agents (ARTAs) and chemotherapy for metastatic castration-resistant prostate cancer (mCRPC), but the answer is still unclear.. To evaluate and compare the clinical outcomes of ARTA and docetaxel (DTX) as second-line treatment in the post first-line ARTA, we conducted a retrospective analysis of chemotherapy-naive mCRPC patients who had received sequential treatment with ARTA followed by another ARTA (ARTA-ARTA) or ARTA followed by DTX (ARTA-DTX).. A total of 97 patients were treated with the ARTA-ARTA sequence and 42 with the ARTA-DTX sequence. A prostate-specific antigen (PSA) response to the second-line treatment was observed in 18.6% in the ARTA-ARTA and in 33.3% in the ARTA-DTX sequence, but the difference in PSA response was not statistically significant (P = .057). The median progression-free survival (PFS) was significantly different between ARTA and DTX in the second-line treatment (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.24-0.59; P < .001). The favorable outcome in the ARTA-DTX sequence compared with the ARTA-ARTA sequence remained (HR, 0.51, 95% CI, 0.33-0.80; P = .004) in the combined PFS (first-line PFS + second-line PFS). However, no statistically significant difference in overall survival (OS) between the 2 groups was observed (HR, 0.60; 95% CI, 0.34-1.09; P = .095). In multivariate analysis, the ARTA-DTX sequence was identified as an independent prognostic factor for combined PFS, but not OS.. ARTA-DTX might improve clinical outcomes in terms of second-line PFS and combined PFS, compared with the ARTA-ARTA sequence. However, this significance was not observed for OS.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Middle Aged; Molecular Targeted Therapy; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Topics: Abiraterone Acetate; Drug Resistance, Neoplasm; Humans; Male; Neoplastic Cells, Circulating; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

The objective of this study was to investigate the impact of prior treatment with androgen receptor-axis-targeted (ARAT) agents, abiraterone acetate (AA) and enzalutamide (Enz), on the activity of subsequently introduced docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). This study included a total of 114 mCRPC patients consisting of 54 and 60 who progressed following treatment with AA and Enz, respectively, prior to the introduction of docetaxel, and compared oncological outcomes with docetaxel between these two groups. There were no significant differences in the major clinicopathological characteristics before treatment with docetaxel between the AA and Enz groups. The prostate-specific antigen (PSA) response rates to docetaxel in the AA and Enz groups were 40.7 and 43.3%, respectively, with no significant differences in the rates between these two groups. Following the introduction of docetaxel, the median PSA progression-free survival (PFS) and overall survival (OS) in the 114 patients were 7.2 and 17.5 months, respectively. There was no significant difference in the PSA PFS or OS between the AA and Enz groups. Despite the lack of a significant impact of the type of ARAT agent on PSA PFS or OS by univariate analysis, multivariate analyses identified the following independent prognostic predictors: performance status (PS) for PSA PFS and PS and visceral metastasis for OS. Collectively, these findings suggest that the type of ARAT agent may not have a significant impact on disease control by subsequent docetaxel therapy in mCRPC patients.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Disease-Free Survival; Docetaxel; Humans; Kallikreins; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; Signal Transduction; Taxoids

Abiraterone acetate (AA), the prodrug of abiraterone, is FDA-approved for the treatment of castration-resistant prostate cancer. Abiraterone is metabolized in patients to a more potent analogue, D4A. However, we have recently reported that this analogue is further metabolized to additional metabolites in patients treated with AA. Here, we present a liquid chromatography-tandem mass spectrometry method developed to resolve and detect abiraterone and its seven metabolites in human serum using an AB Sciex Qtrap 5500 mass analyzer coupled with a Shimadzu Nexera UPLC station. Analytes and the internal standard (abiraterone-d4) were extracted from human serum using the liquid-liquid extraction procedure. The analytes were separated using a Zorbax Eclipse Plus C18 150×2.1mm, 3.5μm column at 40°C and an isocratic mobile phase 35% A (0.1% formic acid in water), 65% B (0.1% formic acid in methanol:acetonitrile; 60:40). Electrospray ionization in positive mode was applied with multiple reaction monitoring in a total run time of 13min. Abiraterone detection was linear in the range 2-400ng/mL and all metabolites from 0.1-20ng/mL. The method was validated following US FDA guidelines for bioanalytical method validation, and all the metabolite results were within the acceptance limits. Despite the similarity in structure and mass transition between the metabolites, the validated method separated all the metabolites, including diastereomers, to allow accurate identification and quantitation of each compound.

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Biotransformation; Calibration; Chromatography, Liquid; Humans; Limit of Detection; Liquid-Liquid Extraction; Male; Prodrugs; Prostatic Neoplasms, Castration-Resistant; Reference Standards; Reproducibility of Results; Solvents; Stereoisomerism; Tandem Mass Spectrometry

Treatment patterns for metastatic castration-resistant prostate cancer (mCRPC) have changed substantially in the last few years. In trial COU-AA-302 (chemotherapy-naïve men with mCRPC), abiraterone acetate plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival (OS) when compared to placebo plus prednisone (P).. This post hoc analysis investigated clinical responses to docetaxel as first subsequent therapy (FST) among patients who progressed following protocol-specified treatment with AA, and characterized subsequent treatment patterns among older (≥75 yr) and younger (<75 yr) patient subgroups.. Data were collected at the final OS analysis (96% of expected death events). Subsequent therapy data were prospectively collected, while response and discontinuation data were collected retrospectively following discontinuation of the study drug.. At the discretion of the investigator, 67% (365/546) of patients from the AA arm received subsequent treatment with one or more agents approved for mCRPC.. Efficacy analysis was performed for patients for whom baseline and at least one post-baseline prostate-specific antigen (PSA) values were available.. Baseline and at least one post-baseline PSA values were available for 100 AA patients who received docetaxel as FST. While acknowledging the limitations of post hoc analyses, 40% (40/100) of these patients had an unconfirmed ≥50% PSA decline with first subsequent docetaxel therapy, and 27% (27/100) had a confirmed ≥50% PSA decline. The median docetaxel treatment duration among these 100 patients was 4.2 mo. Docetaxel was the most common FST among older and younger patients from each treatment arm. However, 43% (79/185) of older patients who progressed on AA received no subsequent therapy for mCRPC, compared with 17% (60/361) of younger patients.. Patients with mCRPC who progress with AA treatment may still derive benefit from subsequent docetaxel therapy. These data support further assessment of treatment patterns following AA treatment for mCRPC, particularly among older patients.. ClinicalTrials.gov NCT00887198.. Treatment patterns for advanced prostate cancer have changed substantially in the last few years. This additional analysis provides evidence of clinical benefit for subsequent chemotherapy in men with advanced prostate cancer whose disease progressed after treatment with abiraterone acetate. Older patients were less likely to be treated with subsequent therapy.

Topics: Abiraterone Acetate; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Disease-Free Survival; Docetaxel; Humans; Male; Middle Aged; Neoplasm Metastasis; Practice Patterns, Physicians'; Prednisone; Prostatic Neoplasms, Castration-Resistant; Survival Rate; Taxoids

The objective of the present study was to comprehensively compare the clinical outcomes between abiraterone acetate (AA) and enzalutamide (Enz) in Japanese patients with docetaxel-naive metastatic castration-resistant prostate cancer (mCRPC).. The present study retrospectively included 280 consecutive mCRPC patients, consisting of 113 and 167 who had received AA and Enz, respectively, without previous treatment with docetaxel.. Of the several baseline characteristics examined, some parameters, including performance status (PS), prostate-specific antigen (PSA) value, and incidence of lymph node metastasis, significantly favored the Enz over the AA group. The PSA response rate in the Enz group was significantly greater than that in the AA group, and the PSA progression-free survival in the Enz group was significantly superior to that in the AA group. Multivariate analyses of several parameters identified the following independent predictors of PSA progression-free survival: duration of androgen deprivation therapy and PS for the AA group, age and PS for the Enz group, and PS but not the introduced agent (ie, AA vs. Enz) for the overall patients. The common adverse events observed in the present series were fatigue (19.4%) and liver toxicity (11.5%) in the AA group and fatigue (32.3%) and appetite loss (19.2%) in the Enz group. In addition, the proportion of patients with adverse events grade ≥ 3 in the Enz group (11.4%) was significantly greater than that in the AA group (4.4%).. Both AA and Enz were effective and tolerable for patients with docetaxel-naive mCRPC in the routine clinical setting.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Humans; Japan; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Analysis; Treatment Outcome

The objective of this study was to investigate whether the prior use of a novel androgen receptor-axis-targeted (ARAT) agent with or without subsequent taxane therapy could affect the efficacy of another ARAT agent in patients with metastatic castration-resistant prostate cancer (mCRPC).. This study included a total of 302 patients with mCRPC, who were treated with abiraterone acetate and/or enzalutamide. These 302 patients were classified into the following 3 groups: group A, 173 received an ARAT agent without the prior use of another ARAT agent; group B, 102 sequentially received ARAT agents without any treatment between the 2 agents; group C, 27 sequentially received ARAT agents, with taxane therapy between the 2 ARAT agents.. The response rate to the ARAT agent in group A (63.6%) was significantly higher than those to the ARAT agent introduced late-line in groups B and C (20.6% and 29.6%, respectively). In addition, prostate-specific antigen progression-free survival during the ARAT therapy in group A was significantly superior to those during the ARAT therapy conducted late-line in groups B and C. Multivariate analyses of several parameters identified the prior use of an ARAT agent, but not the administration of taxane between the ARAT therapies, as one of the independent predictors of prostate-specific antigen progression-free survival.. Cross-resistance between ARAT agents may be a common phenomenon in patients with mCRPC, irrespective of the introduction of taxane between the ARAT therapies.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Humans; Kallikreins; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Analysis; Taxoids; Treatment Outcome

Topics: Abiraterone Acetate; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Humans; Male; Prostatic Neoplasms, Castration-Resistant

Enzalutamide (ENZA) and abiraterone acetate plus prednisone (AA) are approved second-generation hormone therapies for chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). This study compared ENZA with AA in chemotherapy-naïve mCRPC by calculating the number needed to treat (NNT) and associated incremental costs to achieve one additional chemotherapy-naïve patient with mCRPC free of radiographic progression, chemotherapy, or death over a 1-year time horizon.. Clinical outcomes were obtained from the PREVAIL and COU-AA-302 trials. Three outcomes were evaluated: radiographic progression-free survival, time to cytotoxic chemotherapy initiation, and overall survival at 1 year. NNT was calculated as the reciprocal of the outcome event rate difference for ENZA compared with AA. The incremental costs to achieve one additional outcome at 1 year were calculated as the difference in cost per treated patient multiplied by the NNT. Per-treated-patient costs were considered from a US payer perspective and included medications, monitoring, adverse events, post-progression treatments, and end-of-life care.. Within a 1-year time horizon, the total cost per treated patient for ENZA was $2,666 less than AA. Compared with AA, treating 14 patients with ENZA resulted in one additional patient free of progression or death over 1 year; treating 26 patients with ENZA resulted in one additional patient with chemotherapy delayed over 1 year; and treating 91 patients with ENZA resulted in one additional patient free of death over 1 year. Therefore, ENZA is cost-effective compared with AA for all three outcomes evaluated, and the modeled results suggest ENZA is associated with potentially improved clinical outcomes in delaying chemotherapy initiation and disease progression for chemotherapy-naïve patients. The results are robust in sensitivity analyses, where the effect of changes in key model inputs and assumptions were tested.. The results modeled in the present study suggest ENZA is cost-effective compared with AA for treating chemotherapy-naïve patients with mCRPC.

