abiraterone-acetate and Prostatic-Neoplasms

Evolving data suggest that men with high-risk localized prostate cancer may benefit from more potent androgen receptor inhibition in the context of curative intent radiotherapy. Recently updated American Society for Clinical Oncology (ASCO) evidence-based guidelines and the National Comprehensive Cancer Network (NCCN) Guidelines have updated recommendations for the consideration of adding second generation anti-androgens to androgen deprivation therapy (ADT) in men receiving radiation therapy (RT) for noncastrate locally advanced high and very high risk nonmetastatic or node positive prostate cancer.. We conducted a comprehensive review of existing published and abstract presented evidence behind RT with ADT for the definitive management of high-risk prostate cancer, particularly focused on the current phase II and III trial evidence for the addition of second generation anti-androgens to ADT in definitive RT treatment of high-risk prostate cancer and specifically focused on the recent STAMPEDE trial results with abiraterone acetate. We review the biological mechanisms in which second generation anti-androgens may help mitigate ADT resistance and provide radiosensitization through inhibition of DNA repair. Finally, we discuss ongoing clinical trials of potent androgen receptor (AR) inhibitors with ADT in this non-metastatic high-risk radiotherapy setting that may inform on future treatment guidelines.. Recent data suggest an overall survival benefit as well as increased probabilities of disease free and metastasis free survival in men with high and very high-risk localized, node positive, and oligometastatic hormone sensitive prostate cancer with abiraterone acetate and prednisone and support the use of potent AR inhibitors in this setting after informed decision making.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgen Receptor Antagonists; Humans; Male; Prednisone; Prostatic Neoplasms; Receptors, Androgen

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

The treatment paradigm for metastatic castrate-sensitive prostate cancer (mCSPC) has evolved rapidly in the past decade with the approval of several life-prolonging therapies including docetaxel chemotherapy and multiple androgen receptor pathway inhibitors (ARPI) in combination with androgen deprivation therapy (ADT). Recently reported phase-three trials have demonstrated a survival benefit of upfront triplet therapy with ADT, docetaxel plus either abiraterone acetate or darolutamide when compared to ADT plus docetaxel alone. However, multiple questions including the incremental benefit of docetaxel to a combination of ADT and ARPI, the timing of ARPI, optimal patient selection for triplet therapy and clinical and genomic biomarkers still remain to be answered. Moreover, real-world data suggest suboptimal treatment intensification with many patients treated with ADT alone highlighting challenges in implementation. In this article, we review the phase-three data associated with triplet therapy in mCSPC. We also discuss the knowledge gaps that exist despite the completion of these studies and how ongoing studies are likely to change the paradigm in the near future. Finally, we provide a simple algorithm based on current data that clinicians can use in daily practice to select patients for appropriate treatment strategies.

Topics: Abiraterone Acetate; Androgen Antagonists; Docetaxel; Humans; Male; Prostatic Neoplasms; Standard of Care

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

Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population.. These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0-2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544.. Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63-73) and median PSA 34 ng/ml (14·7-47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60-84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]-NE) than in the control groups (not reached, 97-NE; hazard ratio [HR] 0·53, 95% CI 0·44-0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79-85) in the combination-therapy group and 69% (66-72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70-1·50, p=0·91) and no evidence of between-trial heterogeneity (I. Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population.. Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Male; Multicenter Studies as Topic; Neoplasm Grading; Neoplasm Recurrence, Local; Nitriles; Phenylthiohydantoin; Prednisolone; Progression-Free Survival; Prostatectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic

To assess the cost-effectiveness of systemic treatments for metastatic castration-sensitive prostate cancer from the US healthcare sector perspective with a lifetime horizon.. We built a partitioned survival model based on a network meta-analysis of 7 clinical trials with 7287 patients aged 36 to 94 years between 2004 and 2018 to predict patient health trajectories by treatment. We tested parameter uncertainties with probabilistic sensitivity analyses. We estimated drug acquisition costs using the Federal Supply Schedule and adopted generic drug prices when available. We measured cost-effectiveness by an incremental cost-effectiveness ratio (ICER).. The mean costs were approximately $392 000 with androgen deprivation therapy (ADT) alone and approximately $415 000, $464 000, $597 000, and $959 000 with docetaxel, abiraterone acetate, enzalutamide, and apalutamide, added to ADT, respectively. The mean quality-adjusted life-years (QALYs) were 3.38 with ADT alone and 3.92, 4.76, 3.92, and 5.01 with docetaxel, abiraterone acetate, enzalutamide, and apalutamide, added to ADT, respectively. As add-on therapy to ADT, docetaxel had an ICER of $42 069 per QALY over ADT alone; abiraterone acetate had an ICER of $58 814 per QALY over docetaxel; apalutamide had an ICER of $1 979 676 per QALY over abiraterone acetate; enzalutamide was dominated. At a willingness to pay below $50 000 per QALY, docetaxel plus ADT is likely the most cost-effective treatment; at any willingness to pay between $50 000 and $200 000 per QALY, abiraterone acetate plus ADT is likely the most cost-effective treatment.. These findings underscore the value of abiraterone acetate plus ADT given its relative cost-effectiveness to other systemic treatments for metastatic castration-sensitive prostate cancer.

Topics: Abiraterone Acetate; Androgen Antagonists; Castration; Cost-Benefit Analysis; Docetaxel; Humans; Male; Network Meta-Analysis; Prostatic Neoplasms

The management of patients with metastatic hormone-sensitive prostate cancer (mHSPC) has been significantly modified by the availability of innovative but expensive treatments, increasing the economic burden of prostate cancer. Here, we aimed to systematically identify and review published economic evaluations (EEs) related to the treatment of mHSPC and assess their quality. A systematic search was performed of the PubMed and Cochrane databases. Three reviewers independently selected EEs by defined inclusion and exclusion criteria. They extracted all data from each EE (general information, study population, data about the EE, interventions and comparators, and outcomes). They also assessed the quality of the selected EEs according to Drummond's checklist. Fourteen EEs published between 2016 and 2021 were eligible for the systematic review. The EEs found ADT + docetaxel to be the most cost-effective of all available treatments as a first-line strategy for mHSPC (abiraterone acetate plus prednisone, enzalutamide, and apalutamide). Five EEs showed that a simple price reduction of abiraterone acetate of 50% to 75% could change the results to render this treatment also cost-effective relative to that with docetaxel. Twelve EEs were of high quality, with a Drummond score ≥ 7. Analysis of the 14 EEs identified by our systematic review, amongst which 78.6% met high quality standards, showed that ADT + docetaxel tends to be the most cost-effective alternative for mHSPC. These results were assessed by sensitivity analysis. The data provided by this systematic review help to provide a better understanding of these treatments and the better use of healthcare resources.

Topics: Abiraterone Acetate; Cost-Benefit Analysis; Docetaxel; Hormones; Humans; Male; Prostatic Neoplasms; Treatment Outcome

Research overlap and duplication is a recognised problem in the context of both pairwise and network systematic reviews and meta-analyses. As a case study, we carried out a scoping review to identify and examine duplicated network meta-analyses (NMAs) in a specific disease setting where several novel therapies have recently emerged: hormone-sensitive metastatic prostate cancer (mHSPC).. MEDLINE and EMBASE were systematically searched, in January 2020, for indirect or mixed treatment comparisons or network meta-analyses of the systemic treatments docetaxel and abiraterone acetate in the mHSPC setting, with a time-to-event outcome reported on the hazard-ratio scale. Eligibility decisions were made, and data extraction performed, by two independent reviewers.. A total of 13 eligible reviews were identified, analysing between 3 and 8 randomised comparisons, and comprising between 1773 and 7844 individual patients. Although the included trials and treatments showed a high degree of overlap, we observed considerable variation between identified reviews in terms of review aims, eligibility criteria and included data, statistical methodology, reporting and inference. Furthermore, crucial methodological details and specific source data were often unclear.. Variation across duplicated NMAs, together with reporting inadequacies, may compromise identification of best-performing treatments. Particularly in fast-moving fields, review authors should be aware of all relevant studies, and of other reviews with potential for overlap or duplication. We recommend that review protocols be published in advance, with greater clarity regarding the specific aims or scope of the project, and that reports include information on how the work builds upon existing knowledge. Source data and results should be clearly and completely presented to allow unbiased interpretation.

Topics: Abiraterone Acetate; Docetaxel; Humans; Male; Network Meta-Analysis; Prostatic Neoplasms

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

Abiraterone acetate, marketed as Zytiga®, is an antiandrogen medication used in the treatment of prostate cancer. Abiraterone acetate is a BCS Class IV compound associated with several oral delivery challenges. Its low solubility and high lipophilicity lead to poor oral bioavailability (<10%) and a dramatic positive food effect (5-10-fold). Hence, a large dose of abiraterone acetate (1000 mg per day) is prescribed to patients who must fast for at least 1 h before and 2 h after administration. The recent expiry of Zytiga®s' patent has led to the emergence of publications describing improved oral formulation strategies for abiraterone acetate. This review aims to discuss the characteristics of abiraterone acetate that lead to its unfavorable oral delivery, examine the oral formulation strategies that have been applied, and to describe potential alternative oral formulation strategies that have been used for other BCS Class IV drugs, to determine the most valuable strategies to develop novel and improved alternatives to the current commercial product. Specific emphasis of this review is placed on enabling oral formulation strategies that can improve solubilization and bioavailability, reduce the clinical dose and remove the pharmaceutical food effect to ultimately provide prostate cancer patients with a more efficient formulation with greater patient compliance.

Topics: Abiraterone Acetate; Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Dose-Response Relationship, Drug; Drug Delivery Systems; Food-Drug Interactions; Humans; Male; Prostatic Neoplasms; Solubility

A high incidence of fall and fracture in a subset of patients treated with androgen receptor inhibitors (ARIs) has been reported, although the relative risk (RR) of fall and fracture for patients who receive ARI treatment is unknown.. To evaluate whether treatment with ARIs is associated with an elevated relative risk for fall and fracture in patients with prostate cancer.. Cochrane, Scopus, and MedlinePlus databases were searched from inception through August 2019.. Randomized clinical trials comparing patients with prostate cancer treated with any ARI or placebo were included.. Two independent reviewers used a standardized data extraction and quality assessment form. A mixed effects model was used to estimate the effects of ARI on relative risk, with included studies treated as random effects and study groups treated as fixed effects in the pooled analysis. Sample size for each study was used to weight the mixed model. Statistical analysis was performed from August to October 2019.. The primary outcome was RR of fall and fractures for patients receiving ARI treatment.. Eleven studies met this study's inclusion criteria. The total population was 11 382 men (median [range] age: 72 [43-97] years), with 6536 in the ARI group and 4846 in the control group. Participants in the ARI group could have received enzalutamide, apalutamide, or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations; patients in the control group could have received placebo, bicalutamide, or abiraterone. The reported incidence of fall was 525 falls (8%) in the ARI group and 221 falls (5%) in the control group. The incidence of fracture was 242 fractures (4%) in the ARI group and 107 fractures (2%) in the control group. Use of an ARI was associated with an increased risk of falls and fractures: all-grade falls (RR, 1.8; 95% CI, 1.42-2.24; P < .001); grade 3 or greater fall (RR, 1.6; 95% CI, 1.27-2.08; P < .001); all-grade fracture (RR, 1.59; 95% CI, 1.35-1.89; P < .001), and likely grade 3 or greater fracture (RR, 1.71; 95% CI, 1.12-2.63; P = .01).. Use of ARI was associated with an increase in falls and fractures in patients with prostate cancer as assessed by a retrospective systematic review and meta-analysis. Further studies are warranted to identify and understand potential mechanisms and develop strategies to decrease falls and fractures associated with ARI use.

Topics: Abiraterone Acetate; Accidental Falls; Androgen Receptor Antagonists; Anilides; Antineoplastic Agents, Hormonal; Benzamides; Case-Control Studies; Fractures, Bone; Humans; Incidence; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Pyrazoles; Risk Factors; Thiohydantoins; Tosyl Compounds; Trauma Severity Indices

Systemic androgen deprivation therapy (ADT), also referred to as hormone therapy,àhas long been the primary treatment for metastatic prostate cancer. Additional agents have been reserved for the castrate-resistant disease stage when ADT start becoming less effective. Abiraterone is an agent with an established role in that disease stage, which has only recently been evaluated in the hormone-sensitive setting.. To assess the effects of early abiraterone acetate, in combination with systemic ADT, for newly diagnosed metastatic hormone-sensitive prostate cancer.. We searched CENTRAL, MEDLINE, Embase, six other databases, two trials registries, grey literature, and conference proceedings, up to 15 May 2020. We applied no restrictions on publication language or status.. We included randomized trials, in which men diagnosed with hormone-sensitive prostate cancer were administered abiraterone acetate and prednisolone with ADT or ADTàalone.. Two review authors independently classified studies and abstracted data from the included studies. We performed statistical analyses using a random-effects model. We rated the quality of evidence according to the GRADE approach.. The search identified two randomized controlled trials (RCT), with 2201 men, who were assigned to receive either abiraterone acetate 1000 mg once daily and low dose prednisone (5mg) in addition to ADT, or ADT alone. In the LATITUDE trial, the median age and range of men in the intervention group was 68 (38 to 89) years, and 67 (33 to 92) years in the control group. Nearly all of the men in thisàstudy (97.6%) had prostate cancer with a Gleason score of at least 8 (ISUP grade group 4). Primary outcomes The addition of abiraterone acetate to ADT reduces the probability of death from any cause compared to ADT alone (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.56 to 0.73; 2 RCTs, 2201 men; high certainty of evidence); this corresponds to 163 fewer deaths per 1000 men with hormone-sensitive metastaticàprostate cancerà(210 fewer to 115 fewer) at five years. Abiraterone acetate in addition to ADT probably results in little to no differenceàin quality of life compared to ADT alone, measured with the Functional Assessment of Cancer Therapy-prostate total score (FACT-P; range 0 to 156; higher values indicates better quality of life),àat 12 months (mean difference [MD] 2.90 points, 95% CI 0.11 to 5.60; 1 RCT, 838 men; moderate certainty of evidence). Secondary outcomes Abiraterone plus ADT increases the risk of grades III to V adverse events compared to ADT alone (risk ratio [RR] 1.34, 95% CI 1.22 to 1.47; 1 RCT, 1199 men; high certainty of evidence); this corresponds to 162 more grade III to Vàevents per 1000 men with hormone-sensitive metastaticàprostate cancerà(105 more to 224 more) at a median follow-up of 30àmonths. Abiraterone acetate in addition to ADT probably reduces the probability of death due to prostate cancer compared to ADT alone (HR 0.58, 95% CI 0.50 to 0.68; 2 RCTs, 2201 men; moderate certainty of evidence). This corresponds to 120 fewer death from prostate cancer per 1000 men with hormone-sensitive metastaticàprostate cancerà(95% CI 145 fewer to 90 fewer) afteràa median follow-up of 30 months. The addition of abiraterone acetate to ADT probably decreases the probability of disease progression compared to ADT alone (HR 0.35, 95%CI 0.26 to 0.49; 2 RCTs, 2097 men; moderate certainty of evidence). This corresponds to 369 fewer incidences of disease progression per 1000 men with hormone-sensitive metastaticàprostate cancerà(456 fewer to 256 fewer)àafter a median follow-up of 30 months. The addition of abiraterone. The addition of abiraterone acetate to androgen deprivation therapy improves overall survival but probably not quality of life. Itàprobably also extends disease-specific survival, and delays disease progression compared to androgen deprivation therapy alone. However, the risk of grades III to V adverse events is increased, and probably, so is the risk of discontinuing treatment due to adverse events.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Disease Progression; Humans; Male; Middle Aged; Neoplasm Grading; Prostatic Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Withholding Treatment

Prostate cancer (pca) is the most common non-dermatologic cancer and the 3rd leading cause of male cancer mortality in Canada. In patients with high-risk localized or recurrent pca, management typically includes the combination of long-term androgen deprivation therapy (adt) and radiotherapy (rt). New androgen-receptor-axis targeted therapies (arats), which await validation, offer an option to intensify therapy.. In this narrative review, we report the relevant history that has supported combining adt with rt. The literature in PubMed was searched for studies involving pca and novel arats (abiraterone acetate, enzalutamide, apalutamide, darolutamide) published between 1995 and 2019. Literature discussing clinical trials in which those modalities were combined was extracted and synthesized into a combined molecular and clinical discussion. Potential treatment intensification mechanisms and rationales are explored.. Early results from three phase i/ii trials demonstrated that concurrent abiraterone acetate, adt, and rt is safe, improves the extent of chemical castration, and is associated with limited treatment failures. A single

Topics: Abiraterone Acetate; Androgen Antagonists; Benzamides; Combined Modality Therapy; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Pyrazoles; Randomized Controlled Trials as Topic; Thiohydantoins

Clinical trial data forms the foundation of how we treat men with metastatic prostate cancer who are initiating therapy. However, clinical trial data does not answer everything; hence, good clinical practice, pragmatism, and occasionally extrapolation drives how we manage these patients. Fortunately, multiple international guideline committees meet regularly and offer clinical guidance. In this mini-review, we focus on the United States National Comprehensive Cancer Network, European Society for Medical Oncology, and European Association of Urology (EAU) recommendations for the initial treatment of metastatic prostate cancer.

Topics: Abiraterone Acetate; Androgen Antagonists; Clinical Trials as Topic; Docetaxel; Humans; Infusions, Intravenous; Male; Medical Oncology; Neoplasm Metastasis; Practice Guidelines as Topic; Prostatic Neoplasms; Steroid Synthesis Inhibitors; Tubulin Modulators; Urology

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

Recent landmark studies (GETUG-AFU 15, CHAARTED, STAMPEDE (docetaxel), LATITUDE and STAMPEDE (abiraterone)) have changed the treatment of hormone sensitive metastatic prostate cancer (mHSPC) from androgen deprivation therapy (ADT) only to combined therapy with either docetaxelor abiraterone acetate plus prednisone (AAP) together with ADT. In this Review we highlight current evidence and recommendations on how to treat men with newly diagnosed mHSPC beyond ADT.\ \ METHODS: Narrative overview of available evidence retrieved from pubmed searches, hand searches and authoritative texts.. Docetaxel or AAP in combination with ADT improves overall survival (OS) in men fit for combined treatment presenting with newly diagnosed mHSPC. The strongest evidence is for men with high volume mHSPC (four or more bone metastases with at least one outside the axial skeleton and/or visceral metastases) or mHSPC with high risk features (A minimum of two out of three following high-risk features: Gleason score ≥ 8, ≥ 3 bone lesions or visceral metastasis) as per CHAARTED and LATITUDE criteria, respectively. While upfront docetaxel and AAP yield comparable OS improvement, docetaxel has not been shown to increase OS specifically for men with low volume/low risk mHSPC, whereas, a recent post-hoc analysis from the STAMPEDE (abiraterone) trial showed consistent overall survival benefit of AAP plus ADT independent of risk stratification. While these data are limited by their retrospective nature, they do suggest that patients with low-risk mHSPC should be offered AAP. In men with high volume/high risk mHSPC, choosing between six-cycles of docetaxel or AAP until disease progression relies on patient preference, cost and individual assessment of which drug side-effect profile is most suitable.. Offer men presenting with newly diagnosed mHSPC fit enough for combined therapy either ADT plus docetaxel or AAP.. Estudios de referencia recientes (GETUG-AFU 15, CHAARTED, STAMPEDE (docetaxel), LATITUDE y STAMPEDE (abiraterone)) han cambiado el tratamiento del cáncer de próstata hormonosensible metastásico (CPHSm) de la terapia de deprivación androgénica sola a la terapia combinada bien con docetaxel o abiraterona acetato y prednisona junto con deprivación androgénica. En esta revisión, destacamos la evidencia actual y recomendaciones sobrecómo tratar a los hombres con CPHSm de reciente diagnóstico más allá de la deprivación androgénica.MÉTODOS: Repaso narrativo de la evidencia disponible obtenida por busquedas en PubMed, búsquedas manuales y textos fidedignos.. Docetaxel o abiraterona más prednisona en combinación con deprivación androgénica mejoran  la supervivencia global (SG) en pacientes adecuados para tratamiento combinado que presentan un CPHSm de reciente diagnóstico. La mejor evidencia es en varones con CPHSm de alto volumen (cuatro o más metástasis óseas con al menos una fuera del esqueleto axialy/o metástasis viscerales) o CPHSm con características de alto riesgo (un mínimo de dos de las tres siguientes características de alto riesgo: Puntuación de Gleason≥ 8, ≥ 3 lesiones óseas o metástasis viscerales) según los criterios de CHAARTED y LATITUDE respectivamente. Aunque docetaxel inicial y abiraterona más prednisona ofrecen una mejora comparable de la supervivenciaglobal, docetaxel no ha demostrado que mejore la supervivencia global específicamente en hombres con CPHSm de bajo volumen/bajo riesgo; mientras que un reciente análisis post-Hoc del estudio STAMPEDE (Abiraterona) mostró un beneficio consistente en supervivencia global de abiraterona más prednisona junto con deprivación androgénica independientemente de la estratificación por riesgo. Aunque estos datos están limitados por su naturaleza retrospectiva, sugieren que a los pacientes con CPHSm de bajo riesgo debería ofrecérseles abiraterona más prednisona. En varones con CPHSm de alto volumen/alto riesgo, elegir entre seis ciclos de docetaxel o abiraterona-prednisona hastaque la enfermedad progrese se basa en la preferencia del paciente, el coste y la evaluación individual sobre qué perfil de efectos colaterales farmacológicos es más adecuado.. Ofrecer terapia de deprivación andrógénica con docetaxel o abiraterona + prednisona a los pacientes que presentan un CPHSm de recientediagnóstico.

