abiraterone-acetate and Neoplasm-Metastasis

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

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

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

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

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

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

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

Oral abiraterone acetate (Zytiga

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

COU-AA-301 trial has proved that abiraterone acetate (AA), a selective inhibitor of androgen biosynthesis, improved overall survival (OS) of patients with metastatic castration resistant prostate cancer (mCRPC) after a first line of docetaxel. Based on this result, a Temporary Authorization for Use (TAU) was performed between December 2010 and July 2011 to provide patients with mCRPC the opportunity to receive AA before its commercialization. The aim of this study was to evaluate safety and efficacy of AA treatment in this TAU.. Between December 2010 and July 2011, we conducted an ambispective, multicentric cohort study and investigated data from 20 centres participating to the AA TAU for patients presenting mCRPC and already treated by a first line of chemotherapy (CT). Statistical analyses of the data were performed using the Stata software v13 to identify predictive and prognostic factors.. Among the 408 patients, 306 were eligible with a follow-up at 3 years. Median OS was 37.1 months from beginning of CT and 14.6 months from AA introduction. 211 patients (69%) received ≥ 3 months of AA and 95 patients (31%) were treated less than 3 months. In the multivariate analyses, duration of AA was significantly correlated with PSA decrease at 3 months. Additionally, shorter time under AA treatment, presence of multiple sites of metastasis and previous hormonal treatment duration were three independent factors associated with poorer OS. At the time of analysis ten patients were still under treatment for more than 3 years.. Biochemical response monitored by PSA changes at 3 months is a strong predictive factor for AA treatment duration. Some high responders' patients could beneficiate from AA for more than 3 years.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Follow-Up Studies; France; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Prognosis; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Few data are available concerning the clinical outcome of abiraterone acetate treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) in terms of the duration of androgen deprivation therapy (ADT) before diagnosis of CRPC. We investigated the clinical efficacy of abiraterone acetate according to the duration of ADT.. We reviewed the medical records of 20 patients with mCRPC who received abiraterone acetate after failure of docetaxel chemotherapy from May 2012 to March 2014 at Seoul National University Bundang Hospital. Clinical factors including prostate-specific antigen (PSA) nadir level, time to PSA nadir, PSA doubling time, PSA response, and modes of progression (PSA, radiologic, clinical) were analyzed. Disease progression was classified according to the Prostate Cancer Working Group 2 criteria.. The mean age and PSA value of the entire cohort were 76.0±7.2 years and 158.8±237.9 ng/mL, respectively. The median follow-up duration was 13.4±6.7 months. There were no statistically significant differences in clinical characteristics between patients who received abiraterone acetate with ADT duration<35 months and those who received abiraterone acetate with ADT duration≥35 months. There were also no significant differences in terms of PSA progression-free survival, radiologic progression-free survival, and clinical progression-free survival between patients with ADT duration<35 months and those with ADT duration ≥35 months.. Although this was a retrospective study with a small sample size, we did not observe any statistically significant differences in the clinical response to abiraterone acetate between mCRPC patients with long ADT duration and those with short ADT duration in terms of disease progression-free survival.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Receptor Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Docetaxel; Drug Administration Schedule; Humans; Kallikreins; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Abiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This study's objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone.. All patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation.. A confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%-50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis.. A composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androgen Antagonists; Androstadienes; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; Humans; Kallikreins; L-Lactate Dehydrogenase; Lymphocytes; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neutrophils; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Steroid 17-alpha-Hydroxylase; Treatment Outcome

Abiraterone acetate is an oral medication that has recently been granted approval for the treatment of metastatic castration resistant prostate cancer (mCRPC) prior and/or after chemotherapy with docetaxel. In this article we assess the economics of abiraterone acetate in mCRPC. Relevant studies demonstrated that abiraterone acetate had a minimal budget impact on health plans. A relevant advantage was the cost savings due to the lack of chemotherapy-related side effects as well as the ease of administration. The results of cost/benefit comparative studies with other novel agents (i.e. cabazitaxel, enzalutamide, sipuleucel-T) are warranted as well as the close collaboration between urologists and medical oncologists.

Topics: Abiraterone Acetate; Androstadienes; Cost-Benefit Analysis; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Quality-Adjusted Life Years

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