Topics: Abiraterone Acetate; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Disease-Free Survival; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

Prostate-specific antigen (PSA) flare is a well-known phenomenon in patients with prostate cancer treated with luteinizing hormone-releasing hormone agonist and chemotherapy. However, its incidence and the significance for the clinical outcomes of patients treated with abiraterone acetate (AA) are uncertain.. A multicenter retrospective analysis of chemotherapy-naive patients treated with AA for metastatic castration-resistant prostate cancer (mCRPC) was conducted. The baseline characteristics, treatment history of mCRPC, and serum PSA kinetics during AA treatment were collected. The log-rank test was applied to compare progression-free survival (PFS) between patient groups with a PSA flare according to the different definitions and immediate PSA declines.. The data from 83 patients were analyzed. An immediate PSA decline of any amount was observed in 59 patients (71.1%). According to the various definitions of PSA flare, its incidence ranged from 6.0% to 10.8%. Although the median interval to the peak PSA level was 0.95 month, regardless of the PSA flare definition, the interval to the PSA nadir showed a wide range of 2.8 to 7.6 months. In PSA flare subgroup, the median PFS in patients with any PSA decline to less than the baseline and > 30% decline from the baseline was 12.4 months. The PFS duration of PSA flare patients did not significantly differ from that of patients with an immediate PSA decline of any amount and immediate > 30% decline without PSA flare.. The PSA flare phenomenon is not rare event during AA treatment. A PSA decline during AA treatment, with or without a PSA flare, was associated with favorable clinical outcomes. Thus, AA should not be withdrawn early in patients with mCRPC in whom an initial, isolated PSA increase has been observed.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Humans; Kallikreins; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Abiraterone Acetate; Benzamides; Drug Antagonism; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Spironolactone; Treatment Outcome

Topics: Abiraterone Acetate; Diagnostic Tests, Routine; Humans; Male; Neoplasms, Second Primary; Prostatic Neoplasms, Castration-Resistant; RNA

Topics: Abiraterone Acetate; Humans; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Humans; Male; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

Abiraterone acetate is a potent and irreversible inhibitor of cytochrome p450 17A1 that suppresses androgen synthesis. It is approved for chemotherapy-naive and docetaxel-treated patients with metastatic castration-resistant prostate cancer. We describe the protocol for use of abiraterone in metastatic castration-resistant prostate cancer chemotherapy naive patients has been implanted in our centre and we review the cases of those patients whose adverse effects have forced the discontinuation of treatment. The side effects fit the safety profile of abiraterone, speed of their appearance and severity indicate that you should perform a thorough follow-up of these patients especially in the early phases of treatment.

Topics: Abiraterone Acetate; Aged, 80 and over; Androstenes; Disease Progression; Docetaxel; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Safety-Based Drug Withdrawals; Taxoids; Time Factors; Treatment Outcome

Abiraterone acetate (AA) demonstrated its efficacy in the treatment of patients with metastatic castration resistance prostate cancer (mCRPC) in predocetaxel and postdocetaxel setting. However, we learn from pivotal studies that forms of primary and acquired resistance to this drug exist. Patient selection becomes so crucial to optimize treatment results. Potential predictive biomarkers have been identified but are not yet validated. In this scenario, clinical features and disease characteristics may still be of value in selecting patients for different treatments. The objective of this retrospective study was to assess whether or not a correlation between duration of response to first androgen deprivation therapy (ADT), time to castration-resistant prostate cancer (TTCRPC), and outcome of AA therapy exists. A retrospective analysis of clinical data of mCRPC patients treated with AA at two Italian cancer centers was carried out. The Kaplan-Meier method and Cox proportional hazard model were used to analyze survival data. Correlation between median duration of response to first ADT or median TTCRPC and the outcome of patients treated with AA was analyzed. From January 2015 to November 2015, data of 59 patients with mCRPC were collected. We observed no differences in patient's median progression-free survival (PFS) and biochemical progression-free survival (bPFS), according to both median duration of response to first-line ADT (duration of first ADT<13 months: median PFS and bPFS were 11 and 5 months, respectively; duration of ADT≥13 months: median PFS and bPFS were 9 and 6 months, respectively) and median TTCRPC (TTCRPC<28 months: median PFS and bPFS were 8 and 5 months, respectively; TTCRPC≥28 months: median PFS and bPFS were 10 and 9 months, respectively). Overall survival, in the same group, did not differ between patients with a duration of response to first ADT over or under 13 months (P=0.90) but in patients with a TTCRPC of 28 months or more, there was a trend toward longer survival than patients with TTCRPC less than 28 months (5-year overall survival was 74 vs. 50%; P=0.14). The duration of response to first-line ADT and the TTCRPC showed no significant association with outcome of AA therapy in patients with mCRPC. However, large prospective trials are desirable to confirm these data.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Disease-Free Survival; Drug Resistance, Neoplasm; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

The objective of this study was to compare the efficacies of sequential therapies with novel androgen receptor-axis-targeted (ARAT) agents in patients with docetaxel-naïve metastatic castration-resistant prostate cancer (mCRPC).. This study included 108 consecutive patients with mCRPC who sequentially received abiraterone acetate (AA) and enzalutamide (Enz), in either order, without prior treatment with docetaxel. The combined prostate-specific antigen (PSA) progression-free survival (PFS) was defined as the sum of PFS1 and PFS2, representing PSA PFSs on the first and second ARAT agents, respectively.. Of these patients, 49 and 59 received ARAT therapy with the AA-to-Enz sequence (AA-to-Enz group) and with the reverse sequence (Enz-to-AA group), respectively. No significant differences in the baseline characteristics were noted between the 2 groups. In the overall patient population, the PSA response rate to the second-line ARAT agent (21.3%) was significantly lower than that of the first-line ARAT agent (58.3%). The combined PSA PFS in the AA-to-Enz group (median, 18.4 months) was significantly superior to that of the Enz-to-AA group (median, 12.8 months). Furthermore, multivariate analysis identified the treatment sequence (ie, AA-to-Enz vs. Enz-to-AA group) in addition to performance status as an independent predictor of combined PSA PFS in these patients. However, there was no significant difference in overall survival (OS) between the 2 groups.. Although cross-resistance between ARAT agents is a common phenomenon in docetaxel-naïve patients with mCRPC, different efficacies were observed favoring the AA-to-Enz rather than Enz-to-AA sequence in this series with respect to combined PSA PFS but not OS.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Humans; Kallikreins; Male; Middle Aged; Molecular Targeted Therapy; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; Survival Analysis; Treatment Outcome

To determine the prognostic utility of serum chromogranin A (CgA) and neurone-specific enolase (NSE) variations during the first 3 months of abiraterone acetate (AA) treatment in patients with metastatic castration-resistant prostate cancer (mCRPC).. The serum levels of CgA, NSE were measured at baseline and after 3 months of AA treatment in 40 patients with mCRPC. Outcome measures were prostate-specific antigen progression-free survival (PSA-PFS), radiographic PFS (rPFS), and overall survival (OS).. CgA levels were not correlated with NSE levels (P = 0.296). In multivariate analysis the combination of CgA and NSE (≥1 marker positive vs both markers negative) and the combination of CgA and NSE elevation during the first 3 months of AA treatment (≥1 marker positive vs both markers negative) remained significant predictors of OS, rPFS, and PSA-PFS.. We found that CgA and NSE elevation during the first 3 months of AA treatment and elevated baseline CgA and NSE levels were independent prognostic factors for OS, rPFS and PSA-PFS in patients with mCRPC treated with AA. This suggests that serial CgA and NSE evaluation may help clinicians in distinguishing patients with mCRPC who would obtain the best survival benefit from AA treatment.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Biomarkers, Tumor; Chromogranin A; Humans; Male; Neoplasm Metastasis; Phosphopyruvate Hydratase; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

Bone scan index (BSI) is an objective tool for quantifying bone metastasis load. We assessed its prognostic usefulness in patients with metastatic castration-resistant prostate cancer (CRPC) treated with enzalutamide (ENZ) or abiraterone acetate (AA).. We analyzed 40 patients who received ENZ or AA treatment (ENZ/AA) for metastatic CRPC. The Cox proportional hazards model and a C-index were used to investigate associations between overall survival (OS) and BSI, and patient age, prostate-specific antigen, time to CRPC, previous docetaxel use, and pain.. Median OS after ENZ/AA was 17.8 months. All patient deaths (n = 19; 47.5%) were from prostate cancer. In multivariate analysis, decreased BSI was an independent predictor for longer OS (hazard ratio, 8.97; P = .011). Inclusion of BSI improved the C-index from 0.721 to 0.792 in predicting OS after ENZ/AA.. Decreased BSI after ENZ/AA independently predicts longer OS.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Disease Progression; Humans; Kallikreins; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Analysis; Treatment Outcome

Abiraterone acetate (AA) and enzalutamide (ENZ) are oral therapies offering survival benefit to metastatic castration-resistant prostate cancer (mCRPC) patients. Despite the availability of multiple treatment options for mCRPC, there is a lack of information on the effect that being initiated on AA or ENZ has on the combined prostate cancer treatment duration.. To compare the combined duration of prostate cancer treatments of patients initiated on AA with that of patients initiated on ENZ.. Truven Health MarketScan Research Databases from March 2012 to December 2014 were used to identify males with prostate cancer initiated on AA or ENZ (index therapy). Baseline characteristics were assessed during the 6 months pre-index. Inverse probability of treatment weights (IPTWs) were used to reduce baseline confounding. Treatment duration spanned from the index date to the earliest of treatment discontinuation (defined as a > 60-day gap in treatment), 24 months post-index, health plan disenrollment, or end of data. Weighted Kaplan-Meier and Cox proportional hazard models were used to compare the combined duration of mCRPC treatments (AA, ENZ, chemotherapy, sipuleucel-T, and radium 223) and any prostate cancer treatments (mCRPC, hormonal, and corticosteroid treatments) between patients initiated on either AA or ENZ.. A total of 2,591 patients initiated on AA and 807 patients initiated on ENZ were selected for the study. Patients' characteristics were generally well balanced after IPTW. At 3 months, patients initiated on AA were associated with fewer discontinuations of mCRPC treatments (hazard ratio [HR] = 0.73, P = 0.004) or of any prostate cancer treatments (HR = 0.61, P = 0.002), compared with patients initiated on ENZ. This result was maintained at 6, 9, 12, 18, and 24 months for mCRPC treatments (HR = 0.75, P < 0.001) and for any prostate cancer treatments (HR = 0.69, P < 0.001). Median duration of mCRPC treatments was 4.1 months longer for patients initiated on AA compared with those initiated on ENZ (18.3 vs. 14.2 months, P < 0.001) and similarly, the median duration of any prostate cancer treatment was longer for patients initiated on AA compared with those initiated on ENZ (not reached vs. 22.2 months, P < 0.001).. In this study, patients initiated on AA, compared with those initiated on ENZ, had a longer combined duration of mCRPC or prostate cancer treatments.. This research was funded by Janssen Scientific Affairs. Pilon, Emond, and Lefebvre are employees of Analysis Group, a consulting company that has received research grants from Janssen Scientific Affairs. Behl and Ellis are employees of Janssen Scientific Affairs and stockholders in Johnson & Johnson. Dawson is on the speakers bureau for Janssen, Astellas, and Sanofi Aventis. Emond reports grants from Regeneron, Bristol-Myers Squibb, GlaxoSmithKline, Aegerion, Bayer, Novartis, Allergan, Millenium, and Genentech. Pilon reports grants from Novartis, GlaxoSmithKline, Pfizer, and Bayer. Lefebvre reports grants from GlaxoSmithKline, Novartis, Bayer, Medtronic, Noven, and Novo Nordisk. Study concept and design were contributed primarily by Pilon and Lefebvre, along with the other authors. Pilon, Emond, and Lefebre collected the data, and data interpretation was performed by Behl, Lefebvre, and Dawson, along with Pilon, Ellis, and Emond, The manuscript was written by Pilon, Emond, and Lefebvre and revised by Behl, Ellis, and Dawson.

Topics: Abiraterone Acetate; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Tissue Extracts; Treatment Outcome

Evidence suggests differences in androgen receptor AR signaling between black (B) and white (W) patients with prostate cancer, but pivotal trials of abiraterone acetate (AA) for patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled few black patients, a population with a higher mortality from prostate cancer. Our primary objective was to determine differences in response to AA between B and W patients.. We performed a retrospective case-control study of B vs. W patients treated with AA between May 1, 2008 and June 16, 2015 at Duke University Medical Center. Patients were identified (W control patients were matched 2:1 to B patients stratified based on previous docetaxel exposure) through pharmacy records and were eligible if treated with AA for metastatic castration-resistant prostate cancer. Patients with previous enzalutamide use were excluded. The primary objective was to compare the rate of≥90% prostate-specific antigen (PSA) decline from baseline between B vs. W patients. Secondary outcomes included comparing time on therapy, time to PSA progression, and overall survival among groups.. Baseline characteristics among patients (n = 45 B, n = 90 W) were identified; these included Karnofsky performance status, PSA, Gleason score, alkaline phosphatase, albumin, hemoglobin, lactate dehydrogenase, opiate use for pain, and metastatic sites. Baseline characteristics among groups were similar except for median hemoglobin (B = 11.4g/dl, W = 12.3g/dl). The proportion of B patients achieving a≥90% PSA level decline was 37.8% vs. 28.9% for W patients (P = 0.296). Statistically significant differences were found in the proportion of patients achieving a≥50% PSA level decline (B = 68.9%, W = 48.9% [P = 0.028]) and≥30% PSA level decline (B = 77.8%, W = 54.4% [P = 0.008]). Rates of primary abiraterone-refractory disease (PSA increase as best response) trended higher in W (31.1%) than in B (15.6%) patients (P = 0.052). Median treatment duration (B = 9.4 mo, W = 8.3 mo) did not differ (Wilcoxon P = 0.444). Median overall survival (B = 27.3 mo [95% CI: 13.9, not estimable], W = 24.8 mo [95% CI: 19, 31.6] [P = 0.669]) and median time to PSA progression (B = 11.0 mo [95% CI: 4.3, 18.0], W = 9.4 mo [95% CI: 6.2, 13.0] [P = 0.917]) did not differ.. Black patients may have a higher PSA response to AA than white patients. An ongoing prospective clinical study (NCT01940276) is evaluating outcomes between black and white patients treated with AA.