Topics: Abiraterone Acetate; Androgen Antagonists; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Retrospective Studies; Taxoids

Topics: Abiraterone Acetate; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms; Quality of Life

Randomized clinical trials have recently examined the benefit of adding docetaxel or abiraterone to androgen deprivation therapy (ADT) in hormone-naïve advanced prostate cancer (PCa).. To perform a systematic review and network meta-analysis of randomized clinical trials, indirectly evaluating overall survival (OS) for men treated with abiraterone acetate plus prednisone/prednisolone with ADT (Abi-ADT) versus docetaxel with ADT (Doce-ADT) in hormone-naïve high-risk and metastatic PCa.. Medline, Embase, Web of Science, Scopus, and Clinicaltrials.gov databases were searched in August 2017. We pooled results using the inverse variance technique and random-effects models. The Bucher technique for indirect treatment comparison was used to compare Abi-ADT with Doce-ADT. A priori subgroup and sensitivity analyses were performed.. Overall, 6067 patients from five trials were included: 1181 (19.5%) patients who received Doce-ADT, 1557 (25.7%) patients who received Abi-ADT, and 3329 (54.9%) patients who received ADT-alone. There was a total of 1921 deaths: 391 in the Doce-ADT group, 353 in the Abi-ADT group, and 1177 in the ADT-only group. The pooled hazard ratio (HR) for OS was 0.75 (95% confidence interval [CI]: 0.63-0.91, I. We did not identify a significant difference in OS between Abi-ADT and Doce-ADT for men with hormone-naïve high-risk or metastatic PCa, although Bayesian analysis demonstrates a high likelihood that Abi-ADT was preferred.. We synthesized the evidence available from studies examining the administration of docetaxel or abiraterone in combination with hormonal therapy for patients with newly diagnosed, advanced prostate cancer. While these studies did not directly compare these agents, we used methodological techniques to indirectly compare them and found no significant difference in overall survival.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Neoplasm Metastasis; Network Meta-Analysis; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Survival Rate

To investigate the toxicity profile characteristics of abiraterone acetate and enzalutamide to see if they are of critical clinical value.. Prospective studies were identified by searching the PubMed, EMBASE, Cochrane Library, and American Society of Clinical Oncology Meeting abstracts. Randomized clinical trials that evaluate abiraterone acetate or enzalutamide in patients with prostate cancer were included. The risk ratio (RR) of adverse events (AEs) was calculated for each trial along with appropriate 95% CI using fixed- or random-effects methods.. Ten studies (5 abiraterone acetate, and 5 enzalutamide studies) were included in the meta-analysis. Use of abiraterone acetate was associated with an increased risk of all-grade adverse effects (RR = 1.01, 95% CI: 1.01-1.02) and high-grade adverse effects (RR = 1.29, 95% CI: 1.15-1.45). Also, there was a significantly higher incidence of some individual adverse effects (e.g. liver-function test abnormalities, arthralgia, cardiac adverse effects, diarrhea, oedema, hypertension and hypokalemia). Treatment with enzalutamide did not increase the risk of all-grade adverse effects and high-grade adverse effects, but there was a significantly higher incidence of some individual adverse effects (e.g. back pain, fatigue, hot flush and hypertension).. Both abiraterone acetate and enzalutamide have toxicity profile characteristics that need to be recognized. Understanding the toxicity profile characteristics of both drugs could promote decision making in clinical use.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents, Hormonal; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Randomized Controlled Trials as Topic

Abiraterone acetate, which targets enzymatic complexes playing a central role in steroidogenesis, demonstrated to increase survival significantly in both chemo-naive and docetaxel pretreated, becoming one of the drugs of choice for metastatic castration-resistant prostate cancer. More recently, this agent in combination to androgen deprivation therapy demonstrated to be efficacious also in metastatic castration-sensitive prostate cancer. The present review is aimed to outline the clinical development of abiraterone acetate, the pivotal trials which led to its approval for the clinical practice, new evidence about its efficacy in metastatic castration-sensitive prostate cancer, its place in the therapeutic landscape of prostate cancer and future directions of development.

Topics: Abiraterone Acetate; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Male; Neoplasm Metastasis; Neoplasm Staging; Prostatic Neoplasms; Treatment Outcome

A major, yet precisely studied, shift has occurred in the treatment of advanced hormone-sensitive prostate cancer (HSPC) by the addition of docetaxel to androgen deprivation therapy (ADT) in the first line. Recently, two landmark trials showed that abiraterone acetate (AA) can be an effective alternative along with ADT in the same setting. We implemented a network meta-analysis to compare the safety and efficacy of the two combinations.. PubMed database, ASCO and ESMO meeting library databases of all results published until June 2017 were searched using the keywords: "prostate cancer" AND "docetaxel" OR "abiraterone acetate". Efficacy endpoints including progression-free survival (PFS) and overall survival (OS), and safety endpoints (including treatment related deaths and selected adverse events) were assessed.. Twenty relevant studies were retrieved and assessed for eligibility. Of those trials, eight were found potentially eligible. Inconsistent reporting of efficacy outcomes limited our analysis to M1 HSPC. The pooled hazard ratios (HRs) of OS and PFS of the direct comparison of abiraterone acetate plus ADT versus ADT were 0.63 (95% CI: 0.545-0.717) and 0.38 (95% CI: 0.34-0.43), respectively. Meanwhile, in the trials of docetaxel plus ADT the pooled HRs of OS and PFS were 0.75 (95% CI: 0.65-0.86) and 0.634 (95% CI: 0.57-0.70), respectively. The indirect comparison showed that the HRs of OS and PFS in DOC + ADT in comparison to AA + ADT were 1.2 (95% CI: 0.98-1.46) and 1.65 (1.40-1.94), respectively. The pooled RR of treatment-related mortality in docetaxel + ADT versus AA + ADT was 1.438 (95% CI: 0.508-4.075).. Patients with metastatic HSPC (mHSPC) who received abiraterone acetate with ADT had better PFS and less toxicity compared to those receiving docetaxel with ADT. A trend towards superior OS and fewer treatment-related deaths was also observed, but was statistically non-significant. In view of lacking clear OS advantage, the choice between docetaxel and AA should include a discussion with the patient about the potential toxicities and impact on quality of life of each regimen.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Network Meta-Analysis; Proportional Hazards Models; Prostatic Neoplasms; Quality of Life; 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

Apalutamide (Erleada

Topics: Abiraterone Acetate; Androgens; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Approval; Humans; Male; Prednisone; Prostatic Neoplasms; Receptors, Androgen; Thiohydantoins; United States; United States Food and Drug Administration

The treatment of metastatic prostate cancer has remained unchanged for more than 70 years, based on androgen deprivation therapy (ADT). In 2015, following the CHAARTED and STAMPEDE trials, it was established that the addition of 6 cycles of docetaxel to ADT was associated with significantly increased survival. In June 2017, the LATITUDE trial and the G arm of the STAMPEDE trial showed that the addition of Abiraterone with Prednisone (5 mg/day) to ADT was also associated with a significant increase in survival in metastatic patients. The present study analyzes these two trials.. LATITUDE demonstrated a 38% reduction in the risk of death (HR=0.62, 95% CI, 0.61-0.76) in almost all sub-groups. Risk reduction for radiological progression was 53% (HR=0.47, 95% CI 0.39-0.55). Secondary objectives such as prostate specific antigen progression, time to chemotherapy or a new skeletal event are also significantly delayed. STAMPEDE also showed that the combination of Abiraterone and Prednisone is associated with a 37% increase in survival (HR=0.63, 95% CI, 0.52- 0.76, p<0.001) in metastatic patients, but not in nonmetastatic patients. Progression-free survival was greatly improved in this arm (HR=0.29, 95% CI 0.25-0.34, p<0.001). The side effects reported show the known pattern of mineral corticosteroid excess with increased blood pressure, hypokalemia, and of liver enzymes elevation.. The indirect comparison of docetaxel and abiraterone studies confirms that both populations and results are comparable. Two comparative indirect metanalysis (>6000 patients) gave marginal superiority to abiraterone. In favor of abiraterone we have that it is an oral, comfortable medication with a good tolerance profile and side effects that are easy to manage, useful in patients who are old and fragile, in whom chemotherapy may not be indicated; the downsides are prolonged exposure to the drug and its current price. Future trials, currently in progress, will determine the ideal patient profile, or a potential association of both therapies.

Topics: Abiraterone Acetate; Antineoplastic Agents; Clinical Trials as Topic; Humans; Male; Prostatic Neoplasms

Novel drugs, drug sequences and combinations have improved the outcome of prostate cancer in recent years. The latest approvals include abiraterone acetate, enzalutamide and apalutamide which target androgen receptor (AR) signaling, radium-223 dichloride for reduction of bone metastases, sipuleucel-T immunotherapy and taxane-based chemotherapy. Adding abiraterone acetate to androgen deprivation therapy (ADT) in order to achieve complete androgen blockade has proven highly beneficial for treatment of locally advanced prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC). Also, ADT together with docetaxel treatment showed significant benefit in mHSPC. Ongoing clinical trials for different subgroups of prostate cancer patients include the evaluation of the second-generation AR antagonists enzalutamide, apalutamide and darolutamide, of inhibitors of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, of inhibitors of DNA damage response, of targeted alpha therapy and of prostate-specific membrane antigen (PSMA) targeting approaches. Advanced clinical studies with immune checkpoint inhibitors have shown limited benefits in prostate cancer and more trials are needed to demonstrate efficacy. The identification of improved, personalized treatments will be much supported by the major progress recently made in the molecular characterization of early- and late-stage prostate cancer using “omics” technologies. This has already led to novel classifications of prostate tumors based on gene expression profiles and mutation status, and should greatly help in the choice of novel targeted therapies best tailored to the needs of patients.

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Antigens, Surface; Benzamides; Drug Discovery; Glutamate Carboxypeptidase II; Humans; Immunotherapy; Male; Nitriles; Phenylthiohydantoin; Prostate; Prostatic Neoplasms; Radioisotopes; Radium; Receptors, Androgen; Thiohydantoins

Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies.. Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed.. We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability).. Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Docetaxel; Humans; Male; Network Meta-Analysis; Prednisolone; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Zoledronic Acid

Androgen deprivation therapy (ADT) has long been the gold standard for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Clinical trials have demonstrated significant survival benefits when docetaxel (DOC) or abiraterone acetate (AA) and prednisone (P) are added to ADT, necessitating comparison of these combination treatments.. A systematic review of randomised controlled trials (RCTs) of AA-/ADT-/DOC-containing treatment regimens in newly diagnosed patients with high-risk and/or high-volume mHSPC identified three RCTs (LATITUDE, CHAARTED and GETUG-AFU 15). Network meta-analyses (NMAs) using fixed effects Bayesian methods were performed to compare relative benefits of each treatment on overall survival (OS), radiographic progression-free survival (rPFS) and quality of life (QoL) measured by the Brief Pain Inventory, and the Functional Assessment of Cancer Therapy-Prostate questionnaire. One trial, STAMPEDE, was assessed in exploratory OS analyses.. The hazard ratio (HR) for OS ranged from 0.85 to 0.92, with the Bayesian probability of AA + P + ADT being better than DOC + ADT ranging between 72% and 87%. For rPFS, the HR ranged between 0.71 and 0.76 (Bayesian probability range: 93%-97%). Exploratory analyses including STAMPEDE found similar trends. AA + P + ADT also showed improved QoL compared with DOC + ADT for at least 1 year of therapy, with results being more pronounced at 3 months.. Our findings suggest that AA + P + ADT is at least as effective as DOC + ADT in reducing the risk of death in men with mHSPC and better at preventing disease progression and improving QoL. The NMA provides useful insights to clinicians and other decision-makers on the relative efficacy of treatment options for men with mHSPC.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Docetaxel; Humans; Male; Prednisone; Prostatic Neoplasms; Quality of Life; Randomized Controlled Trials as Topic

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

Elderly patients with cancer may have comorbidities, each requiring additional pharmacologic treatment. Therefore, the occurrence of pharmacokinetic (PK) and pharmacodynamic (PD) interactions is very likely, and the risk of adverse reactions (ADRs), due to the narrow therapeutic window of anticancer drugs, is increased. Drug-drug interactions (DDIs) may occur in prostate cancer patients due to inhibition by abiraterone of liver cytochrome P450 (CYP)-dependent enzymes CYP2C8 and 2D6, which are involved in the metabolism of approximately 25% of all drugs, and induction by enzalutamide of CYP3A4, 2C9 and 2C19, which metabolize up to 50% of medications. Therefore, abiraterone may increase plasma levels of CYP2D6 substrates, including amitriptyline, oxycodone and risperidone, as well as of CYP2C8 substrates including amiodarone and carbamazepine. Since enzalutamide is extensively metabolized by CYP2C8, its plasma levels are likely to be raised if coadministered with strong CYP2C8 inhibitors such as gemfibrozil or pioglitazone. Inducers of CYP2C8 (i.e., rifampin) may reduce the effectiveness of enzalutamide and hence should be avoided. Enzalutamide may decrease plasma levels of CYP3A4, 2C9 and 2C19 substrates including disopiramide, quetiapine, quinidine and warfarin. Growing awareness of the importance of DDIs in cancer patients is now reflected in the variety of web-based sources offering information and guidance. However, the evaluation of the clinical relevance of DDIs is the result of a comprehensive evaluation of many factors, including therapeutic index, amplitude of therapeutic range and presence of comorbidities, requiring a specific expertise in clinical pharmacology.

Topics: Abiraterone Acetate; Antineoplastic Agents; Benzamides; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Male; Nitriles; Phenylthiohydantoin; Polypharmacy; Prednisone; Prostatic Neoplasms

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

To determine whether abiraterone acetate or docetaxel should be regarded as the current standard of care for metastatic hormone-naive prostate cancer (mHNPC).. A network meta-analysis (NMA) using the frequentist approach and generalized pairwise modeling was computed.. The results of this NMA favored abiraterone acetate over docetaxel-based regimens (hazard ratio: 0.79; 95% CI: 0.64-0.99) in patients with mHNPC. The results also suggest a reconsideration of the role of prednisone in view of the absence of a survival benefit (hazard ratio: 0.98; 95% CI: 0.59-1.65) with its use.. Despite the paucity of direct comparative evidence, the results of this NMA favor the use of abiraterone acetate in the first-line treatment of mHNPC.

Topics: Abiraterone Acetate; Androgens; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Docetaxel; Humans; Male; Neoplasm Metastasis; Neoplasm Staging; Prostatic Neoplasms; Steroid Synthesis Inhibitors; Taxoids; Treatment Outcome

With the development of Abiraterone and Enzalutamide new treatment option have become available in addition to Docetaxel for first-line treatment of castration resistant prostate cancer. However, resistance and ultimately failure occurs inevitably with all available treatment options. Moreover, cross-resistance leads to considerably reduced efficacy in second-line treatment. Preclinical data suggest discriminative mechanisms of resistance development for Abiraterone and Enzalutamide. Clinical confirmation of these putative mechanisms for treatment failure might facilitate recommendations for future sequencing of these drugs.

Topics: Abiraterone Acetate; Antineoplastic Agents; Benzamides; Drug Resistance; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms

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

Abiraterone acetate (AA) is a selective inhibitor of cytochrom p450 (CYP)17 which is required for androgen biosynthesis, and can block the androgens synthesis by testicles, surrenals and intratumoral secretion. In phase I and II studies in patients with prostate cancer, therapy with AA 250-2000  mg once daily demonstrated reductions in prostate specific antigen (PSA), and/or circulating tumor cells (CTCs). In two large phase III trials in patients with metastatic castration resistant prostate cancer (CRPC) in post-docetaxel and pre-docetaxel setting, AA plus prednisone compared with placebo plus prednisone demonstrated a significant superior overall survival in post-docetaxel setting, and a superior radiological PFS in pre-docetaxel setting. Based of these results, AA is approved in metastatic CRPC patients in post-docetaxel setting or pre-docetaxel setting in 2013.

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents, Hormonal; Clinical Trials as Topic; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Neoplastic Cells, Circulating; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase; Taxoids

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Denosumab; Docetaxel; Humans; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Taxoids

New drugs have recently been developed, through a better understanding of the mechanisms involved in the progression of prostate cancer, including castration-resistant ones (CRPC). This article aims to describe the mechanisms of action of these new hormonal treatments and their major clinical outcomes and development programs.. A bibliographic research in French and English using Medline(®) and Embase(®) using the keywords "castration-resistant prostate cancer", "abiraterone acetate", "orteronel", "enzalutamide", and "clinical trials" was performed.. the androgen signaling pathway remains the cornerstone of advanced cancers management. Hence, some molecules target the androgen biosynthesis, as abiraterone acetate and orteronel, which are selective inhibitors of the enzyme CYP17. Others act as antagonists of the androgen receptor: the enzalutamide, RNA-509 and ODM201. Finally, galeterone combines the two effects.. Progress conferred by these molecules in terms of overall survival and quality of life in patients with metastatic CRPC, suggest that their use at earlier stages of the disease could reduce morbidity and mortality from prostate cancer. Determining the best strategy for sequence or combination therapy to optimize the use of these new molecules should be investigated.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgen Receptor Antagonists; Androstadienes; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Imidazoles; Male; Naphthalenes; Neoplasm Staging; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Quality of Life; Steroid 17-alpha-Hydroxylase; Treatment Outcome

The objective of this article is to review the mechanisms of action of abiraterone acetate, independently of the androgenic pathway.. A systematic review of the literature was carried out on Medline and Embase databases.. Inhibition of CYP17A1 with abiraterone acetate induces changes in steroid metabolism, whose main component is the reduction of DHEA and androstenedione synthesis. This results in inhibition of androgen pathway in prostatic cancerous epithelial cell. Regardless of androgen activation pathway, abiraterone acetate could also act via an alternative mechanism of action not fully elucidated. Stromal cells, like tumor cells, could undergo the effects of CYP17A1 inhibition, resulting in blocking the production of secondary mediators that contribute to tumor progression. Similarly, it has been suggested that abiraterone acetate efficacy may be related to its ability to alter intratumoral concentrations of estrogen and progesterone.. The validation of these mechanisms could contribute to improved therapeutic strategies based on the use of abiraterone acetate alone or in combination.

Topics: Abiraterone Acetate; Adjuvants, Immunologic; Androgens; Androstadienes; Androstenedione; Antineoplastic Agents; Dehydroepiandrosterone; Disease Progression; Humans; Male; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase; Treatment Outcome

Gynecomastia is a pathological enlargement of male breasts due to hormonal imbalance and elevation of estrogens at the expense of testosterone. It is very important to diagnose this disease precociously because it can be the expression of different underlying pathologies. Besides genetic, chromosomal or chronic diseases, drugs often represent the principal cause of this hormonal disequilibrium. In the elderly population, antiandrogen therapy for prostate cancer frequently induces gynecomastia, thus negatively affecting the patients' compliance to treatment because of physical and psychological discomfort deriving from this condition; gynecomastia can in fact be associated with severe breast pain, and it can modify how patients see their own body. During the past decades and even today, many different surgical, radiotherapeutic or clinical approaches have been proposed to prevent or treat this hypertrophy. This article focuses on gynecomastia associated with antiandrogen-based hormonal treatment and shortly reviews the currently most often used therapeutic options for preventing and treating this pathology.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Combined Modality Therapy; Gynecomastia; Humans; Male; Prostatic Neoplasms

Topics: Abiraterone Acetate; Adenocarcinoma; Androgen Antagonists; Androgens; Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Disease-Free Survival; Docetaxel; Enzyme Inhibitors; Humans; Male; Molecular Targeted Therapy; Multicenter Studies as Topic; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Prednisone; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Receptors, Androgen; Steroid 17-alpha-Hydroxylase; Survival Rate; Taxoids

The survival and progression of prostate cancer are generally dependent on expression of the androgen receptor (AR), as well as the availability of endogenous AR agonists. Originating from the gonads, testosterone is released into circulation and is converted by steroid-5α-reductase in prostate cancer to 5α-dihydrotestosterone (DHT), potently activating AR and driving tumor progression. Advanced prostate cancer is initially treated with gonadal testosterone depletion, which suppresses this cascade of events and typically leads to a treatment response. Eventually, resistance to testosterone deprivation occurs with "castration-resistant" prostate cancer (CRPC) and is driven by the intratumoral synthesis of DHT. The generation of DHT occurs in large part from adrenal 19-carbon precursor steroids, which are dependent on expression of CYP17A1. Although the path from adrenal precursor steroids to DHT was generally thought to require 5α-reduction of testosterone, recent data suggest that it instead involves conversion from Δ-androstenedione by steroid-5α-reductase isoenzyme-1 to 5α-androstanedione, followed by subsequent conversion to DHT. The 5α-androstanedione pathway to DHT therefore bypasses testosterone entirely. Abiraterone acetate effectively inhibits CYP17A1, blocks the synthesis of androgens, and extends the survival of men with CRPC. Further progress in the hormonal treatment of CRPC is dependent on an understanding of the mechanisms that underlie CRPC and resistance to abiraterone acetate.

Topics: Abiraterone Acetate; Androstadienes; Biosynthetic Pathways; Dihydrotestosterone; Etiocholanolone; Humans; Male; Orchiectomy; Prostatic Neoplasms

The palliative goal of the treatment of metastatic prostate cancer is to prolong survival and decrease cancer-related complications. Androgen ablation therapy is widely accepted as the initial treatment of choice; when the disease becomes resistant to castration-resistant prostate cancer (CRPC), docetaxel-based chemotherapy aids in prolonging overall survival and controlling disease-related symptoms. Until a few years ago, no drug had showed efficacy in docetaxel-resistant patients. Recently, cabazitaxel, a taxane family compound, has been shown to help prolong survival in patients previously treated with docetaxel, even if a high grade of myelotoxicity has been reported. Moreover, a better understanding of the biology of CRPC has demonstrated that prostate cancer proliferation is largely mediated through the androgen receptor, which could be reactivated by androgens produced by the adrenal glands. Abiraterone acetate is an orally active acetate salt of the steroidal compound abiraterone with antiandrogen activity. Abiraterone inhibits the enzymatic activity of steroid 17α-monooxygenase, a member of the cytochrome P450 family that catalyzes the 17α-hydroxylation of steroid intermediates involved in testosterone synthesis from the adrenal glands. This review focuses on abiraterone acetate, the first compound that, through the inhibition of adrenal gland production of testosterone, increases the overall survival in CRPC patients. The role of possible predictive biomarkers and future perspectives are also discussed.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Clinical Trials as Topic; Docetaxel; Humans; Male; Orchiectomy; Prednisolone; Prostatic Neoplasms; Taxoids

It is now almost 70 years since Charles Huggins described the relationship between testosterone and the prostate gland. Arguably defining one of the first targeted therapies, the reduction of testosterone to castrate levels remains unaltered as the standard of care for men with metastatic prostate cancer. The failure of castration to permanently control the growth of prostate cancer leads to a state called castration-resistant prostate cancer (CRPC). Whilst numerous mechanisms have been suggested for the emergence of castration resistance [Scher and Sawyers (J Clin Oncol 23(32):8253-8261, 2005); Chen et al. (Curr Opin Pharmacol 8(4):440-448, 2008), Pienta and Bradley (Clin Cancer Res 12(6):1665-1671, 2006); Feldman and Feldman (Nat Rev Cancer 1(1):34-45, 2001); Mostaghel and Nelson (Best Pract Res Clin Endocrinol Metab 22(2):243-258, 2008)], a greater understanding of prostate cancer biology suggests that many such cancers retain a dependency on androgens and endeavour to increase bioavailable androgens through mechanisms such as AR amplification and intracrine androgen synthesis [Mohler et al. (Clin Cancer Res 10(2):440-448, 2004); Attard et al. (Clin Cancer Res 17(7):1649-1657, 2011); Hu et al. (Expert Rev Endocrinol Metab 5(5):753-764, 2010)]. With the recent approval of abiraterone acetate (Zytiga) and the pending approval of MDV3100, this article previews the future directions in clinical development and issues that will arise with the next generation of androgen-targeted agents.

Topics: Abiraterone Acetate; Androstadienes; Benzamides; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Male; Neoplasms, Hormone-Dependent; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Steroid 17-alpha-Hydroxylase

In April 2011, abiraterone acetate (AA) was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic castration-resistant prostate cancer (CRPC) after chemotherapy. The development of AA is the direct result of our increased understanding of the intricacies of the androgen receptor (AR) pathway and its natural evolution in prostate cancer cells over the course of treatment. In this paper we review the biology of the AR and how it led to the rational design of AA. We also examine the clinical development of AA, its current use, and questions to be addressed for future development.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Androstadienes; Animals; Antineoplastic Agents, Hormonal; Clinical Trials as Topic; Humans; Male; Prostatic Neoplasms; Receptors, Androgen

Prostate cancer has long since been recognised as being hormonally driven via androgen receptor signalling. Abiraterone acetate (AA) is a rationally designed CYP17 inhibitor that blocks the conversion of androgens from non-gonadal precursors effectively, thus reducing testosterone to undetectable levels. AA has recently been proved to extend survival for men with metastatic castration-resistant prostate cancer who have progressive disease after first-line chemotherapy treatment. In addition, it is currently being tested in a Phase III trial in the pre-chemotherapy setting. This paper will review the preclinical discovery and clinical development of AA and will outline the strategy of parallel translational research.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Hormone Replacement Therapy; Humans; Male; Prostatic Neoplasms

Improved understanding of mechanisms underlying metastatic castration-resistant prostate cancer (mCRPC) progression has led to the recognition of multiple molecular targets and advances in the therapeutic landscape. The addition of abiraterone acetate, sipuleucel-T, cabazitaxel, and denosumab to the therapeutic armamentarium and the impending addition of MDV-3100 and radium-223 underscore the importance of androgen pathway inhibition, immunotherapy, tubulin antagonism, and pathophysiology of bone metastasis.. Review the next generation of molecular targets in mCRPC.. Medline databases were searched for >100 original articles published as of October 18, 2011, with the search terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy. Proceedings from the last 5 yr of conferences of the American Society of Clinical Oncology, American Urological Association, European Society of Medical Oncology, and the European Association of Urology were also searched. We included novel and promising drugs that have reached clinical trial evaluation.. The major findings were addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed.. mCRPC is a disease with multiple molecular drivers. Molecular pathways being targeted in ongoing phase 3 trials are androgen signaling (MDV3100, TAK700), immunoregulatory pathways (ipilimumab, Prostvac-VF-TRICOM), Src (dasatinib), Met (cabozantinib), clusterin (custirsen), and angiogenesis (aflibercept, tasquinimod). The strides made in identifying multiple other novel molecular targets offer potential opportunities for further improving outcomes.

Topics: Abiraterone Acetate; Androstadienes; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Bone Neoplasms; Cancer Vaccines; Carcinoma; Clinical Trials, Phase III as Topic; Clusterin; Dasatinib; Denosumab; Humans; Ipilimumab; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms; Pyridines; Pyrimidines; Quinolines; Quinolones; Radium; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Taxoids; Thiazoles; Tissue Extracts; Treatment Outcome; Vaccines, Synthetic

Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC), which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17). This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC.

Topics: Abiraterone Acetate; Administration, Ophthalmic; Androgen Antagonists; Androgens; Androstadienes; Animals; Antineoplastic Agents; Enzyme Inhibitors; Humans; Male; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Steroid 17-alpha-Hydroxylase

The rapid approval of several novel agents has given prostate cancer patients and their treating physicians many new and effective therapeutic options. Three new medical therapies were recently approved on the basis of prolonged overall survival in castration-resistant prostate cancer patients: sipuleucel-T (Provenge), cabazitaxel (Jevtana), and abiraterone acetate (Zytiga). Additionally, there are several other promising prostate cancer agents in late-stage development, including MDV3100, PROSTVAC-VF (Prostvac), orteronel (TAK-700), and radium-223 chloride (Alpharadin), each with a novel mechanism of action. Taken together, we have entered a period of accelerated drug development and optimism in the care of advanced prostate cancer. The treatment paradigm for these patients is rapidly evolving, with future study needed to define the optimal sequencing and potential combinations of these new agents.

Topics: Abiraterone Acetate; Androstadienes; Humans; Male; Prostatic Neoplasms; Taxoids; Tissue Extracts; Treatment Outcome

Abiraterone acetate and cabazitaxel have shown an overall survival benefit in patients with metastatic castration-resistant prostate cancer following docetaxel failure. Both have been approved in this indication. The search, follow-up and characterisation of circulating tumor cells should help for the response evaluation and the choice between the two treatments. Recently, alpharadin (radium-223 chloride) has demonstrated also an overall survival advantage in a large phase III trial. Other hormone therapies as MDV3100 or TAK700 are very promising. In undifferentiated cancers with neuroendocrine features, etoposide and platinum salts combinations have shown low efficiency.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Angiogenesis Inhibitors; Antineoplastic Agents; Benzamides; Docetaxel; Humans; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms; Radioisotopes; Radium; Taxoids; Treatment Failure

If androgen deprivation, chemical with LH-RH analogs or surgical with bilateral orchiectomy, still remains the stone edge of treatment of prostate cancer, in the metastatic setting, this hormonosensitivity, most of the time long, finally move on in hormonal-failure. If rare changes in the therapeutic strategy have been achieved in this setting since 2004 and the arrival of docetaxel, it is the global perception of the disease that has been modified and the definition of one specific entity: the castrate-resistant prostate cancer. This new definition and the changes of design and end-points of clinical trials testing new agents with strong recruitment during the past years have conducted to a real revolution in the management of castrate-refractory prostate cancer. The place of secondary hormonal manipulations, such as withdrawal of the anti-androgen, oestrogen or ketoconazole, still exists for a selected group of patients. In case of aggressive disease and symptoms, chemotherapy should be selected, docetaxel, in a three weeks schedule, and may be combined with Estracyt. It is time to consider the revolution of the post-chemotherapy setting with the arrival of two new drugs ; a cytotoxic one, the cabazitaxel and hormonal for the second one, the abiraterone acetate. The place of the immunotherapy with the sipuleucel-T may be more difficult to precise, especially in Europe, even if it has been finally indicated in the United States in the metastatic setting. Concerning bone metastasis, zoledronic acid was during a long time the only bone-targeted agent, effective in reducing the incidence of skeletal related events, and was recently exceeded by the denosumab, an anti-RANK ligand. Finally, let us hope that other changes will be achieved in the near future, with the cabazitaxel-docetaxel confrontation in the first-line setting, and the introduction of the abiraterone acetate before chemotherapy with docetaxel, already tested in ongoing trials.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bone Density Conservation Agents; Bone Neoplasms; Cancer Vaccines; Denosumab; Diphosphonates; Docetaxel; Estramustine; Humans; Imidazoles; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts; Zoledronic Acid

The treatment landscape for men with castration-resistant prostate cancer (CRPC) is undergoing significant changes; a redefinition of the respective roles of oncologists and urologists will probably occur. In addition, the advent of the multidisciplinary team or coordinated-care approach, which has been gathering momentum over the last decade, will become not simply a preference but a clear necessity. In the present review, we explore the current wave of new treatments and describe the possibility of more complex approaches to combined therapy. New treatment options include abiraterone acetate, cabazitaxel, MDV3100 (in development), radium-223 (in development) and sipuleucel-T. We also present the traditional roles of the urologist and oncologist in caring for patients with CRPC and discuss how these may change. Compounding the new potential for treatment success, as well as the complexity of therapeutic strategies, is the emergence of novel biomarkers to evaluate treatment efficacy and to assist in patient prognosis. The prospects for successful treatment of patients with CRPC have developed considerably so that these patients may soon have a reasonable expectation of therapeutic efficacy and meaningful extension of their lives.

Topics: Abiraterone Acetate; Administration, Oral; Androgen Receptor Antagonists; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers, Tumor; Humans; Male; Medical Oncology; Nitriles; Orchiectomy; Palliative Care; Phenylthiohydantoin; Physician's Role; Professional Practice; Prostatic Neoplasms; Taxoids; Therapies, Investigational; Tissue Extracts; Urology

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents; Cancer Vaccines; Humans; Male; Neoplasm Grading; Prostatic Neoplasms; Taxoids; Tissue Extracts

• It is >70 years since the responsiveness of symptomatic metastatic prostate cancer to androgen deprivation was first demonstrated. • Since those pivotal studies, progress in hormonal therapy of prostate cancer has been marked by several important developments and the availability of various androgen-suppressing agents. • Treatment guidelines have continued to evolve with clinical and therapeutic progress, but androgen-deprivation therapy (ADT) remains the standard of care for non-localised prostate cancer. • Because of the long-term experience (>20 years) and wealth of evidence from the large number of clinical trials, the luteinizing hormone-releasing hormone (LHRH) agonists are currently the main forms of ADT. • Treatment strategies should be adapted to the individual patient in terms of timing, duration and choice of agent. • Prostate cancer remains the most common type of cancer in men and the development of castration-resistant disease seems inevitable, which together drive the clear and continuing need for new, effective agents for ADT to be used alongside the LHRH agonists.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antineoplastic Agents, Hormonal; Benzamides; Combined Modality Therapy; Humans; Imidazoles; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Treatment Outcome

Topics: 3-Hydroxysteroid Dehydrogenases; Abiraterone Acetate; Androstadienes; Androstenediol; Antineoplastic Agents; Dehydroepiandrosterone; Etiocholanolone; Humans; Male; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Testosterone

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents; Benzamides; Cancer Vaccines; Disease Progression; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids; Tissue Extracts

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

Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer.. This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile.. The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078).. Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.

Topics: Abiraterone Acetate; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices.. A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints.. Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2;. Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prostatic Neoplasms; Quality of Life

To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib.. This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non-small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding; (ii) monotherapy dose expansion; (iii) AZD8186/abiraterone acetate (with prednisone); and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses.. In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID; 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction.. AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate/prednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway-dependent cancers.

Topics: Abiraterone Acetate; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Chromones; Humans; Lung Neoplasms; Male; Neoplasms; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms

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

Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011-2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE's £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP's indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup.

Topics: Abiraterone Acetate; Acetates; Androgen Antagonists; Cost-Benefit Analysis; Hormones; Humans; Male; Prednisolone; Prednisone; Prostatic Neoplasms; State Medicine

Intermittent androgen deprivation therapy (ADT) in biochemically recurrent castration-naïve prostate cancer is non-inferior to continuous therapy. We hypothesised that finite-duration abiraterone acetate plus prednisone (Abi +P) added to ADT will further reduce the duration of treatment exposure by prolonging time to prostate-specific antigen (PSA) recurrence without impacting eugonad state recovery.. This phase II, randomised, open-label trial enrolled patients with rising PSA ≥ 0.2 ng/ml after radical prostatectomy and/or a PSA ≥ 1 following radiotherapy. Patients were randomised 1:1 to receive Abi (1 g PO daily) + P (5 mg PO daily) + ADT or ADT alone for 8 months. The primary end-point was PSA-free survival difference at 1 year following completion of therapy.. Between February 2013 and July 2016, 200 patients were enrolled. Of 100 patients randomised to each arm, 99 in the Abi +P arm and 98 in the ADT arm were evaluable. Median follow-up was 64.4 months. Median PSA-free survival was 27.0 months for the Abi +P-treated group versus 19.9 months for the ADT-treated group (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47-0.87). The PSA-free survival at 1 year post-treatment completion was 98% for the Abi +P group and 88% for the ADT group. Median time to eugonad state was 13.1 months for the abiraterone-treated group and 12.8 months for the ADT-treated group. Median eugonad PSA-free survival was 12.5 months for the abiraterone-treated group versus 9.0 for the ADT-treated group (HR 0.72, 95% CI 0.53-0.98). There were no significant between-group differences in androgen deprivation-related adverse events.. In men with biochemically recurrent prostate cancer following definitive treatment of the primary, finite duration treatment with ADT and Abi +P results in a significantly longer PSA relapse-free interval than treatment with ADT alone.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Disease-Free Survival; Drug Administration Schedule; Follow-Up Studies; Humans; Kallikreins; Male; Middle Aged; Neoplasm Recurrence, Local; Prednisone; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Time Factors

Systemic therapy with androgen deprivation therapy (ADT) and intensification with agents such as docetaxel, abiraterone acetate and enzalutamide has resulted in improved overall survival in men with. Using a prospective, multicentre discrete choice experiment (DCE), we aim to determine the attributes associated with treatment that are most important to men with mHSPC. Furthermore, we plan to determine men's preferences for, and trade-offs between, the attributes (survival and side effects) of different treatment options including systemic therapy, local cytoreductive approaches (external beam radiotherapy, cytoreductive radical prostatectomy or minimally invasive ablative therapy) and metastases-directed therapies (metastasectomy or stereotactic ablative body radiotherapy). All men with newly diagnosed mHSPC within 4 months of commencing ADT and WHO performance status 0-2 are eligible. Men who have previously consented to a cytoreductive treatment or have developed castrate-resistant disease will be excluded. This study includes a qualitative analysis component, with patients (n=15) and healthcare professionals (n=5), to identify and define the key attributes associated with treatment options that would warrant trade-off evaluation in a DCE. The main phase component planned recruitment is 300 patients over 1 year, commencing in January 2021, with planned study completion in March 2022.. Ethical approval was obtained from the Health Research Authority East of England, Cambridgeshire and Hertfordshire Research Ethics Committee (Reference: 20/EE/0194). Project information will be reported on the publicly available Imperial College London website and the Heath Economics Research Unit (HERU website including the HERU Blog). We will use the social media accounts of IP5-MATTER, Imperial Prostate London, HERU and the individual researchers to disseminate key findings following publication. Findings from the study will be presented at national/international conferences and peer-reviewed journals. Authorship policy will follow the recommendations of the International Committee of Medical Journal Editors.. NCT04590976.

Topics: Abiraterone Acetate; Androgen Antagonists; Attitude; Humans; Male; Multicenter Studies as Topic; Observational Studies as Topic; Prospective Studies; Prostatic Neoplasms

Long-term androgen-deprivation therapy (ADT) is the standard of care in combination with radiation therapy (RT) in high-risk prostate cancer (PC), despite substantial toxicity from the resulting hypogonadism. We hypothesized that a combination of more potent but shorter-term androgen inhibition in men with intermediate- or high-risk localized PC would synergize with definitive RT to provide short-term testosterone recovery and improve disease control.. This prospective phase 2 single-arm trial enrolled men with low-volume unfavorable intermediate or high-risk localized PC. Treatment included 6 months of ADT concurrent with abiraterone acetate plus prednisone (AAP) once daily and RT to prostate and seminal vesicles. The primary endpoint was the proportion of men with an undetectable prostate-specific antigen (PSA) at 12-months; secondary objectives included biochemical progression-free survival (PFS), testosterone recovery, toxicity, and sexual and hormonal quality of life.. We enrolled 37 men between January 2014 and August 2016, 45% of whom were high risk. All patients had T1-2 disease and PSA < 20 ng/mL. Median follow-up is 37 months (95% confidence interval [CI], 35.7-39.1). Treatment noted 32% grade 3 toxicities related to AAP, predominantly hypertension, with no toxicities ≥G4. The rate of undetectable PSA at 12 months was 55% (95% CI, 36%-72%). With 46 months of median follow-up, 2 of 37 patients developed PSA progression (36-month PFS = 96%; 95% CI, 76%-99%), and 81% of patients recovered testosterone with a median time to recovery of 9.2 months. Hormonal or sexual function declined at 6 months with subsequent improvement by 24 months.. The combination of RT and 6 months of ADT and AAP demonstrated acceptable toxicity and a high rate of testosterone recovery with restoration of quality of life and excellent disease control in men with low-volume, intermediate- or high-risk localized prostate cancer. Prospective comparative studies are justified.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Confidence Intervals; Drug Therapy, Combination; Humans; Male; Middle Aged; Prednisone; Progression-Free Survival; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Seminal Vesicles; Testosterone; Time Factors

This multicenter randomized phase 2 trial investigates the impact of intense androgen deprivation on radical prostatectomy pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368).. Eligible patients had a Gleason score ≥4+3=7, prostate specific antigen >20 ng/mL or T3 disease and lymph nodes <20 mm. In Part 1, patients were randomized 1:1 to apalutamide, abiraterone acetate, prednisone and leuprolide (AAPL) or abiraterone, prednisone, leuprolide (APL) for 6 cycles (1 cycle=28 days) followed by radical prostatectomy. Surgical specimens underwent central review. The primary end point was the rate of pathologic complete response or minimum residual disease (minimum residual disease, tumor ≤5 mm). Secondary end points included prostate specific antigen response, positive margin rate and safety. Magnetic resonance imaging and tissue biomarkers of pathologic outcomes were explored.. The study enrolled 118 patients at 4 sites. Median age was 61 years and 94% of patients had high-risk disease. The combined pathologic complete response or minimum residual disease rate was 22% in the AAPL arm and 20% in the APL arm (difference: 1.5%; 1-sided 95% CI -11%, 14%; 1-sided p=0.4). No new safety signals were observed. There was low concordance and correlation between posttherapy magnetic resonance imaging assessed and pathologically assessed tumor volume. PTEN-loss, ERG positivity and presence of intraductal carcinoma were associated with extensive residual tumor.. Intense neoadjuvant hormone therapy in high-risk prostate cancer resulted in favorable pathologic responses (tumor

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Drug Therapy, Combination; Humans; Leuprolide; Male; Middle Aged; Prednisone; Preoperative Period; Prostatectomy; Prostatic Neoplasms; Risk Assessment; Thiohydantoins; Treatment Outcome

The neutrophil-lymphocyte ratio (NLR) is an inexpensive and accessible prognostic marker for many cancers, including metastatic castration-resistant prostate cancer (mCRPC).. In this study, we assess the role of NLR as a predictive biomarker through a retrospective analysis of the pivotal COU302 study of abiraterone acetate (AA) as first-line therapy for men with asymptomatic or minimally symptomatic mCRPC.. The COU302 study randomized asymptomatic or minimally symptomatic men with mCRPC to receive AA plus prednisone or prednisone as first-line treatment. Baseline NLR, overall survival, radiographic progression-free survival, and prostate-specific antigen (PSA) progression-free survival were evaluated.. Descriptive statistics, as well as Kaplan-Meier and Cox survival models were used to assess the effect of baseline NLR and changes in NLR on response to AA plus prednisone versus prednisone, with adjustment for important covariates.. Among the 1082 patients who received treatment, baseline NLR values showed no significant differences according to baseline covariates except for albumin. Baseline variables were similar between dichotomous groups with an NLR cutoff of 2.5, except for a lower proportion of patients with >10 bone metastases in the NLR <2.5 group. Our survival results demonstrate that higher NLR values corresponded to poorer overall survival and PSA response to AA but not to placebo, which was confirmed in our adjusted regression models. No significant differences were seen in time to radiographic progression. In separate analyses, an increase or decrease in NLR by 2 from treatment baseline did not clearly signal subsequent lack of benefit with continued AA.. Our results suggest that baseline NLR may be able to predict response to AA in men with asymptomatic mCRPC but that changes in NLR during treatment are insufficient to guide treatment. Further validation studies are warranted.. In this report, we look at the ratio of circulating immune cells as a predictor of response to abiraterone acetate (AA), using data from a large trial. Our results suggest that this ratio derived from routinely obtained bloodwork can predict which patients respond better to AA.