Topics: Abiraterone Acetate; Black People; Case-Control Studies; Disease Progression; Humans; Kallikreins; Male; Neoplasm Metastasis; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; White People

Abiraterone acetate has been approved for metastatic castration-resistant prostate cancer (mCRPC). Coadministration with prednisone has been recommended to prevent the toxicity from secondary mineralocorticoid excess, such as hypertension, hypokalemia, and edema. However, the use of prednisone is often not desired by patients because of the potential for detrimental effects of long-term therapy with corticosteroids, especially in those with comorbidities such as diabetes or who have received previous immunotherapeutic agents. Eplerenone is a nonsteroidal mineralocorticoid antagonist demonstrated to abrogate mineralocorticoid excess. In the present retrospective study, we report our real-world experience with the use of eplerenone with abiraterone in men with mCRPC who wished to avoid concomitant prednisone therapy.. The incidence and grade (Common Terminology Criteria for Adverse Events, version 4) of mineralocorticoid excess toxicities, baseline demographics, disease characteristics, and progression-free survival (PFS) were collected retrospectively. The patient population included men with mCRPC treated with abiraterone, who were not willing to receive corticosteroids, and thus received eplerenone. Their data were compared with the data from those treated with abiraterone and prednisone during the same period. Continuous variables were assessed using the Wilcoxon rank sum test or Student t test, and categorical variables were assessed using Fischer's exact test or χ. Of the 106 men treated with abiraterone, 40 received eplerenone and 66 received prednisone. The baseline and disease characteristics, incidence and grade of adverse events related to the syndrome of mineralocorticoid excess, and the median PFS were similar in both cohorts.. In a real-world population of men with mCRPC treated with abiraterone, corticosteroids can be avoided by concomitant treatment with eplerenone. These data require further validation.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Eplerenone; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Spironolactone; Survival Analysis; Treatment Outcome

The objective of this study was to compare the prognostic effect of time to prostate-specific antigen (PSA) nadir (TTPN) after treatment with abiraterone acetate (AA) and enzalutamide (Enz) in patients with docetaxel-naïve, metastatic castration-resistant prostate cancer (mCRPC).. This study included a total of 297 consecutive patients with mCRPC, of whom 125 and 172 received AA and Enz, respectively, without previous treatment with docetaxel and subsequently achieved any degree of PSA reduction after the administration of either agent.. The mean values of TTPN in the AA and Enz groups were 19 and 14 weeks, respectively. Despite the lack of significant differences in several parameters according to the mean TTPN in the Enz group, patients with TTPN>19 weeks were characterized by longer duration of androgen deprivation therapy, better performance status, lower incidence of bone metastasis, lower value of nadir PSA, and higher incidence of PSA response than those with TTPN ≤19 weeks in the AA group. The PSA progression-free survival (PFS) in patients with TTPN >19 weeks was significantly superior when compared with TTPN ≤19 weeks in the AA group; however, there was no significant effect of the mean TTPN on the PSA-PFS in the Enz group. Furthermore, TTPN was identified as one of the independent predictors of PSA-PFS in the AA group but not in Enz group.. A longer time to reach a PSA nadir after treatment with AA, but not Enz, appeared to be associated with favorable disease control in patients with docetaxel-naïve mCRPC.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Disease-Free Survival; Docetaxel; Humans; Kallikreins; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Time Factors; Treatment Outcome

Renal cell carcinoma (RCC) is one of the most lethal genitourinary cancers. The presence of androgen receptor (AR) in RCC has recently been shown to be associated with higher tumour stage irrespective of gender. Because the clinical context of androgens in female RCC patients is similar to that of prostate cancer patients undergoing androgen-deprivation therapy, mechanisms underlying the emergence of castration-resistant prostate cancer (CRPC) may be at play in AR-positive RCC cells. Therefore, we hypothesized that AR-positive RCC has intratumoral steroidogenesis and that anti-androgen therapy may result in tumour suppression.. Mice were injected with an AR-positive RCC cell line. When tumours became palpable, surgical castration was performed and tumour volume was measured. Using ELISA, the levels of intracellular testosterone and dihydrotesterone were measured in AR-positive human RCC cell lines. Lastly, male mice containing xenografts were treated with enzalutamide or abiraterone acetate (AA) for 3 weeks to measure tumour volume.. We first observed in vivo that castration retards the growth of AR-positive RCC tumour xenograft in mice. Next, AR-positive human RCC cell lines and tissues were found to have elevated levels of testosterone and dihydrotestosterone and express key enzymes required for intracellular androgen biosynthesis. A mouse xenograft study with AR-positive RCC cell line using the commonly used anti-androgen therapies showed significant tumour suppression (P<0.01).. Intracrine androgen biosynthesis is a potential source of androgen in AR-positive RCC and that the androgen signaling axis is a potential target of intervention in RCC.

Topics: Abiraterone Acetate; Androgens; Animals; Antineoplastic Agents; Apoptosis; Benzamides; Blotting, Western; Carcinoma, Renal Cell; Cell Proliferation; Dihydrotestosterone; Female; Humans; Immunoenzyme Techniques; Kidney Neoplasms; Male; Mice; Mice, Nude; Nitriles; Orchiectomy; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Real-Time Polymerase Chain Reaction; Receptors, Androgen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Testosterone; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Abiraterone acetate (AA) increases overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel. However, survival time varies substantially between individuals. Our goal was to identify prognostic factors that better estimate OS.. This is a retrospective multicentric analysis of 368 patients with mCRPC starting AA with prednisone after docetaxel. Cox proportional hazards statistics were applied. A multivariate model was constructed based on significant univariate predictors by using a manual stepwise forward and backward selection strategy. Model performance was determined by using receiver operating characteristic (ROC) curves.. Univariate analysis identified 20 significant OS predictors. A multivariate model was constructed, based on 220 patients, incorporating 5 independent risk factors for decreased OS at the time of AA initiation: hemoglobin < 12 g/dL (hazard ratio [HR] 2.02), > 10 metastases (HR 1.80), ECOG performance status ≥ 2 (HR 1.88), radiographic progression (HR 1.50), and time since diagnosis < 90 months (HR 1.66, all P < .05). Patients were stratified into 3 groups: good (0-2 risk factors, median OS 22.6 months), intermediate (3 risk factors, median OS 13.9 months), and poor prognosis (4-5 risk factors, median OS 6.2 months). The area under the ROC curve based on the event "death by the time of median OS (13.3 months)" was 0.736 (95% confidence interval 0.670-0.803).. We identified 5 readily available risk factors independently associated with decreased OS. The resulting model may be used for patient counseling in daily clinical practice, as well as patient stratification in clinical trials.

Topics: Abiraterone Acetate; Aged; Docetaxel; Humans; Male; Prednisone; Prognosis; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; ROC Curve; Survival Analysis; Taxoids; Treatment Outcome

Metastatic castration-resistant prostate cancer mainly affects older men, opening issues about the efficacy and safety of therapies in this population. We have demonstrated that abiraterone, a selective androgen biosynthesis inhibitor, is a safe and active therapeutic option in a subgroup of 47 very elderly adults (aged > 80 years) enrolled in the Italian named patient program, with a tolerability profile and clinical outcomes comparable to those of younger population.. Prostate cancer mainly affects elderly men, who are often frail and whose reduced physiological reserves and multiple comorbidities increase the risk of side effects. The availability of new drugs has improved the overall survival (OS) of patients with castration-resistant prostate cancer (CRPC) but has increased the number of very elderly CRPC patients receiving anticancer drugs, raising questions about their efficacy and safety in this population.. We assessed the tolerability of abiraterone (AA) in a cohort of very elderly adults with metastatic CRPC (mCRPC) enrolled in the Italian AA named patient program and analyzed their clinical outcomes. We retrospectively reviewed the clinical records of 47 mCRPC patients aged > 80 years who had received AA after docetaxel. The Kaplan-Meier method was used to calculate OS and progression-free survival (PFS). Safety and clinical outcomes were also analyzed by age group (< 80 and > 80 years). Cox regression analysis was used to calculate the differences in PFS and OS between the groups according to the stratification variables.. In very elderly men, the prostate-specific antigen response rate was 48.9%, and the median PFS and OS were 8 and 18 months, respectively. The differences in toxicities between the older and younger age groups were not major. The limitation of the present study was mainly its retrospective nature.. Our data show that AA is active and safe in very elderly patients and leads to outcomes similar to those observed in younger patients, thus confirming that AA is a manageable therapeutic option for this patient population.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Compassionate Use Trials; Disease-Free Survival; Docetaxel; Humans; Kaplan-Meier Estimate; Male; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Abiraterone Acetate (AA) represents a highly effective androgen-receptor (AR) axis targeted agent. Treatment with AA in castration-resistant prostate cancer (CRPC) may partly mediate neuroendocrine differentiation (NED) as an escape mechanism, which may have implications for the choice of sequential therapy in CRPC. We evaluated how treatment with AA influences circulating neuromediators chromogranin A (CGA), neuron-specific enolase (NSE), and pro-gastrin-releasing peptide (Pro-GRP) in chemotherapy-naïve CRPC patients.. We conducted an analysis in chemotherapy-naïve CRPC patients with clinical or radiographic progression of disease. A total of 35 patients were included at five institutions between February 2013 and December 2014. Sixteen of them had received AA. Serum samples were obtained before a docetaxel-based chemotherapy and analyzed in a reference laboratory. Univariable and multivariable analyses were performed to test the influence of AA treatment, its duration of treatment, and other clinicopathological variables on circulating neuromediators.. CGA and NSE levels were above the upper limit of normal (ULN) in n = 20 (57.1%) and n = 13 (37.1%), respectively. Treatment with AA and duration of treatment were not associated with levels above the ULN (CGA and NSE) or higher levels (Pro-GRP) of neuromediators. CGA levels were associated with age (P = 0.092), lymph node metastasis (P = 0.014), duration of androgen deprivation therapy (ADT; P = 0.083), and intake of proton pump inhibitors (P = 0.069). Pro-GRP levels were significantly associated with PSA levels (P = 0.002). On multivariate analysis, CGA levels above the ULN were significantly correlated with ADT (P = 0.01) and intake of proton pump inhibitors (P = 0.03).. Circulating neuromediators in chemotherapy-naïve CRPC patients were elevated in a high percentage of patients. ADT was found to be a relevant NED driver in this cohort. Our results may imply that patients with CRPC after first-line treatment with AA in CRPC are not at a higher risk for developing NED. The major limitation of the study represents the one-time analysis of neuromediators. Larger studies with serial blood measurements or biopsy analysis before and after treatment are needed to confirm our results.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chromogranin A; Disease Progression; Docetaxel; Gastrin-Releasing Peptide; Humans; Lymphatic Metastasis; Male; Middle Aged; Phosphopyruvate Hydratase; Prostatic Neoplasms, Castration-Resistant; Taxoids

Abiraterone acetate (AA) is licensed for treating metastatic castration-resistant prostate cancer (mCRPC). Real-world data on oncological outcome after AA are scarce. The current study assesses efficacy and safety of AA in mCRPC patients previously treated with docetaxel who started treatment during the Belgian compassionate use program (January 2011-July 2012).. Records from 368 patients with mCRPC from 23 different Belgian hospitals who started AA 1000mg per day with 10mg prednisone or equivalent were retrospectively reviewed (September 2013-December 2014). Prostate-specific antigen (PSA) response (decrease≥50%), time to PSA progression (increase>50% over PSA nadir in case of PSA response/>25% in absence of PSA response), time to radiographic progression (on bone scans or for soft tissue lesions using Response Evaluation Criteria In Solid Tumors 1.1), overall survival and adverse event rate (Common Terminology Criteria for Adverse Events v4.03) were analyzed. Kaplan-Meier statistics were applied.. Overall, 92 patients (25%) had an Eastern Cooperative Oncology Group performance status≥2. Median age was 73 years, median PSA was 103ng/dl. PSA response was observed in 131 patients (37.4%). Median time to PSA and radiographic progression was 4.1 months (95% CI: 3.6-4.6) and 5.8 months (5.3-6.4), respectively. Median overall survival was 15.1 months (13.6-16.6). Most common grade 3 to 4 adverse events were anemia (13.9%), hypokalemia (7.3%), fatigue (6.8%), and pain (6.3%). Median duration of AA treatment was 5.3 months (interquartile range: 2.8-10.3). The main study limitation is its retrospective design.. These real-world data on post-docetaxel AA efficacy are in line with the COU-AA-301 trial. Importantly, incidence of severe anemia and hypokalemia is up to 50% higher than reported in previous studies.

Topics: Abiraterone Acetate; Aged; Belgium; Compassionate Use Trials; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Significant progress has been made in the management of aggressive prostate cancer. The established old and new treatments have resulted in the significant delay in progression of disease, improvement of the quality of life, as well as the increase in the overall survival of men with advanced prostate cancer. However, these therapies carry with them possible adverse effects that primary care physicians are experienced in managing. Thus, there is an increasing need for the urologist to involve and partner closely with the primary care practitioner to prevent, identify and manage the potential side effects of these life-changing therapies.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents; Benzamides; Denosumab; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Nitriles; Phenylthiohydantoin; Physicians, Primary Care; Professional Role; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Time Factors

The availability of multiple new treatments for metastatic castration-resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an intermediate endpoint for overall survival (OS).. To evaluate the association between early PSA decline and OS following abiraterone acetate (AA) treatment.. We identified mCRPC patients treated with AA before or after docetaxel at the Royal Marsden NHS Foundation Trust between 2006 and 2014. Early PSA decline was defined as a 30% decrease in PSA at 4 wk relative to baseline, and early PSA rise as a 25% increase.. Association with OS was analyzed using multivariate Cox regression and log-rank analyses. Spearman's rho correlation coefficient (r) was calculated to evaluate the association between PSA changes at 4 wk and 12 wk.. There were 274 patients eligible for this analysis. A 30% PSA decline at 4 wk was associated with longer OS (25.8 vs 15.1 mo; hazard ratio [HR] 0.47, p<0.001), and a 25% PSA rise at 4 wk with shorter OS (15.1 vs 23.8 mo; HR 1.7, p=0.001) in both univariate and multivariable models. The percentage PSA decline at 4 wk was significantly correlated with the percentage PSA change at 12 wk (r=0.82; p<0.001). Patients achieving a 30% PSA decline at 4 wk were 11.7 times more likely to achieve a 50% PSA decrease at 12 wk (sensitivity 90.9%, specificity 79.4%). Limitations include the retrospective design of this analysis.. Patients not achieving 30% PSA decline after 4 wk of AA have a lower likelihood of achieving PSA response at 12 wk and significantly inferior OS. Prospective multicentre validation studies are needed to confirm these findings.. Prostate-specific antigen (PSA) is commonly used to evaluate response to treatment in metastatic castration-resistant prostate cancer. Expert recommendations discourage reliance on PSA changes earlier than 12 wk after treatment initiation. Our data suggest that early PSA changes are associated with survival in patients receiving abiraterone acetate.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Docetaxel; Drug Monitoring; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Outcome Assessment, Health Care; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Registries; Statistics as Topic; Survival Analysis; Taxoids; United Kingdom

Abiraterone acetate (AA) is the prodrug of abiraterone, which inhibits CYP17A1 and testosterone synthesis and prolongs the survival of patients with metastatic castration-resistant prostate cancer (mCRPC). AA plus prednisone (P) (AA+P) is approved for the treatment of patients with mCRPC.. To investigate whether long-term use of low-dose P with or without AA leads to corticosteroid-associated adverse events (CA-AEs) in mCRPC patients.. The study included 2267 patients in COU-AA-301 and COU-AA-302. We used an inclusive Standardized MedDRA Queries-oriented approach to identify 112 preferred terms for known CA-AEs, and assessed the incidence of CA-AEs during 3-mo exposure intervals and across all P exposure levels.. All 2267 patients received 5mg of P twice daily, and 1333/2267 received AA (1g) plus P.. The CA-AE incidence after any P exposure was 25%, 26%, and 23% for any grade, and 5%, 5%, and 4% for grade ≥3 CA-AEs for all patients and the AA+P and P alone groups, respectively. The most common any-grade CA-AEs were hyperglycemia (7.4%, 7.8%, and 6.9% for all patients, AA+P, and P alone, respectively) and weight increase (4.3%, 3.9%, and 4.8%, respectively). When assessed by duration of exposure (3-mo intervals up to ≥30 mo), no discernable trend was observed for CA-AEs, including hyperglycemia and weight increase. The investigator-reported study discontinuation rate due to CA-AEs was 11/2267 (0.5%), and one patient had a CA-AE resulting in death.. Low-dose P given with or without AA is associated with low overall incidence of CA-AEs. The frequency of CA-AEs remained low with increased duration of exposure to P.. We assessed adverse events in patients with metastatic castration-resistant prostate cancer during long-term treatment with a low dose of a corticosteroid. We found that long-term treatment with this low-dose corticosteroid is safe and tolerable.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Humans; Hyperglycemia; Male; Middle Aged; Prednisone; Prostatic Neoplasms, Castration-Resistant; Time Factors; Weight Gain

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Humans; Patient Safety; Prednisone; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Docetaxel; Drug Monitoring; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Outcome Assessment, Health Care; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Registries; Statistics as Topic; Survival Analysis; Taxoids; United Kingdom

There is much interest in confirming whether the efficacy of abiraterone acetate (AA) demonstrated within the trial setting is reproducible in routine clinical practice. We report the clinical outcome of metastatic castration-resistant prostate cancer (mCRPC) patients treated with AA in real-life clinical practice.. The clinical records of mCRPC patients treated with AA from all 6 public oncology centers in Hong Kong between August 2011 and December 2014 were reviewed. The treatment efficacy and its determinants, and toxicities were determined.. A total of 110 patients with mCRPC were treated with AA in the review period, of whom 58 were chemo-naive and 52 had received prior chemotherapy (post-chemo). The median follow-up time was 7.5/11.4 months for chemo-naive/post-chemo patients. 6.9/15.4 % of chemo-naive/post-chemo patients had visceral metastases. The median overall survival (OS) and progression-free survival (PFS) were 18.1/15.5 months and 6.7/6.4 months for chemo-naive/post-chemo patients, respectively. Among chemo-naive patients, those with visceral diseases had significantly inferior OS (2.8 vs 18.0 p = 0.0007) and PFS (2.8 vs 6.8 months, p = 0.0088) than those without. Pain control was comparable in both groups of patients. The most common grade 3 or above toxicities were hypertension (6.9/5.8 %) and hypokalemia (3.4/3.8 %) in chemo-naive/post-chemo patients. In multivariate analysis, the presence of prostate-specific antigen (PSA) response (≥50 % drop of PSA from baseline) within the first 3 months of therapy was associated with favorable OS and PFS in both chemo-naive and post-chemo group.. In clinical practice outside the trial setting, OS after AA in our chemo-naive patient cohort (18.1 months) was considerably shorter than that reported in the COU-AA-302 trial (34.7 months), and the OS was particularly short in those with visceral metastases (2.8 months). Conversely, AA was efficacious in post-chemo patients. AA resulted in comparable pain control in both groups of patients. The presence of PSA response within the first 3 months of treatment was a significant determinant of survival.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Bone Neoplasms; Disease-Free Survival; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Prostate cancer is expected to account for approximately one quarter of all new diagnoses of cancer in American men in 2015. The cost of prostate cancer care is expected to reach $15.1 billion by the year 2020, up from $11.9 billion in 2010. Given the high burden of prostate cancer, health care payers are interested in quantifying the potential budget impact of new therapies.. To estimate the budget impact of enzalutamide for the treatment of chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) from a U.S. payer perspective.. A model was developed to assess the budget impact of enzalutamide for treatment of chemotherapy-naïve mCRPC patients in a hypothetical 1-million-member U.S. health plan over a 1-year time horizon. Comparators included abiraterone acetate, sipuleucel-T, radium Ra 223 dichloride, and docetaxel. Epidemiologic data, including National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) incidence rates, were used to estimate the number of chemotherapy-naïve mCRPC patients. Dosing, administration, duration of therapy, and adverse event rates were based on package inserts and pivotal studies. Drug costs were obtained from RED BOOK and Centers for Medicare & Medicaid Services (CMS) average sales price pricing files, costs of administration and monitoring from the CMS physician fee schedule, and adverse events from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project and published literature. Market shares were estimated for each comparator before and after adoption of enzalutamide. The incremental aggregate budget impact, per patient per year (PPPY), per patient per month (PPPM), and per member per month (PMPM), was calculated. One-way sensitivity analyses were performed.. In a population of 115 chemotherapy-naïve mCRPC patients, adopting enzalutamide had an annual incremental budget impact of $510,641 ($4,426 PPPY, $369 PPPM, and $0.04 PMPM). Results were most sensitive to enzalutamide drug cost, size of the chemotherapy-naïve mCRPC patient population, and enzalutamide adoption rate.. Results indicate a modest 1-year budget impact of adopting enzalutamide for chemotherapy-naïve mCRPC patients, partly because of the cost offset of a moderate incidence of adverse events and lack of additional required monitoring.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Budgets; Docetaxel; Drug Costs; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Taxoids; Tissue Extracts; United States

To calculate costs per median overall survival (OS) month in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate plus prednisone (AA + P) or enzalutamide.. Median treatment duration and median OS data from published Phase 3 clinical trials and prescribing information were used to calculate costs per median OS month based on wholesale acquisition costs (WACs) for patients with mCRPC treated with AA + P or enzalutamide. Sensitivity analyses were performed to understand how variations in treatment duration and treatment-related monitoring recommendations influenced cost per median OS month. Cost-effectiveness estimates of other Phase 3 trial outcomes were also explored: cost per month of chemotherapy avoided and per median radiographic progression-free survival (rPFS) month.. The results demonstrated that AA + P has a lower cost per median OS month than enzalutamide ($3231 vs 4512; 28% reduction), based on the following assumptions: median treatment duration of 14 months for AA + P and 18 months for enzalutamide, median OS of 34.7 months for AA + P and 35.3 months for enzalutamide, and WAC per 30-day supply of $8007.17 for AA + P vs $8847.98 for enzalutamide. Sensitivity analyses showed that accounting for recommended treatment-related monitoring costs or assuming identical treatment durations for AA + P and enzalutamide (18 months) resulted in costs per median OS month 8-27% lower for AA + P than for enzalutamide. Costs per month of chemotherapy avoided were $4448 for AA + P and $5688 for enzalutamide, while costs per month to achieve median rPFS were $6794 for AA + P and $7963 for enzalutamide.. This cost-effectiveness analysis demonstrated that costs per median OS month, along with costs of other Phase 3 trial outcomes, were lower for AA + P than for enzalutamide. The findings were robust to sensitivity analyses. These results have important implications for population health decision-makers evaluating the relative value of therapies for mCRPC patients.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Clinical Trials, Phase III as Topic; Costs and Cost Analysis; Disease Progression; Disease-Free Survival; Drug Therapy, Combination; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

In a randomized clinical trial (COU-AA-301), abiraterone acetate (Zytiga(®)) was shown to be superior to prednisone in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the value of abiraterone treatment for patients with mCRPC in clinical practice in Sweden is not known. The aim of this study was to compare the outcomes and treatment patterns of abiraterone treatment in a Swedish observational study to those of the pivotal clinical trial, thereby discussing the external validity of the postchemotherapy clinical trial from a Swedish perspective.. A retrospective chart review was conducted using data from three Swedish hospitals. Data were retrieved from 119 eligible patients diagnosed with mCRPC, treated during 2013 and 2014. Swedish real-world evidence sample characteristics, treatment patterns and duration, and overall survival were compared to the clinical trial data.. Analyses of the data showed that patients were treated for a median of 5.6 months, which was significantly shorter than the treatment duration in the clinical trial (7.3 months). A comparison indicated that the Swedish patients were similar to patients included in the clinical trial in observed patient characteristics, but perhaps less likely to benefit from treatment owing to prior ketoconazole treatment and possibly higher Eastern Cooperative Oncology Group performance status. Despite this, the Swedish patients had non-significantly longer overall survival and significantly shorter treatment duration.. Swedish patients could expect the same overall survival as patients randomized to abiraterone in the clinical trial despite shorter treatment duration, leading to a more cost-effective use of the treatment in the real world compared to the clinical trial.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Humans; Male; Neoplasm Metastasis; Observational Studies as Topic; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Retrospective Studies; Sweden; Treatment Outcome

Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict the response to abiraterone acetate in men with metastatic, castration refractory prostate cancer. The variations may serve as prognostic and predictive biomarkers to allow for more individualized therapy.. We evaluated 832 single nucleotide polymorphisms from the OmniExpress genotyping platform (Illumina®) in the boundaries of 61 candidate genes reported to be involved in the androgen metabolic pathway. The purpose was to investigate them for an association with time to treatment failure in 68 white men with metastatic, castration refractory prostate cancer undergoing treatment with abiraterone acetate. Cox proportional hazard analysis was used with Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation as covariates. Each single nucleotide polymorphism was assessed using an allele carriage genetic model in which carriage of 1 or more minor alleles contributes to increased risk. Subset analyses were done to determine whether metastasis site, or prior treatment with ketoconazole or docetaxel would interact with the single nucleotide polymorphisms investigated.. Six single nucleotide polymorphisms in the estrogen sulfotransferase gene SULT1E1 were associated with time to treatment failure on abiraterone acetate therapy after false discovery rate (q value) correction for multiple testing while controlling for Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation (q <0.05).. Single nucleotide polymorphisms in SULT1E1 were significantly associated with time to treatment failure in men on abiraterone acetate therapy. The single nucleotide polymorphisms may serve as predictive markers for treatment with abiraterone acetate.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; DNA, Neoplasm; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Orchiectomy; Polymorphism, Genetic; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Sulfotransferases; Treatment Outcome

Topics: Abiraterone Acetate; Adrenal Cortex Hormones; Aged; Humans; Incidence; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

Topics: Abiraterone Acetate; Adrenal Cortex Hormones; Aged; Humans; Incidence; Male; Prednisone; Prostatic Neoplasms, Castration-Resistant

Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Abiraterone Acetate; Administration, Oral; Androgen Antagonists; Androgens; Androstenes; Animals; Cell Line, Tumor; Disease Progression; Dutasteride; Humans; Male; Mice; Oxidation-Reduction; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Xenograft Model Antitumor Assays

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Substance Withdrawal Syndrome

Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a mCRPC cohort was performed. Five common single-nucleotide polymorphisms (SNPs) in CYP17A1 identified using a haplotype-based tagging algorithm were genotyped. Clinical outcomes included biochemical response and time to biochemical progression on AA/P. Logistic regression was used to assess the association between tag SNPs and biochemical response. Proportional hazards regression was used to assess the association between tag SNPs and time to biochemical progression. Odds or hazard ratio per minor allele were estimated and p-values below 0.05 were considered statistically significant. Germline DNA was successfully genotyped for four tag SNPs in 87 patients. The median age was 73 years (54-90); the median prostate-specific antigen was 66 ng/dL (0.1-99.9). A single SNP, rs2486758, was associated with lower odds of experiencing a biochemical response (Odds ratio 0.22, 95% confidence interval 0.07-0.63, p = 0.005) and a shorter time to biochemical progression (Hazard ratio 2.23, 95% confidence interval 1.39-3.56, p < 0.001). This tag SNP located in the promoter region of CYP17A1 will need further validation as a predictive biomarker for AA/P therapy.

Topics: Abiraterone Acetate; Aged; Alleles; Antineoplastic Agents; Disease Progression; Genotype; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Prednisone; Proportional Hazards Models; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Treatment Outcome

In this retrospective study, we evaluated the benefit of repeated carbon 11 (C11)-acetate positron emission tomography/computed tomography (PET/CT) to assess response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA).A total of 30 patients with mCRPC were monitored with C11-acetate PET/CT and PSA levels during their treatment with AA. Retrospective evaluation of their response was made after 102 days (median; range 70-155) of treatment. Statistical analyses were employed to detect predictors of progression-free survival (PFS) and overall survival (OS), and potential correlation between serum levels of PSA, standardized uptake values (SUVpeak), and bone lesion index measured from PET were investigated.At follow-up 10 patients exhibited partial response (PR), 10 progressive disease (PD), and 10 stable disease (SD), as assessed by PET/CT. In survival analysis, both PR and PD were significantly associated with PFS and OS. CT response was also associated with OS, but only 19/30 patients demonstrated a lesion meeting target lesion criteria according to RECIST 1.1. No PET/CT baseline characteristic was significantly associated with PFS or OS. A PSA response (reduction in the level by >50%) could also predict PFS and OS. In the subgroup lacking a PSA response, those with PD had significantly shorter OS than those with PR or SD.PFS and OS in patients with mCRPC treated with AA can be predicted from repeated C11-acetate PET/CT. This may be of particular clinical value in patients who do not exhibit a PSA response to treatment.

Topics: Abiraterone Acetate; Acetates; Administration, Oral; Aged; Antineoplastic Agents; Carbon; Cohort Studies; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Predictive Value of Tests; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Analysis; Treatment Outcome

Androgen receptor signaling remains important in castration-resistant prostate cancer (CRPC) as demonstrated by the efficacy of abiraterone acetate (henceforth abiraterone) in phase III trials. Given that heterogeneous patient responses are observed, we sought to identify clinical factors associated with duration of abiraterone.. We retrospectively identified patients with CRPC treated with abiraterone in our database. Patient characteristics and types and duration of prostate cancer (PC) therapies were analyzed. These parameters were analyzed with duration of abiraterone in univariate and multivariable analyses.. We identified 161 patients who had received abiraterone. All had received primary androgen-deprivation therapy (ADT), 86% prior secondary hormone therapy (SHT) and 33% prior chemotherapy. The median duration of primary ADT was 23 months, duration of SHT (excluding abiraterone) was 17 months and duration of chemotherapy was 8 months. We demonstrated that lower PSA at abiraterone initiation, longer primary ADT duration, no prior ketoconazole, no prior chemotherapy and longer chemotherapy duration were associated with a longer duration on abiraterone in univariate analysis. In multivariable analysis, duration of primary ADT (duration of abiraterone 9 versus 13 months for ⩽12 versus >12 months, P=0.03) and no use of prior chemotherapy (duration of abiraterone 16 versus 7 months for no versus yes prior chemotherapy, P<0.01) were associated with duration of abiraterone.. Several clinical parameters, including type and duration of prior therapy, are predictive of responsiveness to abiraterone. These parameters are logical and correlate with smaller disease burden or less exposure to PC therapies. This information can help physicians counsel patients about the potential durability of efficacy of abiraterone. Identifying predictive biomarkers that inform patient selection for therapy is critical to optimizing treatment outcomes.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; Treatment Outcome

Metabolic abnormalities including hyperglycemia and hyperlipidemia have been associated with worse prognosis of prostate cancer (PCa), but there are limited data regarding their impact on the prognosis of castrate-resistant prostate cancer (CRPC) and the response of novel antiandrogens, namely abiraterone acetate (AA) and enzalutamide. Retrospective analysis of 61 patients with CRPC on AA or enzalutamide, treated at the Boston Medical Center, was performed. We evaluated hemoglobin A1c (HbA1c), HDL, LDL, Triglycerides and BMI within 2months before the initiation of treatment with AA or enzalutamide and progression-free survival (PFS) under this treatment. Regression analysis and analysis of variance were used to evaluate the data. HbA1c levels were found to predict adversely the PFS on the novel agents (df (1, 37), P=0.00, R(2)=0.40, coeff=-3.28). The Kaplan-Meier analysis showed that there is significant difference in survival between the HbA1c 4.7-5.9% compared with patients with HbA1c 7.8-11.6% (6.72±1.3months, log rank test P<0.0001) LDL (P=0.07), HDL (P=0.14), and triglycerides (P=0.33) were not found to predict PFS. BMI predicted PFS positively (df (1.59), P=0.02, R(2)=0.09, coeff=0.03), but not independently of HbA1c (P=0.07). No significant implications of social and family history, previous chemotherapy regimen, and Gleason score with PFS were found. Multiple markers of patients' health state were not associated with HbA1c values. Uncontrolled diabetes can predict for poor response of CRPC patients to AA and enzalutamide determining PFS under this treatment. Elevated BMI can positively affect PFS at this stage of disease.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Benzamides; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus; Disease-Free Survival; Glycated Hemoglobin; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome; Triglycerides

To evaluate the efficacy of enzalutamide (Enz) as fourth- or fifth-line treatment in men with metastasized castration-resistant prostate cancer (mCRPC), by analyzing a retrospective cohort of heavily pretreated patients.. We evaluated toxicity, overall survival (OS), progression-free survival (PFS) and time to prostate-specific antigen (PSA) progression data from 47 CRPC patients treated with fourth- or fifth-line Enz.. All patients were treated with docetaxel and abiraterone acetate and 42 patients (89%) with cabazitaxel. The median age of the patients was 69 years (IQR, 63-73.5), 79% had bone metastases, 55% had lymph node metastases, and 17% had visceral metastases. The median duration of Enz treatment was 12.0 weeks (IQR, 8.3-20.4), and 11 patients (23%) responded to Enz (maximum PSA decline ≥50%). In general, Enz was well tolerated, with the most frequently reported adverse events being fatigue and nausea. The median OS was 40.1 weeks (95% CI, 25.4-61.4), the median PFS was 12.1 weeks (95% CI, 9.9-14.0) and the median time to PSA progression was 15.7 weeks (95% CI, 14.0-28.7).. Analysis of this retrospective cohort suggests that Enz is well tolerated and that there is a 23% response rate in heavily pretreated CRPC patients, which is comparable with third-line treatment outcomes.

Topics: Abdominal Neoplasms; Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Bone Neoplasms; Disease Progression; Disease-Free Survival; Docetaxel; Humans; Lymphatic Metastasis; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Retreatment; Retrospective Studies; Survival Rate; Taxoids

Abiraterone acetate (AA), used to treat metastatic castration-resistant prostate cancer (mCRPC), inhibits androgen biosynthesis by blocking cytochrome P450 (CYP) 17A1. It also inhibits other cytochromes involved in the metabolism of various widely used medications. As such, there is presumably a high potential for drug-drug interactions (DDIs) that can diminish the efficacy of AA or concurrent medications, or increase the risk of DDI-related adverse events (AEs). However, the scale of AA-associated DDIs is currently unknown.. We conducted a retrospective review of pharmacy records and electronic patient charts to retrieve individual drug histories and on-treatment AEs of mCRPC patients beginning AA therapy in a tertiary care setting. Potential DDIs were analyzed using two commercial databases, Lexicomp and Micromedex.. Eighty-four informative patients were identified. Sixty-five patients (77 %) and 44 patients (52 %) were flagged for one or more potential DDIs by the Lexicomp and Micromedex databases, respectively. One hundred eighty-four potential DDIs were identified overall, with a median of 1 DDI per patient in both databases. Possibly due to rigorous DDI screening before AA treatment initiation, we did not identify a definite instance of DDI-related AEs.. The use of commercial DDI databases suggests a substantial risk of potentially consequential DDIs in mCRPC patients undergoing AA therapy. However, prospective investigations with larger patient populations are required to better establish the clinical relevance of these DDIs.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Databases, Factual; Drug Interactions; Humans; Male; Middle Aged; Polypharmacy; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

Even though the exact mechanism is largely unknown until now, statins are supposed to improve survival outcomes in various malignancies. For prostate cancer however, statins are known to compete with dehydroepiandrosterone (DHEAS) for the transport into the cytosol both using the cell by the Solute Carrier Transporter and thus diminish the cellular uptake of DHEAS as a precursor of androgens. Abiraterone inhibits CYP17A1 and thus effectively decreases the production of all relevant androgens including DHEAS. In this study we examined whether statins still affect survival outcome in patients with metastatic castration resistant prostate cancer (mCRPC) when treated with Abiraterone.. 108 men with mCRPC treated with Abiraterone from 02/2010 to 07/2015 with (n = 21) or without (n = 87) concomitant treatment with statins were investigated. Progression free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier-estimates and univariate Cox-regression analysis. The influence on best clinical benefit under Abiraterone treatment was analyzed with bivariate and multivariate logistic regression analysis.. PSA-decline ≥ 50% was not significantly different in both groups (57 vs. 53%; p = 0.73). The median PFS (9 vs. 10 months; p = 0.97) and OS (14 vs. 18 months; p = 0.77) did not differ significantly between those men treated with and without concomitant statin therapy, respectively. Accordingly, there was no improvement for best clinical benefit in patients using statins (odds ratio: 1.2 (CI: 0.4-4.2); p = 0.76).. Use of statins as concomitant medication did not improve survival outcomes or best clinical benefit in men with mCRPC treated with Abiraterone.