Topics: Abiraterone Acetate; Antineoplastic Agents; Double-Blind Method; Humans; Leukocyte Count; Lymphocytes; Male; Neutrophils; Predictive Value of Tests; Prednisone; Prostatic Neoplasms; Retrospective Studies; Treatment Outcome

LATITUDE, a randomized, double-blind trial, compared abiraterone acetate and prednisone (AAP) + androgen deprivation therapy (ADT) versus placebo (PBO) + ADT in high-risk metastatic castration-sensitive prostate cancer (mCSPC).. To assess the correlation of prostate-specific antigen (PSA) kinetics with overall survival (OS) and radiological progression-free survival (rPFS).. A post hoc analysis of data from 597 men receiving AAP + ADT and 602 receiving PBO + ADT.. The associations of PSA-related outcomes (rates of confirmed 50% [PSA50] and 90% [PSA90] decline from baseline PSA [Prostate Cancer Working Group 2 criteria], rates of PSA < 0.2 ng/ml, median nadir PSA, time to PSA nadir [TPN], and time to PSA progression [TPP] with long-term outcomes [OS and rPFS]) were evaluated. Hazard ratios (HRs) were estimated using Cox proportional hazard model. Correlations of TPP with coprimary endpoints rPFS and OS were evaluated using Kendall's tau (KT).. AAP + ADT significantly delayed median TPP versus PBO + ADT (33.2 vs 7.4 mo; HR: 0.3, p <  0.001). TPP correlated with rPFS (KT = 0.921) and OS (KT = 0.666). In the AAP + ADT group, 91% had PSA50 and 79% had PSA90 responses (relative risk [RR]: 1.36 and 2.30, respectively; p <  0.001 for both comparisons vs PBO + ADT). Compared with nonresponders, PSA50 and PSA90 responders had reduced risk of death (RR: 0.44 and 0.12, respectively). At 6 mo, 40% receiving AAP + ADT and 6.5% receiving PBO + ADT achieved PSA ≤0.1 ng/ml, which was significantly associated with longer rPFS and OS. Median nadir PSA was 0.09 ng/ml with AAP + ADT versus 2.36 ng/ml with PBO + ADT. Median TPN (AAP + ADT, 6.4 mo; PBO + ADT, 3.8 mo) positively correlated with rPFS and OS.. Superior PSA response dynamics with AAP + ADT versus ADT + PBO strongly correlated with long-term outcomes of rPFS and OS in high-risk mCSPC.. We found that low prostate-specific antigen levels (≤0.1 ng/ml) after 6 mo may indicate a good long-term response to treatment. Our results need confirmation.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents; Correlation of Data; Double-Blind Method; Drug Therapy, Combination; Humans; Male; Neoplasm Metastasis; Prednisone; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate

LATITUDE was a randomized, double-blind, international and phase 3 study of abiraterone acetate plus prednisone in patients with high-risk metastatic hormone-naïve prostate cancer. In the first interim analysis of LATITUDE (clinical cutoff date: 31 October 2016), significant prolongation in overall survival and radiographic progression-free survival (co-primary endpoints) was observed when compared with placebo. The results of the Japanese subgroup analysis of LATITUDE first interim analysis were consistent with those of the overall population. In this study, overall survival and safety results from the final analysis of the Japanese subgroup of the LATITUDE study are presented (clinical cutoff date: 15 August 2018).. Abiraterone acetate (1000 mg/day) and prednisone (5 mg/day) were administered orally in the abiraterone acetate plus prednisone group, and matching placebos in the placebo group.. Of the 1199 patients included in LATITUDE, 70 constituted the Japanese subgroup (abiraterone acetate plus prednisone: n = 35, placebo: n = 35). Following a median (range) follow-up of 56.6 (2.5, 64.2) months, the median overall survival was not reached in both the treatment arms of the Japanese subgroup (hazard ratio: 0.61; 95% confidence interval: 0.27-1.42; nominal P = 0.2502). A total of 23 deaths (abiraterone acetate plus prednisone: 9 [25.7%], placebo group: 14 [40.0%]) were reported in Japanese subgroup. Grade 3/4 adverse events were reported in 24 (68.6%) and 9 (25.7%) patients in the abiraterone acetate plus prednisone and placebo groups, respectively.. In this Japanese subgroup analysis, addition of abiraterone acetate plus prednisone to androgen-deprivation therapy demonstrated favorable efficacy and safety outcomes in patients with newly diagnosed, high-risk metastatic hormone-naïve prostate cancer. Survival benefits observed in the Japanese subgroup first interim analysis were sustained long-term and were consistent with the overall population.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Humans; Japan; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms; Survival Analysis

Abiraterone acetate is a highly variable drug and has been approved for the treatment of patients with metastatic castration-resistant prostate cancer in many countries. This study was conducted to compare the pharmacokinetic profile between the test product (abiraterone acetate tablet) and reference product ZYTIGA® (250 mg) mainly.. To overcome the high intra-subject variability of abiraterone, a two-sequence and four-period crossover study was designed to assess bioequivalence between the two products in 32 healthy male Chinese subjects under fasting conditions. The plasma concentration of abiraterone was analyzed by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay and the reference-scaled procedure was used to determine bioequivalence for the pharmacokinetics parameters.. The point estimate of geometric mean ratios with 90% confidence interval (CI) of maximum observed concentration (C. Bioequivalence was demonstrated between the two abiraterone acetate products. The study also confirmed high intra-subject variability, for abiraterone: coefficient of variation (CV, %) of C. http://www.chinadrugtrials.org.cn/ : CTR20170997.

Topics: Abiraterone Acetate; Administration, Oral; Adult; Antineoplastic Agents; Area Under Curve; Asian People; Biological Availability; Biological Variation, Individual; Cross-Over Studies; Drugs, Generic; Healthy Volunteers; Humans; Male; Middle Aged; Prostatic Neoplasms; Steroid Synthesis Inhibitors; Tablets; Therapeutic Equivalency; Young Adult

The treatment paradigm for metastatic hormone-sensitive prostate cancer (mHSPC) patients is evolving. PET/CT now offers improved sensitivity and accuracy in staging. Recent randomized trial data supports escalated hormone therapy, local primary tumor therapy, and metastasis-directed therapy. The impact of combining such therapies into a multimodal approach is unknown. This Phase II single-arm clinical trial sponsored and funded by Veterans Affairs combines local, metastasis-directed, and systemic therapies to durably render patients free of detectable disease off active therapy.. Patients with newly-diagnosed M1a/b prostate cancer (PSMA PET/CT staging is permitted) and 1-5 radiographically visible metastases (excluding pelvic lymph nodes) are undergoing local treatment with radical prostatectomy, limited duration systemic therapy for a total of six months (leuprolide, abiraterone acetate with prednisone, and apalutamide), metastasis-directed stereotactic body radiotherapy (SBRT), and post-operative fractionated radiotherapy if pT ≥ 3a, N1, or positive margins are present. The primary endpoint is the percent of patients achieving a serum PSA of < 0.05 ng/mL six months after recovery of serum testosterone ≥150 ng/dL. Secondary endpoints include time to biochemical progression, time to radiographic progression, time to initiation of alternative antineoplastic therapy, prostate cancer specific survival, health related quality-of-life, safety and tolerability.. To our knowledge, this is the first trial that tests a comprehensive systemic and tumor directed therapeutic strategy for patients with newly diagnosed oligometastatic prostate cancer. This trial, and others like it, represent the critical first step towards curative intent therapy for a patient population where palliation has been the norm.. Clinicaltrials.gov identifier: NCT03298087 (registration date: September 29, 2017).

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Combined Modality Therapy; Humans; Leuprolide; Male; Middle Aged; Neoplasm Micrometastasis; Prednisone; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Radiosurgery; Thiohydantoins; Treatment Outcome; Veterans; Young Adult

In the interim analyses of the LATITUDE study, the addition of abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) led to a significant improvement in overall survival and radiographic progression-free survival compared with placebos plus ADT in men with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (mCSPC). Here, we present long-term survival outcomes and safety of abiraterone acetate plus prednisone and ADT from the final analysis of the LATITUDE study.. This is a multicentre, randomised, double-blind, phase 3 trial done at 235 sites in 34 countries. Eligible patients (men aged ≥18 years) had newly diagnosed, histologically or cytologically confirmed prostate cancer with metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and at least two of the three high-risk prognostic factors (Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis except lymph node metastasis). Patients were randomly assigned (1:1) to receive abiraterone acetate (1000 mg) once daily orally plus prednisone (5 mg) once daily orally and ADT (abiraterone acetate plus prednisone group) or matching placebos plus ADT (placebo group); each treatment cycle was 28 days. Randomisation was done by a centralised interactive web response system in a country-by-country scheme using permuted block randomisation, stratified by presence of visceral disease and ECOG performance status. The coprimary endpoint of overall survival was assessed in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT01715285 and is complete.. Between Feb 12, 2013, and Dec 11, 2014, 1209 patients were screened, of whom ten were ineligible because of study site violations. 1199 patients were randomly assigned to either the abiraterone acetate plus prednisone group (n=597) or placebo group (n=602). After the results of the first interim analysis (cutoff date Oct 31, 2016), the study was unmasked to patients and investigators, and patients in the placebo group were allowed to cross over to receive abiraterone acetate and prednisone plus ADT treatment as per a protocol amendment (Feb 15, 2017) in an open-label extension phase of the study (up to 18 months from the protocol amendment). This final analysis (data cutoff Aug 15, 2018) was done after a median follow-up of 51·8 months (IQR 47·2-57·0) and 618 deaths (275 [46%] of 597 in the abiraterone acetate plus prednisone group and 343 [57%] of 602 in the placebo group). Overall survival was significantly longer in the abiraterone acetate plus prednisone group (median 53·3 months [95% CI 48·2-not reached]) than in the placebo group (36·5 months [33·5-40·0]), with a hazard ratio of 0·66 (95% CI 0·56-0·78; p<0·0001). The most common grade 3-4 adverse events were hypertension (125 [21%] in the abiraterone acetate plus prednisone group vs 60 [10%] in the placebo group vs three [4%] in the 72 patients who crossed over from placebo to abiraterone acetate plus prednisone) and hypokalaemia (70 [12%] vs ten [2%] vs two [3%]). Serious adverse events of any grade occurred in 192 (32%) of 597 patients in the abiraterone acetate plus prednisone group, 151 (25%) of 602 in the placebo group, and four (6%) of 72 in the crossover group. The most common treatment-related serious adverse event was hypokalaemia (four [1%] patients in the abiraterone acetate plus prednisone group and none in the other groups). Treatment-related deaths occurred in three (<1%) patients each in the abiraterone acetate plus prednisone group (gastric ulcer perforation, sudden death, and cerebrovascular accident) and the placebo group (sudden death, cerebrovascular accident, and pneumonia), with none in the crossover group.. The combination of abiraterone acetate plus prednisone with ADT was associated with significantly longer overall survival than placebos plus ADT in men with newly diagnosed high-risk mCSPC and had a manageable safety profile. These findings support the use of abiraterone acetate plus prednisone as a standard of care in patients with high-risk mCSPC.. Janssen Research & Development.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease Progression; Double-Blind Method; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Orchiectomy; Progression-Free Survival; Prostatic Neoplasms; Risk Assessment; Risk Factors; Steroid Synthesis Inhibitors; Time Factors

Optimal therapeutic strategy remains an unmet need in localised high-risk prostate cancer (LHRPC). Androgen biosynthesis inhibition in the preoperative setting may improve outcomes. In this single-centre randomised trial, we looked at therapy outcomes of preoperative treatment with abiraterone acetate+prednisone (AAP)+luteinising hormone-releasing hormone agonist (LHRHa) or LHRHa alone followed by radical prostatectomy in 65 men. We did not see a significant difference of organ-confined carcinoma (p=0.27). However, tumour volume measures were significantly lower for AAP+LHRHa treatment (p≤0.001). Of note, lower tumour epithelium volume correlated with improved biochemical recurrence-free survival at ≥4-yr follow-up (p=0.0014). Tumours pretreated with AAP+LHRHa had lower proliferation and androgen signalling expression than LHRHa. On multivariate analysis, glucocorticoid receptor (GR) overexpression correlated with persistent tumours in AAP+LHRHa (p=0.018). The presence of nuclear androgen receptor splice variant (nARV7) correlated with persistent tumours in both arms. No new safety signals were observed. This is the first study investigating the role of preoperative AAP+LHRHa versus LHRHa alone in LHRPC. We report significant cytoreduction by tumour volume measures inversely correlating with biochemical relapse. Validation of these proposed tumour volume measures is planned. A potential role of GR in resistance to androgen biosynthesis inhibition warrants further study. PATIENT SUMMARY: This is the first study of abiraterone acetate plus leuprolide versus leuprolide alone in high-risk localised prostate cancer followed by prostatectomy. Patients in the combination arm had a significantly smaller tumour size.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Drug Combinations; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Prednisone; Preoperative Period; Prostatectomy; Prostatic Neoplasms; Risk Assessment

Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP.. Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP.. A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm.. This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs.. Clinicaltrials.gov: NCT00268476.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Network Meta-Analysis; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms; Standard of Care

To evaluate the efficacy and safety of abiraterone acetate plus prednisone (AAP) plus androgen-deprivation therapy (ADT) in Japanese subgroup with newly diagnosed, metastatic hormone-naïve prostate cancer (mHNPC) from Phase 3, randomized, global LATITUDE study.. Men with mHNPC having ≥2 of 3 high-risk factors (Gleason score ≥8, ≥3 bone lesions or measurable visceral metastases) randomly received abiraterone acetate 1000-mg+ prednisone 5-mg+ADT (AAP group) or ADT+Placebos (Placebo group). Coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS).. Of total 1199 patients in the LATITUDE study, 70 (5.8%) were Japanese (n = 35 each in the AAP and placebo group). After a median follow-up of 35.02 months (range: 2.5-42.3), median OS was not reached in both AAP group and placebo group (HR: 0.635; 95% CI, 0.152-2.659) and the median length of rPFS was not reached in the AAP group and was 22 months in the placebo group (HR:0.219; 95% CI, 0.086-0.560). The most frequently reported adverse events (>20% in either group) in the Japanese subgroup were hypertension, nasopharyngitis, weight increased, hypokalemia, hot flush, back pain, hyperglycemia, ALT and AST elevation. The incidence of Grade 3 or 4 adverse events was 65.7% (23/35) in the AAP group and 20% (7/35) in the placebo group. The efficacy and safety findings of Japanese subgroup were consistent with that of the overall study population.. Treatment with AAP plus ADT has shown a positive risk-benefit balance and may serve as a new treatment option to improve the prognosis of Japanese mHNPC patients with high-risk features.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asian People; Double-Blind Method; Endpoint Determination; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Placebos; Prednisone; Progression-Free Survival; Prostatic Neoplasms; Treatment Outcome

Men with metastatic prostate cancer who have a poor response to initial androgen-deprivation therapy (ADT), as reflected by a prostate-specific antigen (PSA) level higher than 4.0 ng/mL after 7 months of ADT, have a poor prognosis, based on historical controls.. To determine the efficacy of abiraterone acetate with prednisone in these high-risk patients with a suboptimal response to hormonal induction.. A phase 2 single-arm study was conducted through the National Clinical Trials Network-Southwest Oncology Group. Eligible patients had metastatic prostate cancer and a PSA level higher than 4.0 ng/mL between 6 and 12 months after starting ADT. The PSA level could be rising or falling at the time of enrollment, but had to be higher than 4.0 ng/mL. No previous chemotherapy or secondary hormonal therapies were allowed, except in patients receiving a standard, first-generation antiandrogen agent with a falling PSA level at the time of enrollment; this therapy was continued in this cohort. Abiraterone acetate, 1000 mg, once daily with prednisone, 5 mg, twice daily was administered to all participants. A total of 41 men were enrolled between the trial's activation on August 9, 2011, and closure on August 1, 2013. Data analysis was conducted from March 21 to November 29, 2016.. Abiraterone acetate, 1000 mg, once daily by mouth with prednisone, 5 mg, by mouth twice daily.. The primary end point was a PSA level of 0.2 ng/mL or lower within 12 months of starting abiraterone acetate plus prednisone. A partial response (PR) was a secondary end point, defined as a PSA level reduction to lower than 4.0 ng/mL but higher than 0.2 ng/mL.. Of the 41 men enrolled, 1 did not receive any protocol treatment and was excluded from analysis. The median (range) age of the 40 participants was 66 (39-85) years. Five (13%) patients achieved a PSA level of 0.2 ng/mL or lower (95% CI, 4%-27%). Thirteen (33%) additional patients achieved a partial response, with a reduction in the PSA level to lower than 4.0 ng/mL but higher than 0.2 ng/mL. Sixteen (40%) patients had no PSA response and 6 (15%) were not assessable and assumed to be nonresponders. The median progression-free survival was 17.5 months (95% CI, 8.6-25.0 months) and the median overall survival was 25.8 months (95% CI, 15.7-25.8 months). There was 1 incident each of grade 4 adverse events of alanine aminotransferase level elevation and rectal hemorrhage. Eleven patients reported grade 3 adverse events.. This study did not reach its prescribed level of 6 PSA responses of 0.2 ng/mL or lower, although 5 responses were observed. The overall survival and progression-free survival rates observed in this trial are encouraging compared with historical controls. The therapy was generally well tolerated, without any clear signal of any unexpected adverse effects.

Topics: Abiraterone Acetate; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Humans; Kallikreins; Male; Middle Aged; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Analysis; Time Factors; Treatment Outcome; United States

Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer.. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival.. After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group.. The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285 .).

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Middle Aged; Neoplasm Metastasis; Prednisolone; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase; Survival Analysis

Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design.. We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer).. A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events).. Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prednisolone; Prostate-Specific Antigen; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase; Survival Analysis

Neoadjuvant androgen deprivation therapy (NADT) is one strategy for the treatment of early-stage prostate cancer; however, the long-term outcomes of NADT with radical prostatectomy including biochemical failure-free survival are not promising. One proposed mechanism is incomplete androgen ablation. In this study, we aimed to evaluate the efficiency of serum hydroxy-androgen suppression in patients with localized high-risk prostate cancer under NADT (leuprolide acetate plus abiraterone acetate and prednisone) and interrogate the primary sources of circulating hydroxy-androgens using our recently described stable isotope dilution liquid chromatography mass spectrometric method. For the first time, three androgen diols including 5-androstene-3β,17β-diol (5-adiol), 5α-androstane-3α,17β-diol (3α-adiol), 5α-androstane-3β,17β-diol (3β-adiol), the glucuronide or sulfate conjugate of 5-adiol and 3α-adiol were measured and observed to be dramatically reduced after NADT. By comparing patients that took leuprolide acetate alone vs leuprolide acetate plus abiraterone acetate and prednisone, we were able to distinguish the primary sources of these androgens and their conjugates as being of either testicular or adrenal in origin. We find that testosterone, 5α-dihydrotestosterone (DHT), 3α-adiol and 3β-adiol were predominately of testicular origin. By contrast, dehydroepiandrosterone (DHEA), epi-androsterone (epi-AST) and their conjugates, 5-adiol sulfate and glucuronide were predominately of adrenal origin. Our findings also show that NADT failed to completely suppress DHEA-sulfate levels and that two unappreciated sources of intratumoral androgens that were not suppressed by leuprolide acetate alone were 5-adiol-sulfate and epi-AST-sulfate of adrenal origin.

Topics: Abiraterone Acetate; Adrenal Glands; Androgens; Antineoplastic Agents, Hormonal; Glucuronides; Humans; Leuprolide; Male; Neoadjuvant Therapy; Prednisone; Prostatic Neoplasms; Sulfates; Testis; Testosterone; Testosterone Congeners

Abiraterone acetate (AA) was recently approved for castration-resistant prostate cancer in Japan. Two phase 1 studies were conducted to assess the pharmacokinetics of abiraterone after single-dose administration in Japanese healthy men and to evaluate the effects of food timing on abiraterone pharmacokinetics after single-dose administration of AA in Japanese and Caucasian healthy men.. In the dose-proportionality study, subjects (n = 30 Japanese) were randomly assigned to receive single doses of 250, 500, and 1,000 mg AA, and in the food-timing study, subjects (n = 22 Japanese and n = 23 Caucasian) randomly received single doses of 1,000 mg AA under fasted (overnight) and three different modified fasting conditions.. Mean C(max) and AUC(∞) for abiraterone increased dose-dependently in Japanese healthy men; however, 90 % confidential interval (CI) was outside the predefined dose-proportionality criteria. Based on geometric mean ratios and 90 % CIs (versus overnight fasting condition), abiraterone exposure (AUC) increased significantly with dosing 1 h premeal, 2 h postmeal, or in between two meals 4 h apart by 57 %, 595 %, and 649 %, respectively.. No clinically meaningful difference was observed in the pharmacokinetics of abiraterone between Caucasian and Japanese subjects.

Topics: Abiraterone Acetate; Adult; Androstenes; Antineoplastic Agents, Hormonal; Asian; Cross-Over Studies; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Food-Drug Interactions; Half-Life; Humans; Japan; Male; Meals; Metabolic Clearance Rate; Middle Aged; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase; Tablets; United States; White People; Young Adult

Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone-releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression.. A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy.. The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Δ(4)-androstene-3,17-dione, dihydrotestosterone, all P < .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node-positive disease in the majority.. LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Receptors, Androgen; Testosterone

In the phase III study COU-AA-301, abiraterone acetate (AA) plus prednisone (P) prolonged overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel administration. In this article, we investigate the relationship between baseline serum androgen (SA) levels and OS.. COU-AA-301 is a randomized, double-blind study of AA (1,000 mg every day) plus P (5 mg by mouth twice daily; n = 797) versus P alone (n = 398). Randomization was stratified by Eastern Cooperative Oncology Group performance status (0 to 1 v 2), pain (Brief Pain Inventory-Short Form over past 24 hours: 4 to 10, present; v 0 to 3, absent), prior chemotherapy (1 v 2), and progression (prostate-specific antigen v radiographic). Association of baseline SA (testosterone, androstenedione, dehydroepiandrosterone sulfate), was measured by ultrasensitive liquid-liquid extraction or protein precipitation and two-dimensional liquid chromatography coupled to mass spectrometry, with OS determined by bivariate and multivariable Cox models. OS was examined with SA as greater than median and less than or equal to the median.. Median survival increased with each quartile increase in testosterone level regardless of treatment arm. SA levels at baseline strongly associated with survival (P < .0001) in bivariate and multivariable analyses. Longer survival was observed for patients with SA above median compared with below median in both the AA and P arms (eg, testosterone, AA; hazard ratio, 0.64; 95% CI, 0.53 to 0.77; P < .0001). Treatment with AA led to longer survival versus P alone in the above- or below-median group for all androgens.. SA, measured with a novel ultrasensitive assay in COU-AA-301, is prognostic for OS and may be useful for risk stratification in mCRPC clinical trials.

Topics: Abiraterone Acetate; Androgens; Androstadienes; Double-Blind Method; Humans; Liquid-Liquid Extraction; Male; Orchiectomy; Prednisone; Prognosis; Prostatic Neoplasms; Testosterone

In a recent randomised, double-blind, phase III clinical trial among 1195 patients with metastatic castration-resistant prostate cancer (mCRPC) who had failed docetaxel chemotherapy, abiraterone acetate was shown to significantly prolong overall survival compared with prednisone alone. Here we report on the impact of abiraterone therapy on the health-related quality of life (HRQoL) observed during this trial, assessed using the validated Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire.. All analyses were conducted using prespecified criteria for clinically meaningful improvement and deterioration in FACT-P total score as well as subscale scores; all respective thresholds were defined using an accepted methodology. Improvement was assessed only in patients with clinically significant functional status impairment at baseline.. Significant improvements in the FACT-P total score were observed in 48% of patients receiving abiraterone versus 32% of patients receiving prednisone (p < 0.0001). Also, the median time to deterioration in FACT-P total score was longer (p < 0.0001) in patients receiving abiraterone (59.9 weeks versus 36.1 weeks). Similar differences were observed in all FACT-P subscales, with the exception of the social/family well-being domain. Median time to improvement in the physical well-being domain and the trial outcome index was significantly shorter (p < 0.01) with abiraterone when compared with the prednisone arm.. The previously demonstrated survival benefit for abiraterone is accompanied by improvements in patient-reported HRQoL and a significant delay in HRQoL deterioration when compared with prednisone.

Topics: Abiraterone Acetate; Adenocarcinoma; Androstadienes; Antineoplastic Agents; Chemotherapy, Adjuvant; Docetaxel; Humans; Male; Neoplasm Metastasis; Orchiectomy; Placebos; Prostatic Neoplasms; Quality of Life; Surveys and Questionnaires; Taxoids; Treatment Failure

To assess the effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan HBr (CYP2D6 substrate) and theophylline (CYP1A2 substrate) in patients with metastatic castration-resistant prostate cancer (mCRPC).. Men with progressive metastatic mCRPC who failed gonadotropin-releasing hormone therapy and ≥1 lines of chemotherapy were enrolled. Patients received two doses of dextromethorphan HBr-30 mg (n = 18; group A) or theophylline-100 mg (n = 16; group B) under fasting conditions; one dose on cycle 1, day -8, and the other dose on cycle 1, day 8. Only patients with extensive CYP2D6 metabolizing status were assigned to group A. All patients received continuous daily oral abiraterone acetate (1,000 mg) plus prednisone (10 mg) starting on cycle 1, day 1.. Coadministration of abiraterone acetate plus prednisone increased the systemic exposure of dextromethorphan by approximately 100%. Ratios of geometric means for maximum plasma concentration (C(max)) (275.36%) and area under plasma concentration-time curves from time 0 to 24 h (AUC(24h)) (268.14%) of dextromethorphan were outside the bioequivalence limit. The pharmacokinetics of theophylline was unaltered following coadministration of abiraterone acetate plus prednisone. Ratios of geometric means [C(max); 102.36% and AUC(24h); 108.03%] of theophylline exposure parameters were within the bioequivalence limit. The safety profile of abiraterone acetate was consistent with reported toxicities.. Abiraterone acetate plus prednisone increased the exposure of dextromethorphan, suggesting a need for caution when coadministrating with known CYP2D6 substrates. The pharmacokinetics of theophylline was unaffected when coadministered with abiraterone acetate plus prednisone.

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Dextromethorphan; Drug Interactions; Follow-Up Studies; Humans; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms; Theophylline

Fatigue is a common, debilitating side-effect of prostate cancer and its treatment. Patient-reported fatigue was evaluated as part of COU-AA-301, a randomized, placebo-controlled, phase III trial of abiraterone acetate and prednisone versus placebo and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel chemotherapy. This is the first phase III study in advanced prostate cancer to evaluate fatigue outcomes using a validated fatigue-specific instrument.. The Brief Fatigue Inventory (BFI) questionnaire was used to measure patient-reported fatigue intensity and fatigue interference with activities of daily life. All analyses were conducted using prespecified responder definitions of clinically meaningful changes.. A total of 797 patients were randomized to abiraterone acetate and prednisone, and 398 were randomized to placebo and prednisone. Compared with prednisone alone, in patients with clinically significant fatigue at baseline, abiraterone acetate and prednisone significantly increased the proportion of patients reporting improvement in fatigue intensity (58.1% versus 40.3%, P = 0.0001), improved fatigue interference (55.0% versus 38.0%, P = 0.0075), and accelerated improvement in fatigue intensity (median 59 days versus 194 days, P = 0.0155).. In patients with mCRPC progressing after docetaxel chemotherapy, abiraterone acetate and prednisone yielded clinically meaningful improvements in patient-reported fatigue compared with prednisone alone.

Topics: Abiraterone Acetate; Androstadienes; Castration; Docetaxel; Fatigue; Humans; Male; Neoplasm Metastasis; Neoplasm Staging; Prednisone; Prostatic Neoplasms; Surveys and Questionnaires; Taxoids

Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy.. In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival.. The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone-prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the efficacy boundary. Abiraterone-prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone-prednisone.. Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer. (Funded by Janssen Research and Development, formerly Cougar Biotechnology; ClinicalTrials.gov number, NCT00887198.).

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Double-Blind Method; Humans; Male; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms; Survival Analysis

Abiraterone is the active metabolite of the pro-drug abiraterone acetate (AA) and a selective inhibitor of CYP17, a key enzyme in testosterone synthesis, and improves overall survival in postdocetaxel metastatic castration-resistant prostate cancer (mCRPC). This open-label, single-arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval.. The study was conducted in 33 patients with mCRPC. Patients received AA 1,000 mg orally once daily + prednisone 5 mg orally twice daily. Electrocardiograms (ECGs) were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle 1 Day-1. Serial ECG recordings and time-matched pharmacokinetic (PK) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1. Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8.. After AA administration, the upper bound of the 2-sided 90 % confidence interval (CI) for the mean baseline-adjusted QTcF change was <10 ms; no patients discontinued due to QTc prolongation or adverse events. No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [estimated slope (90 % CI): 0.0031 (-0.0040, 0.0102)].. There is no significant effect of AA plus prednisone on the QT/QTc interval in patients with mCRPC.

Topics: Abiraterone Acetate; Androgens; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Electrocardiography; Heart Rate; Humans; Long QT Syndrome; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prednisone; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase

Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events).. Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00091442.. Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4-22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8-17·0] vs 11·2 months [10·4-13·1]; hazard ratio [HR] 0·74, 95% CI 0·64-0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3-11·1, in the abiraterone group vs 6·6 months, 5·6-8·3, in the placebo group; HR 0·63, 0·52-0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6-6·5, vs 3·6 months, 2·9-5·5; HR 0·66, 0·58-0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]).. This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androstadienes; Castration; Double-Blind Method; Humans; Male; Middle Aged; Neoplasm Metastasis; Orchiectomy; Prostatic Neoplasms

Bone metastases are a major cause of morbidity in metastatic castration-resistant prostate cancer. Abiraterone acetate potently disrupts intracrine androgen receptor signalling pathways implicated in the progression of the disease, including bone metastases. We assessed data for pain control and skeletal-related events prospectively collected as part of the randomised, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy.. The COU-AA-301 trial enrolled patients with metastatic castration-resistant prostate cancer in whom one or two lines of chemotherapy (one docetaxel based) had been unsuccessful and who had Eastern Cooperative Oncology Group performance statuses of 2 or less. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form questionnaire at baseline, day 15 of cycle 1, and day 1 of each treatment cycle thereafter until discontinuation. We assessed, with prospectively defined response criteria that incorporated analgesic use, clinically meaningful changes in pain intensity and interference with daily living. We measured time to first occurrence of skeletal-related events, which we defined as pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery, and regularly assessed them throughout the study. Pain palliation was assessed in patients who had clinically significant baseline pain, whereas all other analyses were done in the overall intention-to-treat population. COU-AA-301 is registered with ClinicalTrials.gov, number NCT00638690.. Median follow-up was 20·2 months (IQR 18·4-22·1). In patients with clinically significant pain at baseline, abiraterone acetate and prednisone resulted in significantly more palliation (157 of 349 [45·0%] patients vs 47 of 163 [28·8%]; p=0·0005) and faster palliation (median time to palliation 5·6 months [95% CI 3·7-9·2] vs 13·7 months [5·4-not estimable]; p=0·0018) of pain intensity than did prednisone only. Palliation of pain interference (134 of 223 [60·1%] vs 38 of 100 [38·0%], p=0·0002; median time to palliation of pain interference 1·0 months [95% CI 0·9-1·9] vs 3·7 months [2·7-not estimable], p=0·0004) and median duration of palliation of pain intensity (4·2 months [95% CI 3·0-4·9] vs 2·1 months [1·4-3·7]; p=0·0056) were significantly better with abiraterone acetate and prednisone than with prednisone only. In the overall population, median time to occurrence of first skeletal-related event was significantly longer with abiraterone acetate and prednisone than with prednisone only (25·0 months [95% CI 25·0-not estimable] vs 20·3 months [16·9-not estimable]; p=0·0001).. In patients with metastatic castration-resistant prostate cancer previously treated with docetaxel, abiraterone acetate and prednisone offer significant benefits compared with prednisone alone in terms of pain relief, delayed pain progression, and prevention of skeletal-related events.. Janssen Research & Development and Janssen Global Services.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Androstadienes; Bone Neoplasms; Double-Blind Method; Drug Therapy, Combination; Fractures, Spontaneous; Glucocorticoids; Humans; Male; Middle Aged; Pain Management; Pain Measurement; Palliative Care; Prednisone; Prostatic Neoplasms; Spinal Cord Compression; Steroid 17-alpha-Hydroxylase

Abiraterone is an oral inhibitor of CYP17, which is essential for androgen biosynthesis. This multicenter study assessed its efficacy in patients with castration-resistant prostate cancer (CRPC), without prior chemotherapy or CYP17-targeted therapy, and frequency of bone scans discordant with prostate-specific antigen (PSA) and clinical response.. Thirty-three patients received abiraterone acetate 1,000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for efficacy and safety. Bone scan flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist's report indicating "disease progression" in context of a 50% or more decline in PSA level, with scan improvement or stability 3 months later.. A 50% or more decline in PSA level at week 12 was confirmed in 22 of 33 (67%) patients. Declines in PSA level of 50% or more were seen in 26 of 33 (79%) patients. Undetectable PSA levels (≤0.1 ng/mL) occurred in 2 patients. Median time on therapy and time to PSA progression were 63 weeks and 16.3 months, respectively. Twenty-three patients were evaluable for bone scan flare. Progression was indicated in radiologist's report in 12 of 23 (52%), and 11 of 12 subsequently showed improvement or stability. As prospectively defined, bone scan flare was observed in 11 of 23 (48%) evaluable patients or 11 of 33 (33%) enrolled patients. Adverse events were typically grade 1/2 and consistent with prior published abiraterone reports.. Clinical responses to abiraterone plus prednisone were frequent and durable in men with metastatic CRPC. Further investigation is needed to clarify the confounding effect of bone scan flare on patient management and interpretation of results. Clin Cancer Res; 17(14); 4854-61. ©2011 AACR.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstadienes; Antineoplastic Agents, Hormonal; Bone and Bones; Bone Neoplasms; Humans; Male; Middle Aged; Neoplasm Metastasis; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Radiography; Treatment Outcome

Abiraterone acetate (AA) is an androgen biosynthesis inhibitor shown to prolong life in patients with castration-resistant prostate cancer (CRPC) already treated with chemotherapy. AA treatment results in dramatic declines in prostate-specific antigen (PSA) in some patients and no declines in others, suggesting the presence of molecular determinants of sensitivity in tumors.. To study the role of transmembrane protease, serine 2 (TMPRSS2)-v-ets erythroblastosis virus E26 oncogene homolog (ERG) fusion, an androgen-dependent growth factor, in circulating tumor cells (CTCs) as a biomarker of sensitivity to AA.. The predictive value of TMPRSS2-ERG status was studied in 41 of 48 men with postchemotherapy-treated CRPC enrolled in sequential phase 2 AA trials.. Patients received AA 1000 mg daily and continuously.. TMPRSS2-ERG status was characterized by a sensitive, analytically valid reverse transcription polymerase chain reaction assay in CTCs enriched from ethylene-diaminetetraacetic acid anticoagulated blood obtained prior to AA treatment. Outcomes were measured by PSA Working Group 1 criteria.. Standard procedures for specimen acquisition, processing, and testing using the validated TMPRSS2-ERG assay on a multiplex platform gave intra-assay and interassay coefficients of variation <7%. TMPRSS2-ERG fusion was present in 15 of 41 patients (37%), who had a median baseline CTC count of 17 (interquartile range: 7-103 cells per 7.5 ml). A PSA decline ≥50% was observed in 7 of 15 patients (47%) with the fusion and in 10 of 26 patients (38%) without the fusion. Although limited by the low number of patients, a posttherapy CTC count of less than five per 7.5 ml was prognostic for longer survival relative to a CTC count five or more. TMPRSS2-ERG status did not predict a decline in PSA or other clinical outcomes.. Molecular profiles of CTCs with an analytically valid assay identified the presence of the prostate cancer-specific TMPRSS2-ERG fusion but did not predict for response to AA treatment. This finding demonstrates the role of CTCs as surrogate tissue that can be obtained in a routine practice setting.. ClinicalTrials.gov: NCT00474383 (COU-AA-003), NCT00485303 (COU-AA-004).

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Chemotherapy, Adjuvant; Enzyme Inhibitors; Genetic Markers; Humans; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Male; Neoplastic Cells, Circulating; New York City; Oncogene Proteins, Fusion; Orchiectomy; Patient Selection; Predictive Value of Tests; Prostatectomy; Prostatic Neoplasms; Radiotherapy, Adjuvant; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Steroid 17-alpha-Hydroxylase; Survival Rate; Time Factors; Treatment Outcome

A series of three dose escalating studies were conducted to investigate the ability of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate, to cause maximum suppression of testosterone synthesis when delivered to castrate and noncastrate males with prostate cancer. Study A was a single dose study in castrate males. Study B was a single dose study in noncastrate males and study C was a multiple dose study in noncastrate males. The drug was given orally in a once-daily dose and blood samples taken to assess pharmacokinetic (PK) parameters and hormone levels in all patients. The study drug was well tolerated with some variability in PKs. Suppression of testosterone levels to <0.14 nmol l(-1) was seen in four out of six castrate males treated with a single dose of 500 mg. At 800 mg given days 1-12 in noncastrate males, target suppression was achieved in three out of three patients, but a two- to three-fold increase of Luteinising Hormone (LH) levels in two out of three patients overcame suppression within 3 days. All patients in the multiple dose study developed an abnormal response to a short Synacthen test by day 11, although baseline cortisol levels remained normal. This is the first report of the use of a specific 17alpha-hydroxylase/(17,20)-lyase inhibitor in humans. Repeated treatment of men with intact gonadal function with abiraterone acetate at a dose of 800 mg can successfully suppress testosterone levels to the castrate range. However, this level of suppression may not be sustained in all patients due to compensatory hypersecretion of LH. The enhanced testosterone suppression achieved in castrate men merits further clinical study as a second-line hormonal treatment for prostate cancer. Adrenocortical suppression may necessitate concomitant administration of replacement glucocorticoid.

Topics: Abiraterone Acetate; Administration, Oral; Aged; Aged, 80 and over; Androstadienes; Castration; Enzyme Inhibitors; Humans; Luteinizing Hormone; Male; Middle Aged; Prostatic Neoplasms; Testosterone

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

To describe the changes in systemic treatments (ST) of synchronous metastatic hormone-sensitive prostate cancer (mHSPC) patients in a "real-world" setting and to explore reasons why contemporary standard of care (SOC) was not administrated to the patient.. Since 2014, we prospectively register mHSPCpatients. Patients were grouped in 4 time periods: group 1 (Time period 1, January 2014-July 2015), group 2 after introduction of docetaxel (Time period 2, August 2015-July 2017), group 3 after introduction of abiraterone acetate (Time period 3, August 2017-February 2018) and group 4 after introduction of apalutamide (Time period 4, March 2018-October 2021). For every time period, we evaluated the initiated additional ST. In case patients received treatment that differed from contemporary SOC according to guidelines, reasons for this difference were explored.. In total, 243 patients were included. A progressive decline in ADT monotherapy from 85% to 29% over time was observed. The proportion of patients receiving additional STs increased from 34% to 59%. Forty percent of patients were not treated according to contemporary SOC, but this percentage varied strongly per time period (10%, 67%, 53%, and 32% from time period 1 to time period 4 respectively). Reasons for these variations were heterogenous and varied across the 4 time periods. Patients being unfit for treatment and treating physicians failing to consider additional STs were the most prevalent reasons. The proportion of patients unfit for additional ST decreased from 18% to 4% over time.. Use of ADT monotherapy declined gradually after the introduction of additional systemic treatments. The proportion of patients unfit for additional ST declined as more treatments became available. Although compliance to SOC increased over time, these real-world data show that adherence to clinical practice guidelines remains suboptimal. Efforts should be made by clinicians to increase the adherence to practice guidelines.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Hormones; Humans; Male; Prostatic Neoplasms; Treatment Outcome

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

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

Topics: Abiraterone Acetate; Humans; Indazoles; Male; Piperidines; Prostatic Neoplasms

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

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

Abiraterone acetate + prednisone (AAP) and docetaxel have proven their efficacy in the treatment of patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) in clinical trials. However, real-world data are scarce. The goal of this study is to evaluate real-world data on the efficacy and safety of these therapies in mHSPC patients.. Records of 93 patients from 21 different centres were retrospectively reviewed. Primary and secondary endpoints were radiographic and PSA progression-free survival (RPFS - PSA-PFS) and cancer specific and overall survival (CSS - OS), respectively. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Differences in oncological outcome and AEs were evaluated between three treatment groups: ADT only (N=26) - ADT + AAP (N=48) - ADT + docetaxel (N=19). Survival analysis was performed using Kaplan-Meier statistics.. Median RPFS was 13 months (95% confidence interval [CI]: 9-17) for ADT only, 21 months (95% CI: 19-23) for ADT + AAP and 12 months (95% CI: 11-14) for ADT + docetaxel (p = 0.004). The 1-year PSA-PFS, CSS and OS were 73.5%, 90.7% and 88.7%, respectively, with no significant differences between the three groups. Adverse events of grade 3 or higher were not observed more frequently.. Retrospective real-world data show a significantly longer RPFS for mHSPC patients treated with ADT + AAP compared to ADT only or ADT + docetaxel at short-term follow-up. This can aid in counselling of mHSPC patients in daily clinical practice.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Belgium; Data Analysis; Docetaxel; Hormones; Humans; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Treatment Outcome

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

P2Y receptors belong to the large superfamily of G-protein-coupled receptors and play a crucial role in cell death and survival. P2Y1 receptor has been identified as a marker for prostate cancer (PCa). A previously unveiled selective P2Y1 receptor agonist, the indoline-derived HIC (1-(1-((2-hydroxy-5-nitrophenyl)(4-hydroxyphenyl)methyl)indoline-4-carbonitrile), induces a series of molecular and biological responses in PCa cells PC3 and DU145, but minimal toxicity to normal cells. Here, we evaluated the combinatorial effect of HIC with abiraterone acetate (AA) targeted on androgen receptor (AR) on the inhibition of PCa cells. Here, the presence of HIC and AA significantly inhibited cell proliferation of PC3 and DU145 cells with time-dependent manner as a synerfistic combination. Moreover, it was also shown that the anticancer and antimetastasis effects of the combinratorial drugs were noticed through a decrease in colony-forming ability, cell migration, and cell invasion. In addition, the HIC + AA induced apoptotic population of PCa cells as well as cell cycle arrest in G1 progression phase. In summary, these studies show that the combination of P2Y1 receptor agonist, HIC and AR inhibitor, AA, effectively improved the antitumor activity of each drug. Thus, the combinatorial model of HIC and AA should be a novel and promising therapeutic strategy for treating prostate cancer.

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Indoles; Male; Prostatic Neoplasms; Purinergic P2Y Receptor Agonists; Receptors, Androgen; Receptors, Purinergic P2Y1

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

Topics: Abiraterone Acetate; Humans; Male; Progesterone; Prostatic Neoplasms; Pyrazoles; Receptors, Androgen

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

Topics: Abiraterone Acetate; Hormones; Humans; Male; Prostatic Neoplasms; Pyrazoles

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

Topics: Abiraterone Acetate; Humans; Male; Prostate; Prostatic Neoplasms

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

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

Two pivotal randomized controlled trials (RCTs) demonstrate that abiraterone acetate + prednisone (AAP) combined with androgen deprivation therapy (ADT) significantly extends the survival of men with metastatic hormone-sensitive prostate cancer (mHSPC) compared with ADT alone. Their subgroup analyses indicate that the survival benefit is significant for younger men but not older men. We aimed to assess whether publication of the RCTs was associated with differential real-world AAP utilization by age groups.. Using TriNetX electronic medical records data collected from 43 healthcare organizations across the United States, we performed a difference-in-differences event study among men with newly diagnosed mHSPC observed from June 2014 to June 2019. Eligible subjects were identified based on a comprehensive published algorithm. We analyzed the change in utilization rate of AAP before versus after publication of the RCTs among men aged <70 years versus ≥70 years, adjusting for demographic factors and clinical conditions.. Our study included 6,888 men with newly diagnosed mHSPC with 12,738 observations, of whom 46% were aged <70 years. The prepublication trends of AAP utilization were similar between the age groups, whereas publication of the RCTs was associated with a 3.5% higher adjusted uptake rate of AAP among younger men (95% CI, 1.2%-5.8%) relative to older men. This estimate reflects an uptake rate nearly 3 times higher than would have been expected had younger men followed the same utilization trends as older men. The estimates remained consistent throughout the postpublication period.. Our study suggests that publication of the RCTs was associated with faster uptake of AAP among younger versus older men with newly diagnosed mHSPC, despite the absence of clinical guidance for differential treatment selection. This finding highlights the importance of confirmatory studies among older men, considering the uncertainties of subgroup analyses in RCTs.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Androgens; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prednisone; Prostatic Neoplasms

The treatment landscape for men with metastatic hormone-naïve prostate cancer (mHNPC) has dramatically changed with the approval of next-generation anti-androgen drugs. We compared the treatment efficacy of abiraterone with that of combined androgen blockade (CAB) therapy and androgen deprivation therapy (ADT) alone in men with high-risk mHNPC.. In total, 146 Japanese men with high-risk mHNPC were retrospectively analyzed. As initial hormonal therapy, 30, 83, and 33 men were treated with ADT plus abiraterone (ABI group), ADT plus bicalutamide (CAB group), and ADT alone (ADT group), respectively. Treatment efficacy was compared using time to castration resistance (TTCR) and prostate-specific antigen (PSA) response among the groups. Propensity score matching analysis was also performed to adjust for baseline differences.. The median (95% confidence interval [CI]) TTCR in the ABI, CAB, and ADT groups were not reached, 10.7 (7.6-13.8) months and 11.0 (7.9-12.4) months, respectively, and it was significantly longer in the ABI group than in the other groups (p = 0.0012, p = 0.0008). In propensity score matching analysis, the median TTCR was also significantly longer in the ABI group than in the other groups (hazard ratio [HR], 0.47; 95% CI, 0.22-0.98; p = 0.010; HR, 0.32; 95% CI, 0.12-0.85; p = 0.004). The number of men who achieved PSA levels ≤0.2 ng/mL after propensity score matching were significantly higher in the ABI group than in the other groups.. Our results provide important evidence regarding the superiority of abiraterone over CAB therapy and ADT alone for initial treatment for men with newly diagnosed mHNPC.

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

There is a discrepancy in the efficacy of abiraterone acetate for overall survival (OS) in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). This study aimed to identify predictive factors for the efficacy of abiraterone acetate for OS in high-risk mHSPC patients by analyzing them over a longer observation period.. Five hundred high-risk mHSPC patients were retrospectively identified at our hospital and affiliated hospitals in the Kindai Oncology Study Group and Kyoto Prefectural University of Medicine Oncology Study Group between December 2013 and March 2022. Two hundred patients were treated with abiraterone acetate (1000 mg/day) plus prednisolone (5 mg/day) combined with androgen deprivation therapy (ADT). A total of 300 patients were treated with bicalutamide (80 mg/day) in combination with ADT.. OS was not significantly different between the two treatments in the overall cohort (p = 0.1643). In the subgroup without Gleason pattern 5 at the primary lesion, OS was significantly better in patients treated with abiraterone acetate than in those treated with bicalutamide (p = 0.0192). In the subgroup with Gleason pattern 5 at the primary lesion, no significant difference was found between the two treatments (p = 0.1799). Univariate and multivariate analyses in the subgroup without Gleason pattern 5 at the primary lesion suggested that abiraterone therapy may be an important and independent predictor of OS in high-risk mHSPC patients.. The presence of Gleason pattern 5 at the primary lesion may be a predictor for high-risk mHSPC patients who could benefit from abiraterone acetate treatment.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Hormones; Humans; Male; Prostatic Neoplasms; Retrospective Studies; Treatment Outcome

Topics: Abiraterone Acetate; Administration, Oral; Allergens; Antineoplastic Agents; Drug Hypersensitivity; Exanthema; Humans; Hypersensitivity, Delayed; Immunization; Male; Methylprednisolone; Middle Aged; Nausea; Prostatic Neoplasms; Vomiting

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

Abiraterone acetate (AA), an inhibitor of cytochrome P450 17alpha-hydroxylase/17, 20 lyase, is an FDA-approved drug for advanced prostate cancer. However, not all patients respond to AA, and AA resistance ultimately develops in patients who initially respond. We aimed to identify AA resistance mechanisms in prostate cancer cells.. We established several AA-resistant cell lines and performed a comprehensive study on mechanisms involved in AA resistance development. RNA sequencing and phospho-kinase array screenings were performed to discover that the cAMP-response element CRE binding protein 1 (CREB1) was a critical molecule in AA resistance development.. The drug-resistant cell lines are phenotypically stable without drug selection, and exhibit permanent global gene expression changes. The phosphorylated CREB1 (pCREB1) is increased in AA-resistant cell lines and is critical in controlling global gene expression. Upregulation of pCREB1 desensitized prostate cancer cells to AA, while blocking CREB1 phosphorylation resensitized AA-resistant cells to AA. AA treatment increases intracellular cyclic AMP (cAMP) levels, induces kinases activity, and leads to the phosphorylation of CREB1, which may subsequently augment the essential role of the CBP/p300 complex in AA-resistant cells because AA-resistant cells exhibit a relatively higher sensitivity to CBP/p300 inhibitors. Further pharmacokinetics studies demonstrated that AA significantly synergizes with CBP/p300 inhibitors in limiting the growth of prostate cancer cells.. Our studies suggest that AA treatment upregulates pCREB1, which enhances CBP/p300 activity, leading to global gene expression alterations, subsequently resulting in drug resistance development. Combining AA with therapies targeting resistance mechanisms may provide a more effective treatment strategy.

Topics: Abiraterone Acetate; Cell Line, Tumor; Cyclic AMP Response Element-Binding Protein; Drug Resistance, Neoplasm; Humans; Male; p300-CBP Transcription Factors; Phosphorylation; Prostatic Neoplasms

Localized prostate cancers (PCs) may resist neoadjuvant androgen receptor (AR)-targeted therapies as a result of persistent intraprostatic androgens arising through upregulation of steroidogenic enzymes. Therefore, we sought to evaluate clinical effects of neoadjuvant indomethacin (Indo), which inhibits the steroidogenic enzyme AKR1C3, in addition to combinatorial anti-androgen blockade, in men with high-risk PC undergoing radical prostatectomy (RP).. This was an open label, single-site, Phase II neoadjuvant trial in men with high to very-high-risk PC, as defined by NCCN criteria. Patients received 12 weeks of apalutamide (Apa), abiraterone acetate plus prednisone (AAP), degarelix, and Indo followed by RP. Primary objective was to determine the pathologic complete response (pCR) rate. Secondary objectives included minimal residual disease (MRD) rate, defined as residual cancer burden (RCB) ≤ 0.25cm. Twenty patients were evaluable for the primary endpoint. Baseline median prostate-specific antigen (PSA) was 10.1 ng/ml, 4 (20%) patients had Gleason grade group (GG) 4 disease and 16 had GG 5 disease. At RP, 1 (5%) patient had pCR and 6 (30%) had MRD. Therapy was well tolerated. Over a median follow-up of 23.8 months, 1 of 7 (14%) men with pathologic response and 6 of 13 (46%) men without pathologic response had a PSA relapse. There was no association between prostate hormone levels or HSD3B1 genotype with pathologic response.. In men with high-risk PC, pCR rates remained low even with combinatorial AR-directed therapy, although rates of MRD were higher. Ongoing follow-up is needed to validate clinical outcomes of men who achieve MRD.

Topics: Abiraterone Acetate; Aged; Aldo-Keto Reductase Family 1 Member C3; Androgen Antagonists; Antineoplastic Agents, Hormonal; Humans; Male; Middle Aged; Neoadjuvant Therapy; Prostatectomy; Prostatic Neoplasms; Thiohydantoins; Treatment Outcome

The optimal therapeutic strategies for patients with metastatic hormone-sensitive prostate cancer (mHSPC) followed by metastatic castrate-resistant prostate cancer (mCRPC), in terms of cost and effectiveness, remains unknown. This study aims to compare the cost-effectiveness of various potential strategies, from the start of first-line treatment in mHSPC to the death of the patients.. Two Markov decision-analysis models were developed, one for cohort A "asymptomatic/mildly symptomatic patients in mCRPC", and one for cohort B "symptomatic patients in mCRPC". Each strategy reflects daily practice for mHSPC until progression in mCRPC from the start of first treatment regimen with either docetaxel or abiraterone acetate plus prednisone (AA) in mHSPC to the death of the patient. The cost-effectiveness analysis was performed from the French public health care system perspective. Only direct medical costs were included. Survival data were extracted from results of published randomized clinical trials.. For cohort A, docetaxel followed by AA is the most cost-effective therapeutic strategy (€96,925 for 4.24 life-years). For cohort B, docetaxel followed by docetaxel is the most cost-effective therapeutic strategy (€81,463 for 4.05 life-years). Sensitivity analyses confirmed the robustness of our results except for a price reduction of 70% for AA or enzalutamide.. Our approach is innovative to the extent that our analysis considers various potential strategies for metastatic prostate cancer (mPC). Our economic evaluation suggests that a price reduction of AA or enzalutamide impacts on the results. This approach must continue, including new drugs for patients with mPC.

Topics: Abiraterone Acetate; Cost-Benefit Analysis; Docetaxel; Hormones; Humans; Male; Markov Chains; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Therapies, Investigational; Treatment Outcome

The objective of this study was to compare the efficacy of abiraterone acetate with that of bicalutamide in combination with gonadotropin-releasing hormone (GnRH) antagonist treatment for patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). A total of 149 patients with mHSPC who underwent treatment at our hospital and affiliated hospitals between December 2013 and July 2020 were retrospectively identified. Fifty patients were administered abiraterone acetate (1000 mg/day) plus prednisolone (5 mg/day) with a GnRH antagonist (degarelix) (group A), and 99 patients were administered bicalutamide (80 mg/day) with a GnRH antagonist (group B). The prostate-specific antigen (PSA) progression-free survival (PSA-PFS) was significantly longer in group A than in group B. Abiraterone acetate therapy and Gleason score were significant independent factors of PSA-PFS. Using propensity score matching, 56 matched patients were obtained. The PSA-PFS (p < 0.001) and overall survival (OS) (p = 0.0071) of patients with high-risk mHSPC were significantly longer in group A of matched patients. Abiraterone acetate therapy and Gleason score were significant independent factors for PSA-PFS in matched patients. The PSA-PFS and OS of patients treated with abiraterone acetate in combination with a GnRH antagonist were significantly better than those treated with bicalutamide.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Combined Chemotherapy Protocols; Drug Therapy, Combination; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Neoplasm Grading; Nitriles; Oligopeptides; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Tosyl Compounds; Treatment Outcome

Anemia has been a known prognostic factor in metastatic hormone-sensitive prostate cancer (mHSPC). We therefore examined the effect of anemia on the efficacy of upfront abiraterone acetate (ABI) in patients with mHSPC.. We retrospectively evaluated 66 mHSPC patients with high tumor burden who received upfront ABI between 2018 and 2020 (upfront ABI group). We divided these patients into two groups: the anemia-ABI group (hemoglobin < 13.0 g/dL, n = 20) and the non-anemia-ABI group (n = 46). The primary objective was to examine the impact of anemia on the progression-free survival (PFS; clinical progression or PC death before development of castration resistant PC) of patients in the upfront ABI group. Secondary objectives included an evaluation of the prognostic significance of upfront ABI and a comparison with a historical cohort (131 mHSPC patients with high tumor burden who received androgen deprivation therapy (ADT/complete androgen blockade [CAB] group) between 2014 and 2019).. We found that the anemia-ABI group had a significantly shorter PFS than the non-anemia-ABI group. A multivariate Cox regression analysis showed that anemia was an independent prognostic factor of PFS in the upfront ABI group (hazard ratio, 4.66; P = 0.014). Patients in the non-anemia-ABI group were determined to have a significantly longer PFS than those in the non-anemia-ADT/CAB group (n = 68) (P < 0.001). However, no significant difference was observed in the PFS between patients in the anemia-ABI and the anemia-ADT/CAB groups (n = 63). Multivariate analyses showed that upfront ABI could significantly prolong the PFS of patients without anemia (hazard ratio, 0.17; P < 0.001), whereas ABI did not prolong the PFS of patients with anemia.. Pretreatment anemia was a prognostic factor among mHSPC patients who received upfront ABI. Although the upfront ABI significantly improved the PFS of mHSPC patients without anemia, its efficacy in patients with anemia might be limited.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Anemia; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Hemoglobins; Humans; Male; Prognosis; Progression-Free Survival; Prostatic Neoplasms; Retrospective Studies; Steroid 17-alpha-Hydroxylase; Steroid Synthesis Inhibitors

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents; Benzamides; Disease Progression; Humans; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms; Steroid Synthesis Inhibitors; Thiohydantoins

Elderly patients (≥65yr) with advanced prostate cancer and cardiovascular disease (CVD) conditions are often excluded from clinical trials of abiraterone acetate (AA) or enzalutamide (ENZ). Consequently, little is known about the effects of these medications on these vulnerable patients.. To assess the short-term outcomes of AA and ENZ in patients with pre-existing CVDs.. A population-based retrospective study. The Surveillance, Epidemiology, and End Results-Medicare-linked database was used to identify prostate cancer patients using AA or ENZ.. The primary endpoint was 6-mo all-cause mortality, analyzed using modified Poisson regression modeling of relative risk (RR) adjusted for confounders and comorbidities.. Among eligible patients (2845 with AA and 1031 with ENZ), 67% had at least one pre-existing CVD. Compared with those without pre-existing CVDs, having one to two pre-existing CVDs was associated with 16% higher 6-mo mortality (RR=1.16, 95% confidence interval [CI]: 1.00-1.36), and the risk increased further among those having three or more CVDs (RR=1.56, 95% CI: 1.29-1.88). Most of the differences in survival of patients with pre-existing CVD condition occurred within the first 6mo of treatment.. After treatment with AA or ENZ, elderly prostate cancer patients with pre-existing CVDs experienced higher short-term mortality than otherwise similar patients without CVDs. Mortality associated with CVDs did not depend on having received AA versus ENZ.. Patients with pre-existing cardiovascular diseases (CVDs) experienced higher short-term mortality after abiraterone acetate or enzalutamide than those without pre-existing CVDs. It is recommended that a multidisciplinary team, including a cardiologist, evaluate patients having pre-existing CVDs in the process of making treatment decisions and monitoring potential side effects.

Topics: Abiraterone Acetate; Administration, Oral; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Benzamides; Cardiovascular Diseases; Hospitalization; Humans; Male; Neoplasm Staging; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Retrospective Studies; Risk Assessment; Time Factors; Treatment Outcome

The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens.. To test the hypothesis that AA therapy decreases 11-oxygenated androgens.. Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively.. We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively.. In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation (<0.1-0.3 nmol/L), equivalent to 64-94% reductions from baseline. In 21OHD patients, administration of AA (100-250 mg/day for 6 days) reduced all 11-oxygenated androgens by on average 56-77% from baseline.. We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.

Topics: Abiraterone Acetate; Adrenal Hyperplasia, Congenital; Adult; Androgens; Androstenes; Chromatography, Liquid; Cytochrome P-450 Enzyme Inhibitors; Drug Therapy, Combination; Humans; Male; Prednisone; Prostatic Neoplasms; Tandem Mass Spectrometry; Testosterone

It is projected that approximately 50,000 new cases of prostate cancer will be diagnosed in 2020 in India. Survival has improved because of the development of effective drugs such as abiraterone acetate, but universal accessibility to treatment is not always possible because of cost constraints in lower- and middle-income countries. Recently, the National Comprehensive Cancer Network (NCCN) has included low-dose abiraterone (250 mg/day) with food as an alternative treatment option to full-dose abiraterone (1,000 mg/day) fasting.. The Science and Cost Cancer Consortium conducted a survey to evaluate the use of abiraterone in India and the opinions of medical oncologists about using low-dose treatment. Modeling was used to estimate potential financial benefits to individual patients and to estimate overall costs of health care in India if low-dose abiraterone is prescribed.. Of 251 Indian medical oncologists who were invited to participate in the survey, 125 provided their e-mail address and received the survey; 118 responded (47% of the total). Of these, 25% were not aware of the recent NCCN recommendation, 55% were already prescribing low-dose abiraterone when resources were limited, 7% had already changed their practice, and 29% agreed to switch to a universal practice of using low-dose abiraterone with food; 9% of practitioners would not use low-dose abiraterone. Estimated mean per patient savings was US$3,640, with annual savings of US$182 million in India.. Use of lower-dose abiraterone would increase access to treatment in India and globally and lead to large cost savings.

Topics: Abiraterone Acetate; Androstenes; Humans; India; Male; Prostatic Neoplasms

Topics: Abiraterone Acetate; Androstenes; Humans; Male; Prostatic Neoplasms

Topics: Abiraterone Acetate; Antineoplastic Agents; Benzamides; Cell-Free Nucleic Acids; Epigenome; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms

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

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

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; Absorptiometry, Photon; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Docetaxel; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prednisolone; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Zoledronic Acid

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

Various treatment options are available for metastatic hormone-sensitive prostate cancer. This study aimed to quantify how men with prostate cancer in the United Kingdom (UK), Germany, and Spain perceive the risks and benefits of hypothetical abiraterone acetate plus prednisone treatment and docetaxel-based chemotherapy treatment options.. A targeted literature review, exploratory interviews with prostate cancer patients and oncologists, and pre-test interviews were used to develop a discrete choice experiments (DCE). The final DCE included 32 choice sets, selected using a main-effects orthogonal design, divided into two survey blocks. Paired profiles presented hypothetical treatments for prostate cancer through six attributes that could be presented at two or four levels each. Preference estimates were estimated using a conditional logit regression model. Preference results were stratified by cancer stage.. A total of 152 participants (mean age 69 years) completed the DCE in the UK, Germany, and Spain. Treatment effectiveness was the main concern for the patients (difference in preference estimates between 8 and 32 months 1.443). Participants wanted to avoid pain that was not well controlled (preference dummy coding estimate - 1.157). Participants valued a change from an oral medication to an intravenous treatment (change in preference estimate - 0.416) more negatively than a change from a 1% to a 5% risk of infection (change in preference estimate - 0.313).. This study shows that treatment effectiveness and pain control were the most important attributes for patients with prostate cancer. These two attributes influenced more than 50% of their decision-making in this study. The risk of fatigue and mode of administration were least prioritised by patients. This study highlights the relative importance that Spanish, German, and British patients place on various aspects of treatment options for prostate cancer. Understanding patient preference and taking them into consideration shall help physicians when developing their treatment strategies for their patients.. Janssen.

Topics: Abiraterone Acetate; Adult; Aged; Antineoplastic Agents; Decision Making; Docetaxel; Germany; Humans; Male; Middle Aged; Neoplasm Staging; Patient Preference; Prostatic Neoplasms; Severity of Illness Index; Spain; Surveys and Questionnaires; Treatment Outcome; United Kingdom

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

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

To study the capability of the CYP17A1 inhibitor abiraterone acetate (AER) to antagonize the androgen receptor (AR) activation in human prostate cancer (PCa) cell lines. T877A-AR-LNCaP, WT-AR-VCaP, AR-negative DU145, and PC3 PCa cell lines were used by MTT and cell count to study the ability of AER and enzalutamide (ENZ) to modify cell viability. The role of ARs in LNCaP was demonstrated through a gene-silencing experiment. The mechanism of AER cytotoxicity in LNCaP cells was studied, as well as the ability of AER to modulate AR gene expression. The in silico docking approach was applied to study the interaction of AER and ENZ with T877A-AR. Through high-performance liquid chromatography, the production of the AER main metabolite Δ4A was studied. AER bound AR in an almost identical manner to that of dihydrotestosterone (DHT). The higher binding energy for AER in T877A-AR could explain the major cytotoxic effect observed in LNCaP cells. The capability of LNCaP cells to synthesize Δ4A could mediate, at least in part, this effect. AER cytotoxicity in LNCaP cells was mainly due to the activation of apoptosis. Further, AER induced modification of AR target gene expression, suggesting a direct effect on AR activity. AER-induced cytotoxicity on PCa cell lines seemed to be mediated by binding with AR. The higher affinity of AER for T877A-AR may suggest a potential role of AER in the management of CRPC carrying this mutation; however, T877A-AR expressing CRPC patients developed AER resistance, probably due to the increase of progesterone.

Topics: Abiraterone Acetate; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Survival; Dihydrotestosterone; Humans; Male; Molecular Docking Simulation; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen

Topics: Abiraterone Acetate; Castration; Double-Blind Method; Humans; Male; Prednisone; Prostatic Neoplasms; Survival Analysis

Topics: Abiraterone Acetate; Castration; Humans; Male; Prognosis; Prostatic Neoplasms

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

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

Topics: Abiraterone Acetate; Antineoplastic Agents; Artifacts; Cohort Studies; Cytochrome P-450 Enzyme Inhibitors; Humans; Immunoassay; Limit of Detection; Male; Mass Spectrometry; Prostatic Neoplasms; Testosterone

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

Use of drug combinations that target different pathways involved in the development and progression of prostate cancer (PCa) has emerged as an alternative to overcome the resistance caused by drug monotherapies. The antiandrogen abiraterone acetate and the PI3K/Akt inhibitor NVP-BEZ235 (BEZ235) may be suitable options for the prevention of drug resistance and the inhibition of PCa progression. The aim of the present study was to evaluate whether abiraterone acetate and BEZ235 achieve superior therapeutic effects to either drug administered as monotherapy, in the early stages of PCa in an androgen-dependent system. Our study showed that each drug might impair tumor growth by reducing proliferation and increasing cell death when administered as monotherapy. However, tumor growth continued to progress with each drug monotherapy and some important side effects were related to BEZ. Conversely, when used in combination, the drugs impaired the inflammatory response, decreased hyperplastic lesions, and blocked tumor progression from premalignant to a malignant stage. Our data showed that the strategy to block the androgenic and PI3K/AKT/mTOR pathway is an effective therapeutic option and should be investigated including distinct PI3K pathway inhibitors.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinogenesis; Disease Models, Animal; Drug Synergism; Humans; Imidazoles; Male; Phosphoinositide-3 Kinase Inhibitors; Prostatic Neoplasms; Protein Kinase Inhibitors; Quinolines; Rats; Rats, Inbred F344; Signal Transduction; Tumor Cells, Cultured

Topics: Abiraterone Acetate; Androgen Antagonists; Holidays; Humans; Male; Patient Reported Outcome Measures; Prednisone; Prostatic Neoplasms

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

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; European Union; Fractures, Bone; Humans; Male; Prednisone; Prostatic Neoplasms; Radioisotopes; Radium; Survival Rate

Topics: Abiraterone Acetate; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cell-Free Nucleic Acids; Epigenesis, Genetic; Humans; Male; Prognosis; Prostatic Neoplasms; Treatment Outcome

Treatment landscape in prostate cancer has changed dramatically with the emergence of new medicines in the past few years. The traditional survival partition model (SPM) cannot accurately predict long-term clinical outcomes because it is limited by its ability to capture the key consequences associated with this changing treatment paradigm. The objective of this study was to introduce and validate a discrete-event simulation (DES) model for prostate cancer.. A DES model was developed to simulate overall survival (OS) and other clinical outcomes based on patient characteristics, treatment received, and disease progression history. We tested and validated this model with clinical trial data from the abiraterone acetate phase III trial (COU-AA-302). The model was constructed with interim data (55% death) and validated with the final data (96% death). Predicted OS values were also compared with those from the SPM.. The DES model's predicted time to chemotherapy and OS are highly consistent with the final observed data. The model accurately predicts the OS hazard ratio from the final data cut (predicted: 0.74; 95% confidence interval [CI] 0.64-0.85 and final actual: 0.74; 95% CI 0.6-0.88). The log-rank test to compare the observed and predicted OS curves indicated no statistically significant difference between observed and predicted curves. However, the predictions from the SPM based on interim data deviated significantly from the final data.. Our study showed that a DES model with properly developed risk equations presents considerable improvements to the more traditional SPM in flexibility and predictive accuracy of long-term outcomes.

Topics: Abiraterone Acetate; Antineoplastic Agents; Clinical Decision-Making; Clinical Trials, Phase III as Topic; Computer Simulation; Decision Support Techniques; Disease Progression; Disease-Free Survival; Humans; Kaplan-Meier Estimate; Male; Models, Theoretical; Patient Selection; Process Assessment, Health Care; Prostatic Neoplasms; Reproducibility of Results; Steroid Synthesis Inhibitors; Time Factors; Treatment Outcome

Topics: Abiraterone Acetate; Clinical Trials, Phase III as Topic; Evidence-Based Practice; France; Humans; Male; Medical Oncology; Neoplasm Metastasis; Practice Patterns, Physicians'; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Societies, Medical; Survival Analysis; Therapies, Investigational

Topics: Abiraterone Acetate; Antineoplastic Agents; Clinical Decision-Making; Docetaxel; Humans; Male; Neoplasm Metastasis; Patient Selection; Prostatic Neoplasms; Risk Factors; Steroid Synthesis Inhibitors; Taxoids; Time Factors; Treatment Outcome

Topics: Abiraterone Acetate; Antineoplastic Agents; Clinical Decision-Making; Docetaxel; Humans; Male; Neoplasm Metastasis; Patient Selection; Prostatic Neoplasms; Risk Factors; Steroid Synthesis Inhibitors; Taxoids; Time Factors; Treatment Outcome

Over the last decade, significant advances have been made in the development of therapies for patients with metastatic castration-resistant prostate cancer. Abiraterone and enzalutamide were approved as treatments based on data supporting improved overall survival compared to placebo. Radium-223 became the first approved radiopharmaceutical which decreased skeletal-related events, palliated pain, and showed improved overall survival in symptomatic patients with castration-resistant prostate cancer and bone metastasis only.. We present the case of an eighty-two year old man with metastatic castration-resistant prostate cancer who was treated with sequential therapy (abiraterone - enzalutamide - radium 223). The sequencing and treatment used for our patient was viable because of his clinical characteristics, which have allowed for longer survival time with an acceptable quality of life. These actions must be agreed on by the Multidisciplinary Tumour Board, in order to optimize the use of available courses of treatment.. The treatment of these patients is changing rapidly, but many questions remain regarding the optimal sequencing of the available drugs. Sequential or concomitant use of the next generation hormonal agents - abiraterone and enzalutamide - cannot currently be recommended. Data regarding the safety of concomitant abiraterone, enzalutamide or denosumab with radium-223 is reassuring and timely. However, we cannot advocate the general use of combined radium-223 therapy at this time, irrespective of prior therapy.. A better understanding of active mechanisms, the genetic characteristics of each metastatic castration-resistant prostate cancer and the development of new prognostic and predictive biomarkers will help determine sequencing or different combination treatments for each individual patient.

Topics: Abiraterone Acetate; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers, Tumor; Bone Neoplasms; Combined Modality Therapy; Humans; Male; Neoplasm Metastasis; Neoplasm Staging; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Radium; Tomography, X-Ray Computed; Treatment Outcome

Prostate cancer is the most frequently diagnosed malignancy and the leading cause of cancer related death in men. First line therapy for disseminated disease relies on androgen deprivation, leveraging the addiction of these tumors on androgens for both growth and survival. Treatment typically involves antagonizing the androgen receptor (AR) or blocking the synthesis of androgens. Recurrence is common and within 2-3years patients develop castration resistant tumors that become unresponsive to AR-axis targeted therapies. In order to provide a more effective treatment, we are utilizing an approach that targets a key scaffolding protein, Sigma1 (also known as sigma-1 receptor), a unique 26-kilodalton integral membrane protein that is critical in stabilizing the AR. Herein we report on a new series of Sigma1 compounds for lead optimization derived from a hybrid pharmacophore approach.

Topics: Animals; ERG1 Potassium Channel; Guanidines; Half-Life; Humans; Male; Mice; Microsomes, Liver; Neoplasm Staging; Prostatic Neoplasms; Protein Binding; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship

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

Two papers published recently in the New England Journal of Medicine describe the utility of abiraterone acetate, an androgen biosynthesis inhibitor, in the early treatment of metastatic prostate cancer. In addition to establishing a new standard of care, these two articles pose a number of important questions for future investigation.

Topics: Abiraterone Acetate; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase

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

Topics: Abiraterone Acetate; Androstenes; Androstenols; Humans; Male; Prostatic Neoplasms; Treatment Outcome

A 77-year-old man with castration-resistant prostate cancer (CRPC) received abiraterone acetate in October 2014. He visited our outpatient clinic because of general malaise and anorexia 27 days after starting abiraterone acetate. The lab test showed hepatic dysfunction (aspartate transaminase, AST 440 U/l, alanine transaminase, ALT 420 U/l) and the elevation of liver enzymes continued on the next day even after stopping abiraterone acetate. Three days later, he was hospitalized due to severe elevation of liver enzymes (AST 1,171 U/l, ALT 1,487 U/l) , and the decreased prothrombin activity (60.5%). The result of the lab test were negative for viral and autoimmune hepatitis. Three days after admission, he entered hepatic coma (grade III) and prothrombin activity decreased (23.2%) , compatible with fulminant hepatitis. Plasma exchange and steroid pulse therapy were started the next day, but he died 39 days after starting abiraterone acetate. In addition, the result of drug-induced lymphocyte stimulation test performed 3 days before his death was possibly positive.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Hepatitis; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms

We evaluated the association of PSA and androgen receptor splice variant-7 (AR-V7) transcript levels in patients' blood with time to treatment failure (TTF) and overall survival (OS) with abiraterone acetate and/or enzalutamide treatment in castration-resistant prostate cancer (CRPC) patients.. RNA levels of AR-V7 and PSA in peripheral blood collected before treatment were quantified using droplet digital-PCR in retrospective cohorts treated with abiraterone acetate (N = 81) or enzalutamide (N = 51) for CRPC. Multivariable Cox regression adjusted for known prognostic factors was used for analyses.. PSA transcripts were detected in 57% of abiraterone acetate-treated patients and in 63% of enzalutamide-treated patients. PSA-positive patients had a shorter TTF than PSA-negative patients [adjusted HR = 2.27 (95% confidence interval (CI) 1.26-4.10) and 2.60 (95% CI, 1.19-5.69); P = 0.006 and 0.017 in abiraterone acetate and enzalutamide cohorts, respectively]. Patients with a higher-AR-V7 transcript level had a shorter TTF with abiraterone acetate and enzalutamide in univariate analysis (median 8.0 months vs. 15.6 months, P = 0.046 in abiraterone acetate-cohort and 3.6 months vs. 5.6 months; P = 0.050 in enzalutamide cohort). In multivariable models, the association with TTF remained significant in the enzalutamide cohort (adjusted HR = 2.02; 95% CI, 1.01-4.05; P = 0.048), but statistically insignificant in the abiraterone acetate cohort. In both cohorts, we observed potential prognostic value of both PSA and AR-V7 RNA expression on OS; patients with detectable PSA transcripts and high AR-V7 predicted the poorest OS.. PSA and AR-V7 transcripts in blood potentially serve as biomarkers predicting TTF and OS with abiraterone acetate or enzalutamide treatment. If validated prospectively, their detection could be facilitated without isolation of circulating tumor cells. Clin Cancer Res; 23(3); 726-34. ©2016 AACR.

Topics: Abiraterone Acetate; Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Benzamides; Biomarkers, Tumor; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms, Hormone-Dependent; Nitriles; Phenylthiohydantoin; Prognosis; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Protein Isoforms; Receptors, Androgen; Retrospective Studies; RNA, Messenger; RNA, Neoplasm; Steroid 17-alpha-Hydroxylase

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

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

Residual cancer morphology in radical prostatectomies (RPs) after neoadjuvant hormone therapy includes inconspicuous cytology, and treated tumour cells can be difficult to identify in lymph nodes. The aim of this study was to evaluate the role of immunohistochemistry (IHC) in identifying occult lymph node metastases following neoadjuvant hormone treatment of prostate cancer.. One hundred and twenty-eight lymph nodes from 24 patients treated with neoadjuvant hormone therapy, including abiraterone acetate alone or combined with leuprolide, were stained with antibodies against keratin AE1/AE3, prostate-specific antigen (PSA), prostate-specific acid phosphatase (PrAP), androgen receptor (AR), and NKX3.1. IHC slides were scored 'blind', and then retrospectively compared with haematoxylin and eosin (H&E)-stained slides and pathology reports. IHC identified carcinoma in six lymph nodes from three patients. All metastases were positive for NKX3.1 and AR, five of six were positive for AE1/AE3, and three of six were positive for PSA; PrAP was negative in all metastatic foci. All six lymph node metastases had been identified by H&E staining at the time of RP.. These findings suggest that routine use of IHC on lymph nodes from neoadjuvant-treated prostate carcinomas is not necessary. Nevertheless, for suspicious small foci of atypical cells in neoadjuvant-treated lymph nodes, NKX3.1 and AR appear to have the greatest sensitivity.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma; Follow-Up Studies; Humans; Immunohistochemistry; Leuprolide; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Pelvis; Prostate; Prostatectomy; Prostatic Neoplasms; Retrospective Studies

Inhibition of androgen synthesis by abiraterone acetate (AA) entails enhanced overall survival rates and clinical benefit for patients with locally advanced and metastasized prostate cancer (PC). The expression of heat shock protein 27 (HSP27) is generally associated with cytoprotection and was demonstrated to mediate chemoresistance under cytostatic therapy, for instance, docetaxel treatment. In this study, we investigated the impact of AA treatment on HSP27 expression and PC cell growth.. HSP27 expression levels in docetaxel and AA-treated PC cell lines LNCaP and PC-3 were determined by SDS PAGE and Western blot analysis. Proliferation assays were performed using a CASY Cell Counter and Analyzer Model TT (Roche Applied Science).. Despite significantly increased HSP27 expression in PC cells incubated with docetaxel, Western blot analysis implicated a significant reduction of the cytoprotective HSP27 in AA-treated PC cells. Notably, HSP27 stably overexpressed in PC-3-HSP27 cells did not appear as an HSP27-mediated proliferation benefit in the presence of AA as shown in docetaxel incubation studies.. In contrast to repeatedly demonstrated HSP27-driven chemoresistance related to chemotherapeutics, our results may constitute a broader molecular mode of action of AA chemotherapy. AA efficacy may exert an HSP27 suppressive role that goes beyond the primarily assumed inhibition of androgen biosynthesis.

Topics: Abiraterone Acetate; Cell Survival; Cytochrome P-450 Enzyme Inhibitors; HSP27 Heat-Shock Proteins; Humans; Male; Prostatic Neoplasms; Tumor Cells, Cultured

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

The purpose of this study was to examine, using a US electronic medical records (EMR) database, the clinical characteristics and real-world treatment sequences in men with advanced prostate cancer who initiated treatment with abiraterone acetate or enzalutamide.. This retrospective, observational study evaluated adult male patients with a diagnosis of prostate cancer (International Classification of Diseases, Ninth Revision, Clinical Modification code 185) in the EMR database between July 1, 2011, and March 31, 2014, who had initiated first-line treatment with abiraterone acetate or enzalutamide between September 1, 2012, and March 31, 2014. The first record for a patient initiating abiraterone acetate or enzalutamide was the index date. Patients had 6 months of pre-index medical record history and a variable length follow-up period, extending from the index date to the end of medical record data availability or date of the end of the study (March 31, 2014). The sequence of first- and second-line therapies for advanced prostate cancer therapy was reported.. A total of 809 patients met study inclusion and exclusion criteria. This study found that the majority of patients who initiated treatment with either abiraterone acetate or enzalutamide between September 1, 2012, and March 31, 2014, received a single line of therapy (72%); abiraterone acetate was the most common first-line treatment (74% of first-line patients). A subset of patients treated first-line with either abiraterone acetate or enzalutamide were transitioned to an oral second-line agent (17% of first-line abiraterone acetate-treated patients transitioned to second-line enzalutamide, and 16% of first-line enzalutamide-treated patients transitioned to second-line abiraterone acetate). Chemotherapy with docetaxel was also a commonly observed second-line treatment selection, occurring in 8% of first-line abiraterone acetate-treated patients and in 7% of first-line enzalutamide-treated patients.. This EMR study is among the first to present evidence of US physician practice prescribing patterns regarding initiation of oral antineoplastic agents and use of subsequent therapies in patients with advanced prostate cancer.