Topics: Abiraterone Acetate; Aged; Cohort Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Survival Analysis

The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [-2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8-12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS < vs. ≥12 months by using Mann-Whitney-Wilcoxon Tests, the relative-median-change of tPSA (-0.1% vs. -86.8%; p = 0.02), fPSA (12.1% vs. -55.3%; p = 0.03) and [-2]proPSA (8.1% vs. -59.3%; p = 0.05) differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. -46.3%; p = 0.06). In Kaplan-Meier analyses, declining fPSA and [-2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6-16.4 vs. 10 months, 95% CI: 3.5-16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [-2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7-34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [-2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Disease-Free Survival; Humans; Male; Middle Aged; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Treatment Outcome

Topics: Abiraterone Acetate; Aged; Frail Elderly; Humans; Male; Prostatic Neoplasms, Castration-Resistant

Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17α-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation. Administration of VT-464 in a metastatic CRPC patient presenting with high tumoral expression of both androgen receptor (AR) and CYP17A1, showed significant reduction in the level of both dehydroepiandrosterone (DHEA) and serum PSA. Treatment of a CRPC patient-derived xenograft, MDA-PCa-133 expressing H874Y AR mutant with VT-464, reduced the increase in tumor volume in castrate male mice more than twice as much as the vehicle (P < 0.05). Mass spectrometry analysis of post-treatment xenograft tumor tissues showed that VT-464 significantly decreased intratumoral androgens but not cortisol. VT-464 also reduced AR signaling more effectively than abiraterone in cultured PCa cells expressing T877A AR mutant. Collectively, this study suggests that VT-464 therapy can effectively treat CRPC and be used in precision medicine based on androgen receptor mutation status.

Topics: Abiraterone Acetate; Androgens; Animals; Biopsy; Cell Line, Tumor; Dehydroepiandrosterone; Humans; Hydrocortisone; Male; Mass Spectrometry; Mice; Mice, SCID; Naphthalenes; Neoplasm Transplantation; Precision Medicine; Prednisone; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Steroid 17-alpha-Hydroxylase; Triazoles

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

Both abiraterone acetate (AA) and enzalutamide are promising agents for patients with pre- and post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC). Several retrospective analysis suggested clinical cross-resistance between these agents in patients previously treated with docetaxel. However, data on the antitumor activity of AA as a second androgen receptor-targeting new agent after the failure of enzalutamide in chemotherapy-naive mCRPC patients is unavailable.. Patients with chemotherapy-naïve mCRPC who were treated with AA after disease progression with enzalutamide, were retrospectively reviewed at five institutions. Primary outcome measure was the rate of any prostate-specific antigen (PSA) decline. Secondary outcome measures were progression-free survival (PFS) and overall survival (OS) with subsequent AA treatment. We also performed correlation analysis between previous PSA response, PFS duration to enzalutamide and subsequent PSA response, PFS duration to AA.. A total of 14 patients were identified. Any PSA declines and PSA decline ≥50 % with AA treatment, were observed in 36 and 7 % of patients, respectively. Median PFS with initial enzalutamide was 5.0 months (95 % CI 3.7-6.4 months), and for subsequent AA treatment was 3.4 months (95 % CI 0.8-6.0 months). Median OS from initiation of AA was 9.1 months (95 % CI 5.6-12.5 months). No significant correlations were observed between these PSA responses (Pearson r = -0.67, p = 0.82) and PFS duration (Kendall tau r = 0.33, p = 0.87).. The PSA decline with subsequent AA treatment in chemotherapy-naive mCRPC patients after a failure of enzalutamide was modest, however, the PFS and OS with subsequent AA treatment were comparable to those of enzalutamide previously reported as a second androgen receptor-targeting new agent after AA failure. The PSA response and PFS duration to previous enzalutamide treatment did not predict those of subsequent AA treatment.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Benzamides; Disease Progression; Drug Resistance, Neoplasm; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies

Although abiraterone acetate (abiraterone) has proven efficacy in two randomised phase 3 trials in metastatic castration-resistant prostate cancer (mCRPC), patients who had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 were either excluded or under-represented in these trials.. To compare outcomes in ECOG PS 0-1 and ≥2 in mCRPC patients treated with abiraterone.. Cancer registries from three Canadian centres were used to retrospectively identify mCRPC patients (postdocetaxel and docetaxel-naïve) treated with abiraterone. ECOG PS, clinicopathologic characteristics, prostate-specific antigen (PSA) response, and survival data were collected.. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards modelling was used to examine the effect of clinicopathologic characteristics on overall survival (OS) and time to PSA progression.. A total of 519 patients were identified; 61% (n=318) and 39% (n=201) were ECOG PS 0-1 and ≥2, respectively. ECOG PS 0-1 patients were significantly more likely than PS ≥2 patients to achieve a PSA decline ≥50% from baseline (45% vs 32%; p=0.003, Fisher exact test) and had significantly longer median time to PSA progression (5.2 mo vs 4.1 mo; p=0.023), median treatment duration (7.4 mo vs 4.5 mo; p<0.001), and median OS (20.0 mo vs 9.1 mo; p<0.001). On multivariate analysis, ECOG PS was a significant factor for OS (p<0.001), time to PSA progression (p=0.043), and PSA decline (p=0.002). Potential limitations include the retrospective study design and subjective nature of ECOG PS classification.. ECOG PS ≥2 mCRPC patients treated with abiraterone have inferior outcomes compared with ECOG 0-1 patients, especially in regard to OS. These data indicate that early initiation of abiraterone prior to a decline in PS may be warranted.. We found that advanced prostate cancer patients who have worse performance status (PS) derive less benefit from abiraterone, indicating that earlier treatment before PS declines could improve outcomes.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Canada; Cytochrome P-450 Enzyme Inhibitors; Disease Progression; Health Status; Humans; Kallikreins; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Risk Factors; Steroid Synthesis Inhibitors; Time Factors; Treatment Outcome

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Cytochrome P-450 Enzyme Inhibitors; Health Status; Humans; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors

To assess the safety and efficacy of abiraterone acetate (AA) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated in a compassionate named patient programme (NPP).. We retrospectively reviewed the clinical records of patients with mCRPC treated with AA at the standard daily oral dose of 1000 mg plus prednisone 10 mg/day in 19 Italian hospitals.. We assessed 265 patients with mCRPC treated with AA. The most frequent (>1%) grade 3-4 toxicities were anaemia (4.2%), fatigue (4.2%), and bone pain (1.5%). The median progression-free survival was 7 months; median overall survival was 17 months after starting AA, and 35 months after the first docetaxel administration. Our study reproduced the clinical outcomes reported in the AA pivotal trial, including those relating to special populations such as the elderly, patients with a poor performance status, symptomatic patients, and patients with visceral metastases.. Our data show the safety and activity of AA when administered outside clinical trials, and confirm the findings of the post-docetaxel pivotal trial in the patients as a whole population and in special populations of specific interest.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androstenes; Antineoplastic Agents; Compassionate Use Trials; Docetaxel; Drug Therapy, Combination; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

The activity of enzalutamide after prior treatment with both abiraterone acetate (abiraterone) and docetaxel has been examined in several retrospective studies. However, limited data are available on the efficacy of enzalutamide following abiraterone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC).. To compare the activity of enzalutamide after abiraterone in docetaxel-experienced and docetaxel-naive mCRPC patients.. The British Columbia Cancer Agency Cancer Registry was searched for mCRPC patients who received enzalutamide after prior abiraterone. Clinicopathologic characteristics, confirmed prostate-specific antigen (PSA) response rates (PSA decline ≥ 50% confirmed ≥ 3 wk later), and survival data were collected.. Outcomes on enzalutamide were compared between docetaxel-experienced and docetaxel-naive patients using chi-square for PSA response and log-rank test for time to PSA progression and overall survival (OS). Univariate analysis was performed to identify variables associated with confirmed PSA response on enzalutamide, using either chi-square for categorical variables or logistic regression for continuous variables.. A total of 115 patients received enzalutamide after abiraterone: 68 had received prior docetaxel and 47 were docetaxel naive. Median time on enzalutamide was 4.1 mo. Confirmed PSA response rates (22% vs 26%; p=0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo; p=0.6), and median OS (10.6 mo vs 8.6 mo; p=0.2) did not differ significantly between docetaxel-experienced and docetaxel-naive patients. No clinical variables (including prior response to abiraterone) were found to associate significantly with confirmed PSA response to enzalutamide.. Antitumour activity of enzalutamide following abiraterone was limited in mCRPC patients irrespective of prior docetaxel use. Identifying clinical and molecular factors predictive of response to enzalutamide remains a high priority for future research.. We looked at the effectiveness of enzalutamide after abiraterone acetate for treatment of advanced prostate cancer. We found that patients who had received docetaxel chemotherapy before abiraterone gained similar benefit from enzalutamide compared with patients who had not received docetaxel. These results suggest that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Disease Progression; Docetaxel; Humans; Lymphatic Metastasis; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Survival Rate; Taxoids

Cabazitaxel and abiraterone have both received approval for treating metastatic castrate-resistant prostate cancer (mCRPC) patients after first-line docetaxel therapy. In the cabazitaxel and abiraterone sequential treatment (CAST) study, the clinical outcome of docetaxel-treated mCRPC patients treated sequentially with both cabazitaxel and abiraterone was studied. Data were collected retrospectively from mCRPC patients at 12 hospitals across the Netherlands who initiated cabazitaxel and/or abiraterone before December 2012. Primary outcome measure was overall survival (OS); secondary measures were progression-free survival (PFS), biochemical PFS, and best clinical and PSA response. Hospital admission data during treatment were collected, as well as toxicities resulting in treatment discontinuation or patient death. Sixty-three and 69 patients received Cab→Abi (cabazitaxel prior to abiraterone) and Abi→Cab before July 10th, 2013, respectively. Median OS was 19.1 months and 17.0 months in Cab→Abi and Abi→Cab treated patients, respectively (p = 0.369). Median PFS and biochemical PFS were significantly longer in Cab→Abi treated patients: 8.1 versus 6.5 (p = 0.050) and 9.5 versus 7.7 months (p = 0.024), respectively. Although partial responses to cabazitaxel occurred in both groups, Abi→Cab treated patients had a significantly decreased antitumor response from cabazitaxel than Cab→Abi treated patients (median PFS 5.0 versus 2.6 months, p < 0.001). Minor differences in toxicities were observed based on therapy sequence; generally, toxicity from cabazitaxel could be severe, while abiraterone toxicity was milder. This retrospective analysis indicates that primary progression on cabazitaxel or abiraterone did not preclude a response to the other agent in mCRPC patients. However, tumor response of both agents, particularly cabazitaxel, was lower when administered as higher-line therapy in the selected study population.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling through loss of PTEN can result in resistance to hormonal treatment in prostate cancer.. To explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression.. We retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis.. The primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses.. A total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio [HR]: 1.75; 95% confidence interval [CI], 1.19-2.55; p=0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12-2.28; p=0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis.. Our results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted.. PTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate cancers that lack this protein respond differently to treatment with abiraterone acetate. We demonstrated that the survival of patients with loss of PTEN is shorter than patients with normal PTEN expression.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Male; Middle Aged; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; PTEN Phosphohydrolase; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome

The availability of new agents (NAs) active in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel treatment (abiraterone acetate, cabazitaxel, and enzalutamide) has led to the possibility of using them sequentially to obtain a cumulative survival benefit.. To provide clinical outcome data relating to a large cohort of mCRPC patients who received a third-line NA after the failure of docetaxel and another NA.. We retrospectively reviewed the clinical records of patients who had received at least two successive NAs after the failure of docetaxel.. The independent prognostic value of a series of pretreatment covariates on the primary outcome measure of overall survival was assessed using Cox regression analysis.. We assessed 260 patients who received one third-line NA between January 2012 and December 2013, including 38 who received a further NA as fourth-line therapy. The median progression-free and overall survival from the start of third-line therapy was, respectively, 4 mo and 11 mo, with no significant differences between the NAs. Performance status, and haemoglobin and alkaline phosphatase levels were the only independent prognostic factors. The limitations of the study are mainly due its retrospective nature and the small number of patients treated with some of the sequences.. We were unable to demonstrate a difference in the clinical outcomes of third-line NAs regardless of previous NA therapy.. It is debated which sequence of treatments to adopt after docetaxel. Our data do not support the superiority of any of the three new agents in third-line treatment, regardless of the previously administered new agent.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Cohort Studies; Disease-Free Survival; Docetaxel; Humans; Italy; Male; Multivariate Analysis; Nitriles; Phenylthiohydantoin; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Failure; Treatment Outcome

Metastases of prostate cancer originating from the parotid gland are rare. However, this presentation raises the question of the management of visceral metastasis in castration-resistant prostate cancer. We report the case of an 87-year-old man who presented with a right painless parotid mass in the context of castration-resistant prostate cancer, indicating progression of the disease. He received medical treatment based on docetaxel. Here, we discuss the impact of new hormonotherapies such as enzalutamide and abiraterone acetate, which may be used for the management of these patients.

Topics: Abiraterone Acetate; Aged, 80 and over; Androstenes; Antineoplastic Agents; Benzamides; Docetaxel; Humans; Male; Nitriles; Parotid Neoplasms; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

The treatment of metastatic castration-resistant prostate cancer (mCRPC) represents one of the oncological fields where the most impressive improvements has been observed in the last decades. At the beginning of this century, the expected survival of mCRPC patients was not more than 12 months. After the introduction of docetaxel in the clinical practice in 2004, and the recent availability of new drugs cabazitaxel, abiraterone acetate, enzalutamide, and radium-223 the landscape is dramatically changed with an expected median survival of about three years. The possibility of administering docetaxel, abiraterone acetate, and enzalutamide as first line treatment, and cabazitaxel, abiretone acetate, and enzalutamide as second line, as well as the availability of radium-223 for the treatment of mCRPC patients regardless of chemotherapy administration, changed the natural history of the disease. At the same time, it is probable that also the biology of the disease is changing with the appearance of mechanisms of resistance which are common to all the drugs. This plays a central role in sequencing the available drugs not only in the first and second line setting but also beyond the second line. The future challenges for the oncologists will be to develop new drugs able to overcome the resistances, mainly when they are native, to find the optimal sequence to optimize the use of available drugs, to place at the best place other active drugs, such as vaccines and radiopharmaceuticals, to exploit the new drugs also in a hormone-sensitive phase.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Agents; Benzamides; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids; Time Factors; Treatment Outcome

Abiraterone acetate (AA) has demonstrated improved outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). However, data are lacking on the effect of AA on subsequent efficacy of enzalutamide or docetaxel.. We included men with mCRPC who received AA and subsequent enzalutamide or docetaxel by August 12, 2013. Patients were separated into 3 groups: group A, treated with AA then enzalutamide before chemotherapy; group B, treated with AA then docetaxel; and group C, treated with AA and enzalutamide after chemotherapy. The primary objective was to describe the response and overall survival with subsequent therapy.. There were 28 evaluable patients who received enzalutamide after AA (9 in group A and 19 in group C) and 13 patients who received docetaxel after AA (group B). Group A patients had more visceral disease and higher baseline prostate-specific antigen (PSA) levels, and group C men had a higher level of pain and multiple poor prognostic features. Median progression-free survival was 3.6, 5.1, and 2.8 months, respectively, and median overall survival was 8.5, not reached, and 9.6 months, respectively. A ≥ 50% PSA decline was achieved in 11%, 63%, and 5% of group A, B, and C patients, respectively. Radiographic or clinical progression as best response was noted in 55.5%, 30.8%, and 68.4% in each respective group.. In this chart review of consecutive men with progressive mCRPC after AA, we found modest activity for enzalutamide and docetaxel, with clear cross-resistance for AA and enzalutamide. These data might inform the complex treatment decisions after AA treatment.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstenes; Antineoplastic Agents; Benzamides; Disease Progression; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radiography; Retrospective Studies; Taxoids; Treatment Outcome

Optimal sequencing of cabazitaxel (C) and abiraterone acetate (A) after docetaxel (D) for metastatic castration-resistant prostate cancer (mCRPC) is unclear. We assessed treatment patterns and outcomes in patients with mCRPC receiving different sequences of A or C, or both, after administration of D.. Retrospective analysis was conducted of US Oncology Network iKnowMed (iKM) electronic health record (EHR) data to assess patients with mCRPC who received treatment with D and were subsequently treated with C or A, or both, between April 2011 and May 2012. Patients received 2 or 3 drugs: DA, DC, DAC, or DCA. Overall survival (OS) and time to treatment failure (TTF) were analyzed by the Kaplan-Meier method from the start to the end of second-line therapy after administration of D (TTF1) and to the end of combined second- and third-line therapy (TTF2) for 3-drug sequences. Multivariable Cox proportional hazard models evaluated the impact of baseline clinical prognostic factors and treatment sequence on OS and TTF.. Of 350 patients who were treated with D and subsequent therapies, 183 (52.3%) received DA, 54 (15.4%) received DC, 77 (22.0%) received DCA, and 36 (10.3%) received DAC. In a multivariable analysis, adjusted comparisons suggested that 3-drug sequences were associated with improved OS versus 2-drug sequences (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.092-0.476; P = .0002). There were no statistically significant differences in OS and TTF for DC versus DA, and OS was significantly greater for DCA versus DAC (HR, 0.13; 95% CI, 0.022-0.733; P = .0210). More cycles of C were administered in DCA than in DAC (median 6 vs. 4; t test P < .0001), whereas the duration of A treatment was similar.. Administration of 3 agents in the DCA sequence was more optimal for treating mCRPC in this hypothesis-generating study.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Owing to efficacy and tolerability, abiraterone acetate (AA) is a leading treatment for men with metastatic castration-resistant prostate cancer. Increased serum concentrations of AA, such as by taking AA with food, may lead to the inhibition of additional enzymes in the androgen synthesis pathway implicated in castration-resistant prostate cancer progression.. Medical records of men with metastatic castration-resistant prostate cancer (mCRPC) who received AA between 1 April 2011 and 31 December 2013 were retrospectively reviewed. The primary outcome was the percent of men with a rising PSA on AA who experienced any PSA decline within 3 months after changing the administration of AA from without food to with food. Secondary outcomes were median time on AA therapy in men who received AA therapy without food versus those that switched administration from without food to with food at PSA progression, and the percent of men who experienced any decline in serum testosterone concentration, and the rate of adverse events observed while taking AA with food.. Nineteen men who switched AA administration from without food to with food and 41 patients who administered AA without food only were included in the study. Of those patients who took AA with food at PSA progression, a PSA decline was observed in 3 of the 19 (16%) men, including 3 of the 14 men who had an initial response to AA (21%). Testosterone declined in five out of seven patients from pre-food levels. The median time on AA therapy was increased by nearly 100 days in patients who switched AA administration from without food to with food. No increases in toxicity were observed.. Some men with mCRPC may benefit from taking AA with food. Further prospective comparative studies are needed to determine if changing AA administration is beneficial.

Topics: Abiraterone Acetate; Aged; Disease-Free Survival; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Cytochrome P-450 Enzyme Inhibitors; Health Status; Humans; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Cytochrome P-450 Enzyme Inhibitors; Health Status; Humans; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors

COU-AA-301 trial has proved that abiraterone acetate (AA), a selective inhibitor of androgen biosynthesis, improved overall survival (OS) of patients with metastatic castration resistant prostate cancer (mCRPC) after a first line of docetaxel. Based on this result, a Temporary Authorization for Use (TAU) was performed between December 2010 and July 2011 to provide patients with mCRPC the opportunity to receive AA before its commercialization. The aim of this study was to evaluate safety and efficacy of AA treatment in this TAU.. Between December 2010 and July 2011, we conducted an ambispective, multicentric cohort study and investigated data from 20 centres participating to the AA TAU for patients presenting mCRPC and already treated by a first line of chemotherapy (CT). Statistical analyses of the data were performed using the Stata software v13 to identify predictive and prognostic factors.. Among the 408 patients, 306 were eligible with a follow-up at 3 years. Median OS was 37.1 months from beginning of CT and 14.6 months from AA introduction. 211 patients (69%) received ≥ 3 months of AA and 95 patients (31%) were treated less than 3 months. In the multivariate analyses, duration of AA was significantly correlated with PSA decrease at 3 months. Additionally, shorter time under AA treatment, presence of multiple sites of metastasis and previous hormonal treatment duration were three independent factors associated with poorer OS. At the time of analysis ten patients were still under treatment for more than 3 years.. Biochemical response monitored by PSA changes at 3 months is a strong predictive factor for AA treatment duration. Some high responders' patients could beneficiate from AA for more than 3 years.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Follow-Up Studies; France; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Prognosis; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

The aim of the study was to evaluate the activity and safety of reduced-dose abiraterone acetate (AA) in ≥ 85 year-old patients with advanced castrate-resistant prostate cancer (CRPC).. Patients received 750 mg oral AA as three 250-mg tablets once daily, with concomitant oral prednisone, 5 mg daily.. Twenty-six patients were enrolled; median age was 88 years (range=85-93). Prostate-specific antigen (PSA) response was observed in 18 (69.2%) subjects, median time to PSA progression was 6.4 months (95% confidence interval (CI)=2.8-8.8) and median overall survival was 14.3 months (95% CI=7.2-18.3). The treatment was well-tolerated and adverse events, related to mineralocorticoid excess, were of grade 1-2 in all patients.. Reduced dose of AA combined with a very low dose of prednisone is effective and well-tolerated in very elderly patients with advanced CRPC.

Topics: Abiraterone Acetate; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Humans; Male; Neoplasm Staging; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant

Abiraterone acetate and docetaxel are promising treatment options for metastatic castration-resistant prostate cancer patients. However, the optimal sequencing of these agents is unclear, and no previous reports discuss Japanese metastatic castration-resistant prostate cancer patients. The purpose of this analysis is to reveal the outcomes of Japanese metastatic castration-resistant prostate cancer patients treated with abiraterone acetate followed by docetaxel.. We retrospectively reviewed Japanese Phase 1 and Phase 2 trials of metastatic castration-resistant prostate cancer patients treated with abiraterone acetate until disease progression and subsequently treated with docetaxel. The primary outcome measure was the rates of prostate-specific antigen declines ≧30 and ≧50%, respectively, with docetaxel. Secondary outcome measures included progression-free survival with docetaxel, and overall survival after initiation of abiraterone acetate and docetaxel. We performed correlation analysis between previous prostate-specific antigen response to abiraterone acetate and subsequent prostate-specific antigen response to docetaxel.. We identified 15 patients had experienced disease progression with abiraterone acetate and subsequently were treated with docetaxel. Prostate-specific antigen declines ≧30 and ≧50% with docetaxel were observed in five patients (33%) and two patients (13%), respectively. The median progression-free survival with docetaxel was 3.7 months (95% confidence interval: 2.9-4.6). The median overall survival from initiation of docetaxel and abiraterone acetate were 14.4 months (95% confidence interval: 6.3-22.4), and 25.7 months (95% confidence interval: 20.1-30.7), respectively. No significant correlation was observed between these prostate-specific antigen responses (Pearson r = 0.206, P = 0.46).. The efficacy of docetaxel in Japanese mCRPC patients that was resistant to abiraterone acetate was modest. The prostate-specific antigen response to previous abiraterone acetate could not predict the efficacy of subsequent docetaxel. Larger prospective trials are needed to validate these findings.

Topics: Abiraterone Acetate; Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Docetaxel; Humans; Japan; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy.. Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients.. This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial.. Patients were grouped by concomitant BTT use or no BTT use.. Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models.. While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p=0.01) and increased the time to ECOG deterioration (HR 0.75; p<0.001) and time to opiate use for cancer-related pain (HR 0.80; p=0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients.. AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naïve mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT.. Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone in combination with bone-targeted therapy, there was a continued trend in prolongation of life when compared with patients treated with prednisone alone.. ClinicalTrials.gov NCT00887198.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Bone Neoplasms; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multicenter Studies as Topic; Odds Ratio; Prednisone; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Steroid Synthesis Inhibitors; Time Factors; Treatment Outcome

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Density Conservation Agents; Bone Neoplasms; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors

Few data are available concerning the clinical outcome of abiraterone acetate treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) in terms of the duration of androgen deprivation therapy (ADT) before diagnosis of CRPC. We investigated the clinical efficacy of abiraterone acetate according to the duration of ADT.. We reviewed the medical records of 20 patients with mCRPC who received abiraterone acetate after failure of docetaxel chemotherapy from May 2012 to March 2014 at Seoul National University Bundang Hospital. Clinical factors including prostate-specific antigen (PSA) nadir level, time to PSA nadir, PSA doubling time, PSA response, and modes of progression (PSA, radiologic, clinical) were analyzed. Disease progression was classified according to the Prostate Cancer Working Group 2 criteria.. The mean age and PSA value of the entire cohort were 76.0±7.2 years and 158.8±237.9 ng/mL, respectively. The median follow-up duration was 13.4±6.7 months. There were no statistically significant differences in clinical characteristics between patients who received abiraterone acetate with ADT duration<35 months and those who received abiraterone acetate with ADT duration≥35 months. There were also no significant differences in terms of PSA progression-free survival, radiologic progression-free survival, and clinical progression-free survival between patients with ADT duration<35 months and those with ADT duration ≥35 months.. Although this was a retrospective study with a small sample size, we did not observe any statistically significant differences in the clinical response to abiraterone acetate between mCRPC patients with long ADT duration and those with short ADT duration in terms of disease progression-free survival.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Receptor Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Docetaxel; Drug Administration Schedule; Humans; Kallikreins; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Topics: Abiraterone Acetate; Antineoplastic Agents; Humans; Male; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Abiraterone Acetate; Antineoplastic Agents; Humans; Male; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