Topics: Abiraterone Acetate; Aged, 80 and over; Antineoplastic Agents; Benzamides; Docetaxel; Electronic Health Records; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Retrospective Studies; Taxoids

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

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

Identifying patients who may benefit from targeted therapy is an urgent clinical issue in prostate cancer (PCa). We investigated the molecular relationship between TMPRSS2-ERG (T2E) fusion gene and insulin-like growth factor receptor (IGF-1R) to optimize the use of IGF-1R inhibitors.IGF-1R was analyzed in cell lines and in radical prostatectomy specimens in relation to T2E status. ERG binding to IGF-1R promoter was evaluated by chromatin immunoprecipitation (ChIP). Sensitivity to anti-IGF-1R agents was evaluated alone or in combination with anti-androgen abiraterone acetate in vitro at basal levels or upon ERG modulation.IGF-1R analysis performed in PCa cells or clinical samples showed that T2E expression correlated with higher IGF-1R expression at mRNA and protein levels. Genetic modulation of ERG directly affected IGF-1R protein levels in vitro. ChIP analysis showed that ERG binds IGF-1R promoter and that promoter occupancy is higher in T2E-positive cells. IGF-1R inhibition was more effective in cell lines expressing the fusion gene and combination of IGF-1R inhibitors with abiraterone acetate produced synergistic effects in T2E-expressing cells.Here, we provide the rationale for use of T2E fusion gene to select PCa patients for anti-IGF-1R treatments. The combination of anti-IGF-1R-HAbs with an anti-androgen therapy is strongly advocated for patients expressing T2E.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; DNA-Binding Proteins; Humans; Male; Promoter Regions, Genetic; Prostate; Prostatic Neoplasms; Protein Binding; Receptor, IGF Type 1; Recombinant Fusion Proteins; Serine Endopeptidases; Trans-Activators; Transcriptional Regulator ERG

Several abstracts presented at the 2015 European Association of Urology Meeting highlighted new developments in hormone therapy for prostate cancer management. One abstract described how the luteinizing hormone-releasing hormone (LHRH)/gonadotropin-releasing hormone (GnRH) agonist leuprolide, but not the LHRH/GnRH antagonist degarelix, induced plaque instability in a mouse model. A second abstract showed that in patients with a history of severe cardiovascular disease, degarelix was associated with fewer cardiovascular events than treatment with an LHRH agonist. A third abstract showed how primary androgen-deprivation therapy was linked with increased all-cause mortality in a US registry. A fourth abstract showed that in the ANAMEN study, cognitive performance was not significantly affected by 6 months of treatment with GnRH agonists. Last, a fifth abstract showed that low-dose prednisone, with or without abiraterone, was associated with an overall low incidence of corticosteroid-associated adverse events.

Topics: Abiraterone Acetate; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cognition; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Mice; Mortality; Myocardial Infarction; Oligopeptides; Prednisone; Prostatic Neoplasms; Risk Assessment; Stroke

The orally-active CYP17A1 inhibitor abiraterone acetate (AA) decreases adrenal and intratumoral androgen biosynthesis and is an effective agent for the treatment of prostate cancer. Abiraterone potently inhibits both reactions catalyzed by CYP17, the 17α-hydroxylase (hydroxylase) reaction as well as the 17,20-lyase (lyase) transformation. CYP17 hydroxylase inhibition prevents the synthesis of adrenal glucocorticoids and causes an accumulation of circulating mineralocorticoids. As a consequence of potent CYP17 hydroxylase inhibition (i.e., lack of lyase selectivity), AA must be co-administered with the cortisol replacement prednisone and patients may experience the effects of mineralocorticoid excess syndrome (MES). Herein, we describe rationally-designed, CYP17 lyase-selective inhibitors that could prove safer and more effective than abiraterone. Using proprietary methodology, the high-affinity pyridine or imidazole metal-binding group found in current clinical CYP17 inhibitors was replaced with novel, less avid, metal-binding groups in concert with potency-enhancing molecular scaffold modifications. This process produced a unique series of CYP17 lyase-selective inhibitors that included the oral agent 6 (VT-464), now in Phase 2 prostate cancer clinical trials. The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases.

Topics: Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Male; Molecular Structure; Prostatic Neoplasms; Rats; Steroid 17-alpha-Hydroxylase; Structure-Activity Relationship; Triazoles

Abiraterone, a potent CYP 17 inhibitor, is standard treatment in docetaxel refractory, metastatic castrate resistant prostate cancer (mCRPC). However, in countries where abiraterone has not been approved yet, or for patients who cannot afford it, ketoconazole is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that ketoconazole is a less potent inhibitor of CYP 17, there are limited clinical data comparing both agents. We aimed to compare the clinical effectiveness of abiraterone versus ketoconazole in docetaxel refractory mCRPC.. Records from mCRPC patients treated with ketoconazole (international multicenter database, n = 162) were reviewed retrospectively. Twenty-six patients treated post docetaxel were individually matched by clinicopathologic factors to patients treated with abiraterone (national multicenter database, n = 140). We compared the PSA response, biochemical and radiological progression free survival (PFS), and overall survival (OS) between the groups. PFS and OS were determined by Cox regression.. The groups were matched by Gleason score, pre-treatment disease extent, ECOG PS, pre-treatment risk category (Keizman, Oncologist 2012). Furthermore, they were balanced regarding other known confounding risk factors. In the groups of abiraterone versus ketoconazole, PSA response was 46% versus 19% (OR 4.3, P = 0.04), median biochemical PFS 7 versus 2 months (HR 1.54, P = 0.02), median radiological PFS 8 versus 2.5 months (HR 1.8, P = 0.043), median OS 19 versus 11 months (HR 0.53, P = 0.79), and treatment interruption d/t severe adverse events 8% (n = 2) versus 31% (n = 8) (0R 0.6, P = 0.023).. In docetaxel refractory mCRPC, the outcome of abiraterone treatment may be superior to ketoconazole.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstadienes; Antineoplastic Agents; Combined Modality Therapy; Databases, Factual; Disease Progression; Disease-Free Survival; Docetaxel; Humans; Ketoconazole; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms; Retreatment; Retrospective Studies; Taxoids; Treatment Outcome

Abiraterone acetate (AA) is a selective oral inhibitor of Steroid-17α-Hydroxylase, for patients with castration-resistant prostate cancer. Not all patients respond to therapy, however, there are no biomarkers predicting response to AA therapy. The aim of the present study was the identification of a biomarker for patients who are likely to respond to AA therapy.. We measured thyroid parameters in a collective of 30 patients before and during AA therapy. For statistical analyses, paired and unpaired t-tests were used.. During AA therapy, responders developed a significant increase in thyroid stimulating hormone (TSH) compared to non-responders (p=0.03). In the subgroup of responders, 16 out of 21 patients (76.1%) had a significant increase in TSH level (p=0.001), suggesting that TSH increase is predictive of therapy response. Non-responders showed no change in TSH level during AA therapy.. Hypothyreosis may serve as a simple predictive biomarker for therapy response under AA therapy.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstadienes; Biomarkers, Pharmacological; Bone Neoplasms; Follow-Up Studies; Humans; Hypothyroidism; Male; Middle Aged; Neoplasm Staging; Prognosis; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase; Thyrotropin

Enzalutamide (MDV3100) is a non-steroidal antiandrogen of second generation that has shown efficacy in metastatic castration-resistant prostate cancer (mCRPC). The study AFFIRM demonstrated a statistically significant increase in overall survival among patients who have progressed following a docetaxel chemotherapy. Based on these results, a marketing authorization for enzalutamide has been granted. The enzalutamide has been shown to be generally well tolerated. Other trials are underway to evaluate its earlier use in the management of mCRPC. A pivotal registration phase III study (PREVAIL) is ongoing to investigate the effectiveness of enzalutamide in patients who have not yet received chemotherapy.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antineoplastic Agents, Hormonal; Benzamides; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms

To identify factors predicting primary resistance to new-generation hormonal agents (NHAs), abiraterone acetate and enzalutamide in patients with castration-resistant prostate cancer (CRPC).. Our hospital has conducted two successive named patient NHA programs. A total of 57 patients with progressive CRPC previously treated with first-line docetaxel-based chemotherapy received standard NHA doses: abiraterone acetate 1000 mg once-daily combined with prednisone (5 mg twice daily) or enzalutamide 160 mg once-daily. Patients, who were assessed monthly to check their hematological parameters and prostate-specific antigen (PSA) levels, also underwent imaging investigations every 3-4 months. In total, 24 variables were assessed as potential predictors of primary NHA resistance.. Univariate analysis indicated that baseline pain and lactate dehydrogenase levels, and PSA levels after 1 month's treatment were predictive of primary NHA resistance. Only the predictive value of PSA levels after 1 month of treatment was confirmed at multivariate analysis. This factor strongly predicted progression-free and overall survival.. RESULTS suggest the use of a simple and rapid method of identifying patients with primary resistance to NHAs: patients not achieving a ≥ 50% reduction in PSA levels within the first treatment month should undergo intensive investigations to verify whether they have primary resistance to NHAs.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease Progression; Drug Resistance, Neoplasm; Follow-Up Studies; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

Abiraterone acetate (AA), a highly potent CYP17A1 inhibitor, has demonstrated marked clinical benefit in patients with metastatic castration-resistant prostate cancer (CRPC). Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations. The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor (AR) activity in prostate cancer (PC) cells.. Fluorescence resonance energy transfer (FRET) assay was used to assess the effect of mineralocorticoids on androgen-induced conformational change of the AR. LAPC4, LNCaP and LN-AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations, including levels measured in the serum of AA-treated patients in a phase I trial. AR-dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells.. Corticosterone (CS) and deoxycorticosterone (DOC) inhibited androgen-induced conformational change of the AR in the FRET assay. CS inhibited AR-dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA-treated patients. DOC inhibited AR transcriptional activity and cell growth at 10-fold greater concentrations than measured in the serum of AA-treated patients.. Mineralocorticoids directly inhibit androgen-induced conformational change of the AR. CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA. Further investigation of the potential therapeutic implications of mineralocorticoids in AA-treated CRPC patients is warranted.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgens; Androstenes; Antineoplastic Agents, Hormonal; Cell Line, Tumor; Cell Proliferation; Clinical Trials, Phase I as Topic; Gene Expression Regulation, Neoplastic; Humans; Male; Mineralocorticoids; Prostatic Neoplasms; Receptors, Androgen; Transcription, Genetic

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Androstadienes; Antineoplastic Agents, Hormonal; Drug Administration Schedule; Humans; Kallikreins; Male; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors; Treatment Outcome

We have previously reported the discovery of a new class of potent inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) derived from benzylidene oxazolidinedione and thiazolidinedione scaffolds. In this study, these analogs were designed, synthesized, and evaluated in a human cell-based assay. The detailed structure-activity relationship (SAR) surrounding this pharmacophore were developed, and consequently a number of compounds from this series demonstrated single-digit nanomolar 17β-HDS3 inhibitory activity in vitro. Subsequent optimization work in pursuit of the improvement of oral bioavailability demonstrated in vivo proof-of-concept by prodrug strategy based on phosphate esters for these 17β-HSD3 inhibitors. When a phosphate ester 16 was administered orally at a high dose of 100mg/kg, 16 showed approximately two times more potent testosterone (T)-lowering effect against a positive control in the luteinizing hormone-releasing hormone (LH-RH)-induced T production assay. The T-lowering effect continued at ca 10% level of control over 4h after administration. The nonsteroidal molecules based on this series have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer.

Topics: 17-Hydroxysteroid Dehydrogenases; Administration, Oral; Animals; Antineoplastic Agents; Drug Discovery; Drug Screening Assays, Antitumor; Enzyme Activation; Enzyme Inhibitors; Esters; HeLa Cells; Humans; Inhibitory Concentration 50; Male; Phosphates; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Testosterone

Topics: Abiraterone Acetate; Androstadienes; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Cancer Vaccines; Denosumab; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids; Tissue Extracts

Topics: Abiraterone Acetate; Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Androstadienes; Clinical Trials, Phase III as Topic; Enzyme Inhibitors; Glucocorticoids; Humans; Male; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Steroid 17-alpha-Hydroxylase

At the third annual Interactive Genitourinary Cancer Conference, held in Budapest from 30 April to 1 May 2011, the latest developments in the management of patients with high-risk localised and metastatic prostate cancer were discussed. Prostate cancer is the most common cancer in Western men and, for advanced disease, no curative agents are available. For men with high-risk localised disease there is debate about the best treatment approaches, with both radical prostatectomy and radiation therapy shown to improve outcomes. These approaches have started to be augmented as new techniques and therapies are developed. For instance, radiation therapy combined with androgen deprivation therapy has been shown to be more efficacious than radiation therapy alone, and there may also be a role for adjuvant/neoadjuvant chemotherapy. Ultimately a multidisciplinary approach will most probably result in the best outcomes for patients. The use of androgen deprivation therapy in men with prostate cancer needs to be monitored carefully, given that it results in adverse alterations in several metabolic parameters and an increased risk of further coronary events in men with cardiovascular disease in some studies. Until recently there were limited options for the management of men with advanced prostate cancer, but new agents for use in the post-docetaxel setting have recently been approved. These are cabazitaxel and abiraterone acetate, which have both shown a significant survival benefit in patients who have progressed on docetaxel. Additional agents, for these patients and for patients at other stages of disease, are in the later stages of development. The development of new agents has been aided by a greater understanding of the molecular mechanisms of resistance to current therapies and the recognition of new pathophysiological pathways. As the number of available therapeutic options increases, it will become increasingly important to tailor treatments to the individual patient. This may require the development of novel biomarkers or the use of existing or new predictive tools based on prognostic factors. To ensure optimal patient care, early and continuous involvement of the multidisciplinary team will be required.

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Androstadienes; Cardiovascular Diseases; Chemotherapy, Adjuvant; Congresses as Topic; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prognosis; Prostatectomy; Prostatic Neoplasms; Radiotherapy, Adjuvant; Taxoids

Oral abiraterone acetate (Zytiga®), a selective cytochrome P450 17A1 enzyme inhibitor, is used in combination with prednisone or prednisolone to treat patients with metastatic castration-resistant prostate cancer (CRPC) who have previously received docetaxel-containing chemotherapy. In a clinical trial in patients with CRPC, abiraterone acetate plus prednisone significantly prolonged overall survival, the time to prostate-specific antigen progression and progression-free survival compared with placebo plus prednisone.

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents; Enzyme Inhibitors; Humans; Male; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase

Treatment with abiraterone (abi) acetate prolongs survival in castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to upregulation of steroidogenic enzymes and/or other mechanisms that sustain dihydrotestosterone (DHT) synthesis, which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. On the basis of the 3β-hydroxyl, Δ(5)-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for DHT synthesis in CRPC, regardless of origins or routes of synthesis.. We tested the effects of abi on 3βHSD activity, androgen receptor localization, expression of androgen receptor-responsive genes, and CRPC growth in vivo.. Abi inhibits recombinant 3βHSD activity in vitro and endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [(3)H]-dehydroepiandrosterone (DHEA) to Δ(4)-androstenedione, androgen receptor nuclear translocation, expression of androgen receptor-responsive genes, and xenograft growth in orchiectomized mice supplemented with DHEA. Abi also blocks conversion of Δ(5)-androstenediol to testosterone by 3βHSD. Abi inhibits 3βHSD1 and 3βHSD2 enzymatic activity in vitro; blocks conversion from DHEA to androstenedione and DHT with an IC(50) value of less than 1 μmol/L in CRPC cell lines; inhibits androgen receptor nuclear translocation; expression of TMPRSS2, prostate-specific antigen, and FKBP5; and decreases CRPC xenograft growth in DHEA-supplemented mice.. We conclude that abi inhibits 3βHSD-mediated conversion of DHEA to active androgens in CRPC. This second mode of action might be exploited to reverse resistance to CYP17A1 inhibition at the standard abi dose by dose-escalation or simply by administration with food to increase drug exposure.

Topics: 3-Hydroxysteroid Dehydrogenases; Abiraterone Acetate; Active Transport, Cell Nucleus; Androstadienes; Androstenedione; Animals; Antineoplastic Agents; Cell Line, Tumor; Dehydroepiandrosterone; Dihydrotestosterone; Drug Resistance, Neoplasm; Humans; Isoenzymes; Male; Mice; Mice, Inbred NOD; Mice, SCID; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Testosterone; Tumor Burden; Xenograft Model Antitumor Assays

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer provide multidisciplinary recommendations for the clinical management of patients with prostate cancer. These NCCN Guidelines Insights highlight notable recent updates. Abiraterone acetate is a first-in-class hormonal agent that represents a new standard of care for patients with metastatic castration-recurrent prostate cancer who have previously received docetaxel (category 1 recommendation). Abiraterone acetate also received category 2B recommendations in the prechemotherapy setting for asymptomatic patients or symptomatic patients who are not candidates for docetaxel. The NCCN Prostate Cancer Panel also added new indications for existing agents, including the option of sipuleucel-T as second-line therapy. In addition, brachytherapy in combination with external beam radiation therapy with or without androgen deprivation therapy is now an alternative for patients with high-risk localized tumors or locally advanced disease.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antineoplastic Agents; Brachytherapy; Docetaxel; Humans; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts

Topics: Abiraterone Acetate; Androstadienes; Humans; Male; Prostatic Neoplasms

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Drug Resistance, Neoplasm; Humans; Male; Prednisone; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Bone Neoplasms; Glucocorticoids; Humans; Male; Pain Management; Prednisone; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents, Hormonal; Humans; Male; Placebos; Prostatic Neoplasms

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Enzyme Inhibitors; Humans; Male; Neoplastic Cells, Circulating; Oncogene Proteins, Fusion; Orchiectomy; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents; Drug Labeling; Food-Drug Interactions; Humans; Male; Prostatic Neoplasms; United States; United States Food and Drug Administration

Oral abiraterone acetate, in combination with prednisone/prednisolone, is used to treat patients with metastatic castration-resistant prostate cancer (CRPC) who have previously received docetaxel-containing chemotherapy. Abiraterone acetate was developed to specifically inhibit cytochrome P450 (CYP)17A1, which is an essential enzyme in the biosynthesis of testosterone. In a pivotal phase III trial in patients with metastatic CRPC who have previously received docetaxel-containing chemotherapy, abiraterone acetate 1000 mg once daily plus prednisone 5 mg twice daily significantly prolonged overall survival compared with placebo plus prednisone. In this trial, abiraterone acetate plus prednisone was significantly more effective than placebo plus prednisone in prolonging the time to prostate-specific antigen (PSA) progression and in prolonging progression-free survival. Significantly more abiraterone acetate plus prednisone recipients than placebo plus prednisone recipients were considered to be responders, when assessed by PSA levels or radiographic imaging. Treatment with abiraterone acetate plus prednisone in the phase III trial was associated with an acceptable tolerability profile, which was generally similar to that of the placebo plus prednisone group. However, adverse events of special interest (e.g. cardiac disorders and liver-function test abnormalities and adverse events resulting from elevated mineralocorticoid levels because of CYP17A1 inhibition [i.e. fluid retention and oedema, hypokalaemia, hypertension]) occurred in significantly more abiraterone acetate plus prednisone than in placebo plus prednisone recipients.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Androstadienes; Clinical Trials as Topic; Disease Progression; Humans; Male; Middle Aged; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase; Treatment Outcome

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Androgens; Androstadienes; Humans; Male; Prostatic Neoplasms; Receptors, LHRH; Steroid 17-alpha-Hydroxylase

Steroidal compounds having a 17-(3-pyridyl) substituent together with a 16,17-double bond have been synthesized, using a palladium-catalyzed cross-coupling reaction of a 17-enol triflate with diethyl(3-pyridyl)borane, which are potent inhibitors of human testicular 17 alpha-hydroxylase-C17,20-lyase. The requirement for these structural features is stringent: compounds having 2-pyridyl (9), 4-pyridyl (10), or 2-pyridylmethyl (11) substituents instead of the 3-pyridyl substituent were either poor inhibitors or noninhibitory. Reduction of the 16,17-double bond to give 17 beta-pyridyl derivatives diminished potency with 3-pyridyl substitution (3-->27; IC50 for lyase, 2.9-->23 nM) but increased it with a 4-pyridyl substituent present (10-->28; IC50 1 microM-->53 nM). In contrast, a variety of substitution patterns in rings A-C of the steroid skeleton afforded inhibitors having potencies similar to those most closely related structurally to the natural substrates pregnenolone and progesterone, respectively 17-(3-pyridyl)androsta-5,16-dien-3 beta-ol (3, Kiapp < 1 nM; IC50 for lyase, 2.9 nM) and 17-(3-pyridyl)androsta-4,16-dien-3-one (15; IC50 for lyase, 2.1 nM). Thus compounds having variously aromatic ring A (18), saturated rings A/B (21, 22), and oxygenated ring C (26) exhibited IC50 values for lyase (1.8-3.0 nM) falling within a 2-fold range. The most potent compounds are candidates for development as drugs for the treatment of hormone-dependent prostatic carcinoma.

Topics: Cytochrome P-450 Enzyme Inhibitors; Humans; Magnetic Resonance Spectroscopy; Male; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase; Steroids; Structure-Activity Relationship; Testis