Ureteral metastasis from a primary prostate cancer is a rare event in the initial diagnosis and progression of prostate cancer. We report here the case of a 72- year-old patient who was treated for castration-resistant metastatic prostate cancer involving bone, intra-abdominal lymph nodes, bilateral adrenal glands, and a small distal ureteral lesion with left hydronephrosis considered in remission, with a luteinizing hormone-releasing hormone analog plus abiraterone acetate (AA) and prednisone after initial docetaxel plus prednisone chemotherapy. After an episode of acute left flank pain, the previous left distal intraluminal ureteral mass appeared increased in volume on computed tomographic scan and was compatible with either a metastasis from prostate cancer, transitional cell carcinoma of the ureter, or a collision tumor. After left nephroureterectomy (NU), the mass was confirmed to be of prostatic origin on histopathological examination and the only site of metastatic progression of prostate cancer. Abdominal CT-scan and the operative specimen of the NU showed no direct extension of the abdominal lymph nodes into the ureteral lesion. We speculate that this unique ureteral prostate cancer metastasis was the result of hematogenic spread of prostate cancer, although microscopic spread through the lymphatic system could not be excluded. The transient anti-tumor effect of AA plus prednisone at the level of ureteral metastasis, as far as we are aware of, has never been documented before.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prednisone; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Ureteral Neoplasms

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents, Hormonal; Disease Progression; Drug Administration Schedule; Humans; Kallikreins; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Risk Factors; Substance Withdrawal Syndrome; Time Factors

The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post-chemotherapy setting.. Twenty-four mCRPC patients with progression after abiraterone treatment following primary docetaxel therapy received enzalutamide 160 mg/day. The percentage PSA response was recorded following first line docetaxel, abiraterone and enzalutamide treatment. Fischer's exact test, Mann-Whitney U test and linear regression model were used to test for differences in PSA response.. All patients had a follow-up of at least 3 months. The median PSA response following 1 month of enzalutamide was -12% (range -56% to 76%), while the median best PSA response was -22% (-76% to 76%). Forty-six percent had a greater than 30% decrease in PSA. The PSA response to enzalutamide did not correlate with the number of prior cancer treatments (p = 0.57), time from diagnosis to mCRPC (p = 0.11) or prior response to docetaxel (p = 0.67). However, patients treated with second line cabazitaxel had an inferior PSA response to enzalutamide (p = 0.03), and there was a trend for the PSA response to abiraterone to correlate with the PSA response to the succeeding enzalutamide (B = 0.22, p = 0.05). The median OS was 4.8 months.. Previous abiraterone therapy is associated with a less marked fall in PSA following enzalutamide therapy in post-chemotherapy mCRPC patients compared with reported results in randomized trials. Larger prospective studies of sequencing are warranted.

Topics: Abiraterone Acetate; Aged; Androstadienes; Antineoplastic Agents; Benzamides; Cohort Studies; Compassionate Use Trials; Disease-Free Survival; Docetaxel; Humans; Kallikreins; Linear Models; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Failure; Treatment Outcome

Abiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This study's objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone.. All patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation.. A confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%-50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis.. A composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Androstadienes; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; Humans; Kallikreins; L-Lactate Dehydrogenase; Lymphocytes; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neutrophils; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Steroid 17-alpha-Hydroxylase; Treatment Outcome

To describe the results obtained in 25 males with metastatic castration-resistant prostate cancer (MCRPC) treated with abiraterone (AA). A comparative analysis of abiraterone effectiveness and safety between our results and data published in the literature was conducted.. Bi-institutional prospective analysis of 25 consecutive patients with MCRPC undergoing treatment with abiraterone, with a mean follow-up 7.9 (3-15) months was carried out. Treatment effectiveness and safety analyses regarding baseline characteristics of patients (age, prior treatments, basal PSA, performance status, pain, metastasis) were conducted.. At 13.6 months of follow-up, the overall survival is 80% (CI 95%: 11.8-15.4). Clinical and radiological-free progression survival is 9.5 ± 1 months (CI 95%: 7.7-11.3) and biochemical response is 6.8 ± 1 months (CI 95%: 5-8.7). Only the treatment with chemotherapy impaired significantly the response time to AA [6.4 months for radiological-free progression survival (CI 95%: 4.2-8,6) and 4.3 months for biochemical-free progression survival (CI 95%: 2.6-6)]. The incidence of adverse drug events was 36%, all of them grade 1-2/4 and, in no case, suspension or reduction of the dose of AA was needed.. The treatment with AA has been effective in our series, with a tolerability considerably higher than what other studies published.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Humans; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms, Castration-Resistant

Abiraterone acetate is an oral medication that has recently been granted approval for the treatment of metastatic castration resistant prostate cancer (mCRPC) prior and/or after chemotherapy with docetaxel. In this article we assess the economics of abiraterone acetate in mCRPC. Relevant studies demonstrated that abiraterone acetate had a minimal budget impact on health plans. A relevant advantage was the cost savings due to the lack of chemotherapy-related side effects as well as the ease of administration. The results of cost/benefit comparative studies with other novel agents (i.e. cabazitaxel, enzalutamide, sipuleucel-T) are warranted as well as the close collaboration between urologists and medical oncologists.

Topics: Abiraterone Acetate; Androstadienes; Cost-Benefit Analysis; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Quality-Adjusted Life Years

Topics: Abiraterone Acetate; Aged; Androstadienes; Antineoplastic Agents; Bone Neoplasms; Humans; Lymphatic Metastasis; Male; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retreatment

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cytochrome P-450 Enzyme Inhibitors; Humans; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase

With the growing use of oral anticancer medications, understanding adherence patterns has become increasingly important. Abiraterone acetate (AA) is a prodrug of abiraterone, a novel androgen biosynthesis inhibitor. AA is approved for use in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer.. To evaluate AA and concomitant prednisone utilization and adherence patterns for patients with prostate cancer in the United States.. This study used data from 2 administrative health care claims databases--Dataset 1: Truven Health Analytics MarketScan (December 2010 to August 2012) and Dataset 2: Symphony Health Solutions' ProMetis Lx (June 2009 to March 2013). To evaluate the consistency of medication-taking behavior, adherence was measured using medication possession ratio (MPR), which was calculated as the sum of days of supply divided by the days on therapy in patients with at least 2 AA prescriptions. Additional outcomes included the proportion of patients taking prednisone, mean and median daily dose of AA, and concomitant prednisone use. Adherence was also studied by age, health care plan type, or previous recent chemotherapy subgroups.. 515 patients (mean age: 72.2) and 3,228 patients (mean age: 72.2) with at least 1 AA claim were selected from Dataset 1 and Dataset 2, respectively. The mean (median) daily AA dose per person per prescription was 998.8 (1,000) mg for Dataset 1 and 994.2 (1,000) mg for Dataset 2, which is within 1% of the recommended daily dose (1,000 mg). Mean (median) MPR was 93% (98%; n = 492) in Study Population 1 and 93% (100%; n = 2,449) in Study Population 2. The mean (median) daily prednisone dose per person per prescription was similar in both datasets with 10.1 (10.0; n = 488) mg and 10.6 (10.0; n = 2,425) mg in Dataset 1 and 2, respectively. Similar adherence patterns were observed for patients in different age groups, for patients with commercial health care plans versus patients with Medicare coverage, and for patients with recent chemotherapy compared with patients without.. Results from 2 observational studies reported high levels of adherence to AA dosing and administration patterns consistent with prescribing information. These findings provide useful insights into the treatment patterns in patients with prostate cancer treated with AA and can contribute to the current discussion in oncologic research and practice.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Drug Prescriptions; Drug Utilization Review; Health Knowledge, Attitudes, Practice; Humans; Insurance, Pharmaceutical Services; Male; Managed Care Programs; Medicare; Medication Adherence; Middle Aged; Practice Patterns, Physicians'; Prednisone; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Time Factors; Treatment Outcome; United States

Cabazitaxel and AA have been approved by the US Food and Drug Administration for use after docetaxel in mCRPC. Recently, CAB appeared to be active when given after AA. AA is capable of inducing AR splice variants that confer ligand-independent AR transactivation. Because microtubule-targeting agents impair AR nuclear transport and activity, we raised concerns about CAB efficacy after AA failure in mCRPC.. One hundred thirty mCRPC patients received AA after docetaxel treatment in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data using conventional methods.. Twenty-four patients received a median of 4 (range, 1-13) CAB cycles. Nineteen (79.1%) of them received primary prophylaxis with growth factors. Median patient characteristics were: age 65 (range, 57-85) years; Gleason score: 8 (range, 6-10); and PSA: 128.1 (range, 0.01-1700) ng/mL. A PSA response (≥ 50% decrease from baseline) occurred in 6 (31.5%) of 19 evaluable patients (95% confidence interval [CI], 11.8-54.2%). CAB therapy obtained a partial response in 2 of the 13 (15.3%) evaluable patients (95% CI, 2.9-45.4%). Median survival from initiation of CAB was 8.2 (95% CI, 3.34-13.05) months, from AA 16.1 (95% CI, 11.56-20.64) and from docetaxel 32.0 (95% CI, 11.56-39.69).. A limited number of patients with mCRPC received CAB after docetaxel and AA treatment. In this selected population, CAB was active.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Resistance, Neoplasm; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

Abiraterone acetate (AA), oral CYP17 inhibitor, is an active agent in the treatment of metastatic castrate-resistant prostate cancer (mCRPC).. We (R.L.A and N.A) retrospectively evaluated outcome in 12 men who were re-treated with AA following prior treatment with AA at the Princess Margaret Cancer Centre.. All men were heavily pre-treated for mCRPC with a median of four prior lines of therapy, one of which was AA (given either pre- or post-chemotherapy). Eleven out of 12 (92%) men stopped their first treatment course of AA due to progression and one stopped for financial reasons. Seven men had a PSA decrease ≥50% following their first AA treatment, of which three (46%) had a PSA decrease ≥50% to AA re-treatment. The responses to AA re-treatment were generally short-lived with a median biochemical progression-free survival of 2.3 months and median treatment duration of 3.2 months. No PSA responses to AA re-treatment were seen in five men who did not have an initial PSA response to AA.. Our data suggest that AA re-challenge may have limited benefit in select men with mCRPC, and warrants further formal research.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstadienes; Enzyme Inhibitors; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Steroid 17-alpha-Hydroxylase

Abiraterone acetate(AA)has been approved in more than 80 countries for the treatment of patients with metastatic castration-resistant prostate cancer(mCRPC). In July 2013, a marketing approval application for AA was submitted to the Japanese Ministry of Health, Labour, and Welfare. AA is a selective inhibitor of CYP17A1, a crucial enzyme for androgen biosynthesis. AA exerts its anti-tumor activity by directly inhibiting androgen production at all three sources, i. e., the testes, adrenal glands, and tumor itself. Data from international phase III studies and phase I and II studies in Japan have indicated that AA improves the overall survival and quality of life(QoL)of patients with mCRPC. Herein, we have summarized the development of AA and the results of important international and local clinical trials in Japan. In addition, the effect of food on AA bioavailability, concomitant steroid use, and liver function test abnormalities have been discussed regarding the appropriate use of AA.

Topics: Abiraterone Acetate; Androstadienes; Androstenes; Androstenols; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase

Topics: Abiraterone Acetate; Aged; Androstadienes; Drug Resistance, Neoplasm; Humans; Male; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Substance Withdrawal Syndrome; Tomography, X-Ray Computed; Treatment Failure

Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation.

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Androstadienes; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Disease Models, Animal; Down-Regulation; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Male; Mice; Mice, Nude; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyridazines; Rats; Rats, Wistar; Receptors, Androgen; Seminal Vesicles; Signal Transduction; Xenograft Model Antitumor Assays

To describe the incidence and clinical relevance of biochemical and objective responses to abiraterone acetate (AA) withdrawal (AAWD) in patients with castration-resistant prostate cancer (CRPC).. Twenty-six patients with progressive CRPC treated with first-line docetaxel-based chemotherapy were administered with AA at the standard dose of 1000 mg/day in combination with prednisone until progression. The patients were regularly followed up during treatment and after AAWD.. Nineteen of the 26 patients discontinued AA because of progression. Three of the patients undergoing AAWD experienced a biochemical response, which was accompanied by a metabolic and radiological response as revealed by choline positron emission tomography in 2 cases.. Regardless of the underlying molecular bases, AAWD response does not occur rarely. It is sometimes long-lasting and accompanied by a metabolic and radiographic improvement. AAWD response should be taken into account when further therapeutic strategies are planned in patients with CRPC with progressive disease during abiraterone therapy.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Androstadienes; Disease Progression; Docetaxel; Follow-Up Studies; Humans; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome