Clinical development of novel therapeutics for castration-resistant prostate cancer: historic challenges and recent successes.

There have been more drugs approved by the US Food and Drug Administration for the treatment of castration-resistant prostate cancer in the past 3 years than in the prior 3 decades, with additional drugs on the verge of approval based on the results of recently reported randomized trials. While an improvement in the understanding of the pathogenesis of castration-resistant prostate cancer has undeniably accelerated the transition of novel approaches from "bench to bedside," the recent successes in the treatment of prostate cancer are also a result of the efforts of clinical investigators to redefine the framework in which drugs for castration-resistant disease are evaluated. This review will explore the shifting paradigm in drug development for castration-resistant prostate cancer over the past several decades, and highlight how new definitions, trial designs, and endpoints have facilitated the emergence of new therapies for this challenging disease.

AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.

BACKGROUND: The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. METHODS: We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival. RESULTS: A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA. CONCLUSIONS: Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).

Effect of as-needed use of intranasal PH94B on social and performance anxiety in individuals with social anxiety disorder.

BACKGROUND: There are no medications approved for as-needed use for feared situations for individuals with social anxiety disorder (SAD). In the present study, intranasal PH94B was provided for use as needed during stressful events. METHODS: Twenty-two subjects were randomized (double-blind) to 2 weeks of treatment with intranasal PH94B or placebo. Following self-administration of medication prior to a feared event, peak levels of anxiety were recorded using the Subjective Units of Distress Scale (SUDS). After 2 weeks, subjects were crossed over to the opposite treatment for 2 weeks. Average peak SUDS during treatment with PH94B and placebo were compared using a paired t-test. RESULTS: Significant differences in favor of PH94B were found on the primary outcome measure: mean peak SUDS change from baseline for all subjects receiving PH94B was 15.6 points versus 8.3 points for placebo (paired t = 3.09, P = .006, effect size of .658). PH94B showed less superiority over placebo when placebo was given second rather than first, likely due to a carryover effect. Looking between groups at just the first 2 weeks of treatment, PH94B also showed trend superiority to placebo on the Liebowitz Social Anxiety Scale (LSAS) (P = .07) and a significant difference on the Patient Global Impression of Change (P = .024) and the LSAS Avoidance subtotal (P = .02). CONCLUSIONS: While further study is needed, these results, combined with earlier findings, suggest that PH94B could represent a useful as-needed treatment for SAD, and continue to validate the nasal chemosensory system as a novel mechanism for medication delivery.

TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer.

Androgen receptor (AR) target genes direct development and survival of the prostate epithelial lineage, including prostate cancer (PCa). Thus, endocrine therapies that inhibit the AR ligand-binding domain (LBD) are effective in treating PCa. AR transcriptional reactivation is central to resistance, as evidenced by the efficacy of AR retargeting in castration-resistant PCa (CRPC) with next-generation endocrine therapies abiraterone and enzalutamide. However, resistance to abiraterone and enzalutamide limits this efficacy in most men, and PCa remains the second-leading cause of male cancer deaths. Here we show that AR gene rearrangements in CRPC tissues underlie a completely androgen-independent, yet AR-dependent, resistance mechanism. We discovered intragenic AR gene rearrangements in CRPC tissues, which we modeled using transcription activator-like effector nuclease (TALEN)-mediated genome engineering. This modeling revealed that these AR gene rearrangements blocked full-length AR synthesis, but promoted expression of truncated AR variant proteins lacking the AR ligand-binding domain. Furthermore, these AR variant proteins maintained the constitutive activity of the AR transcriptional program and a CRPC growth phenotype independent of full-length AR or androgens. These findings demonstrate that AR gene rearrangements are a unique resistance mechanism by which AR transcriptional activity can be uncoupled from endocrine regulation in CRPC.

Abiraterone and novel antiandrogens: overcoming castration resistance in prostate cancer.

Suppression of gonadal androgens by medical or surgical castration remains the mainstay of treatment for patients with advanced prostate cancer. However, the response to treatment is not durable, and transition to a "castration-resistant" state is invariable. Recent advances in our understanding of the androgen receptor signaling pathway have led to the development of therapeutic strategies to overcome castration resistance. This article reviews current concepts and challenges behind targeting continued androgen receptor signaling in castration-resistant prostate cancer and provides an overview of recently completed and ongoing clinical trials of novel hormonal agents, with a focus on abiraterone acetate and enzalutamide (MDV3100).

A retrospective, Canadian multi-center study examining the impact of prior response to abiraterone acetate on efficacy of docetaxel in metastatic castration-resistant prostate cancer.

BACKGROUND: Questions about optimal sequencing of systemic therapy in metastatic castration-resistant prostate cancer (mCRPC) and whether cross-resistance occurs between different drugs remain largely unanswered. Previous studies have produced conflicting data on the activity of docetaxel in patients who did not attain a prostate-specific antigen (PSA) response to abiraterone acetate (abiraterone). We investigated whether the biochemical response to abiraterone is associated with efficacy of subsequent docetaxel therapy. METHODS: mCRPC patients treated with docetaxel after abiraterone were retrospectively identified at three Canadian institutions. Patients who had also received docetaxel prior to abiraterone were termed "docetaxel-experienced," while those not treated with docetaxel prior to abiraterone were termed "docetaxel-naïve." Treatment outcomes on docetaxel were stratified by prior response to abiraterone and compared using χ(2) -square test for confirmed PSA response rate (≥ 50% decline from baseline maintained for ≥ 3 weeks) and the log-rank method for progression-free survival (PFS) and overall survival (OS). RESULTS: Eighty-six patients were treated with abiraterone, of whom 49 were docetaxel-experienced and 37 were docetaxel-naïve. Prior PSA response to abiraterone was no decline, <50% decline and ≥ 50% decline in 37%, 26%, and 37% of patients respectively. The overall PSA response rate to docetaxel was 34.9%, median PFS was 4.0 months and median OS was 11.66 months. Notably, no differences were seen in confirmed PSA response rates (38% vs. 36% vs. 31%, P = 0.86), median PFS (4.04 months vs. 3.94 months vs. 4.24 months, P = 0.43) and median OS (11.86 months vs. 15.38 months vs. 11.00 months, P = 0.56) on docetaxel for patients with no PSA decline, <50% decline and ≥ 50% decline on abiraterone respectively. Importantly, PSA response rates to docetaxel were comparable in the docetaxel-experienced and docetaxel-naïve cohorts and were not linked to prior response to abiraterone in either group. CONCLUSION: Activity of docetaxel was not associated with the biochemical response to prior abiraterone therapy. These data suggest that prior response to abiraterone should not influence decisions on subsequent use of docetaxel in mCRPC.

Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone.

BACKGROUND: The optimal sequencing of the multiple active agents now available for metastatic castration-resistant prostate cancer (mCRPC) is unclear. Prior reports have suggested diminished responses to sequential lines of androgen receptor (AR)-targeted therapies, but it is unknown whether subsequent taxane-based chemotherapy may be more effective than sequential AR-targeting treatment. We sought to evaluate the clinical activity of enzalutamide versus docetaxel in men with mCRPC who progressed on abiraterone. METHODS: We performed a single-institution retrospective analysis of consecutive mCRPC patients who had progressed on abiraterone therapy and subsequently received either enzalutamide (n=30) or docetaxel (n=31). We evaluated clinical outcomes including prostate-specific antigen decline of >30% (PSA30) or >50% (PSA50), PSA-progression-free survival (PSA-PFS), and clinical/radiographic PFS. We performed multivariable modeling to control for baseline and on-treatment differences between groups. RESULTS: Compared to subjects who received enzalutamide post-abiraterone, subjects who received docetaxel post-abiraterone had more bone metastases, more visceral metastases, higher baseline PSA, and had more frequent PSA tests while on-treatment. There were no significant differences in PSA30 (41% for enzalutamide vs. 53% for docetaxel) or PSA50 (34% vs. 40%) response rates between the two groups; there remained no difference after stratifying by presence/absence of prior response to abiraterone. Median PSA-PFS was 4.1 versus 4.1 months for the enzalutamide and docetaxel cohorts, respectively (HR 1.35, 95% CI, 0.53-3.66, P=0.502). Median PFS was 4.7 versus 4.4 months, respectively (HR 1.44, 95% CI, 0.77-2.71, P=0.257). PSA-PFS and PFS did not differ after stratifying by prior response to abiraterone. In multivariable analyses, there were no significant differences in PSA-PFS or PFS between the two groups. CONCLUSIONS: Treatment with either enzalutamide or docetaxel produced modest PSA responses and PFS intervals in this abiraterone-pretreated mCRPC population. In this retrospective study with small sample size, no significant differences in outcomes were observed between groups. Therefore, either enzalutamide or docetaxel may be a reasonable option in men who have progressed on abiraterone.

Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment.

BACKGROUND: Enzalutamide (Enz) and abiraterone acetate (AA) are hormone treatments that have a proven survival advantage in patients with metastatic, castration-resistant prostate cancer who previously received docetaxel (Doc). Recently, limited activity of AA after Enz and of Enz after AA was demonstrated in small cohort studies. Here, the authors present the activity and tolerability of Enz in patients who previously received AA and Doc in the largest cohort to date. METHODS: The efficacy and tolerability of Enz were investigated in men with progressive, metastatic, castrate-resistant prostate cancer who previously received Doc and AA. Toxicity, progression-free survival, time to prostate-specific antigen (PSA) progression, and overall survival were retrospectively evaluated. RESULTS: Sixty-one patients were included in the analysis. The median age was 69 years (interquartile range [IQR], 64-74 years), 57 patients (93%) had an Eastern Cooperative Oncology Group performance status from 0 to 2, 48 patients (79%) had bone metastases, 33 patients (54%) had lymph node metastases, and 13 patients (21%) had visceral metastases. The median duration of Enz treatment was 14.9 weeks (IQR, 11.1-20.0 weeks), and 13 patients (21%) had a maximum PSA decline ≥50%. The median progression-free survival was 12.0 weeks (95% confidence interval [CI], 11.1-16.0 weeks), the median time to PSA progression was 17.4 weeks (95% CI, >16.0 weeks), and the median overall survival was 31.6 weeks (95% CI, >28.7 weeks). Enz was well tolerated, and fatigue and musculoskeletal pain were the most frequent grade ≥2 adverse events. The PSA response to Doc and AA did not predict the PSA response to Enz. CONCLUSIONS: Enz has modest clinical activity in patients with metastatic, castrate-resistant prostate cancer who previously received Doc and AA. PSA response to Doc and AA does not predict for PSA response to ENz.

Abiraterone and increased survival in metastatic prostate cancer.

BACKGROUND: Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. METHODS: We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. RESULTS: After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group. CONCLUSIONS: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.).

Abiraterone in heavily pretreated patients with metastatic castrate-resistant prostate cancer.

The aim of this study was to evaluate the activity and tolerability of abiraterone acetate in patients with metastatic castrate-resistant prostate cancer treated previously with more than three lines of chemotherapy. Patients received 1 g of abiraterone acetate (administered as four 250 mg tablets) orally once daily with prednisone at a dose of 5 mg orally twice daily. The primary endpoint was prostate-specific antigen (PSA) response. From August 2011 to January 2013, 36 patients were enrolled. PSA response was observed in 22 patients (61.1%, 95% confidence interval: 0.41-0.81). The median time to PSA progression was 7.3 months and after a median follow-up of 10.1 months, all patients were alive. The treatment was generally well tolerated; side effects secondary to mineralocorticoid excess resulting from blockade of CYP17 were largely controlled with prednisone. Abiraterone acetate seems to be an effective and well-tolerated treatment option for patients with metastatic castrate-resistant prostate cancer irrespective of the number of chemotherapy lines administered previously.

The use of the EVITA algorithm for clinical assessment of novel agents used in prostate cancer, metastatic melanoma, and systemic lupus erythematosus.

PURPOSE: Existing health technology assessment methods can be time-consuming and complicated to use in practice. EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage (EVITA) is a recently developed drug assessment strategy that provides a detailed and clinically relevant evaluation of new agents compared to standard therapies. We therefore sought to use EVITA to evaluate eight novel agents recently introduced to clinical practice or in late-stage trials for the treatment of prostate cancer, metastatic melanoma, or systemic lupus erythematosus (SLE). METHODS: Eight agents (abiraterone, enzalutamide, sipuleucel-T, Prostvac, radium 223, ipilimumab, vemurafenib, and belimumab) were selected for study using the EVITA algorithm. A comprehensive literature search was performed to find clinical trial data, which were then classified using the EVITA protocol. EVITA was also compared to results from health technology assessments (HTAs) or reimbursement decisions. RESULTS: The EVITA scores for the eight drugs ranged from 5.5 to 9: all the selected agents are therefore classed as 'recommended' and are likely to produce a therapeutic advantage. In particular, vemurafenib is likely to be highly beneficial to patients with metastatic melanoma and radium 223 to patients with metastatic prostate cancer affecting the bone. The EVITA results were generally concordant with HTAs. CONCLUSIONS: All the agents show favourable EVITA scores and are therefore recommended for clinical practice. EVITA is an easy-to-use tool that provides clinical context to the assessment of newly introduced agents and can be easily used by non-specialists.

Secondary hormonal manipulation in castration resistant prostate cancer.

INTRODUCTION: Castration resistant prostate cancer (CRPC) is the single common pathway to prostate cancer death. For men with symptomatic metastatic disease, docetaxel chemotherapy remains a standard of care. However, blood prostatic-specific antigen (PSA) testing allows the identification of CRPC before clinical metastases or symptoms occur, providing a long diagnostic lead time in many patients. The use of secondary hormonal manipulations (SHMs) in men not candidates for immediate chemotherapy is reviewed. MATERIALS AND METHODS: PubMed was searched for randomized clinical trials, systematic reviews or clinical practice guidelines addressing SHMs in CRPC. RESULTS: A recent systematic review and practice guideline was identified, and used as the evidence base for this review along with reports from randomized trials over the past year. CONCLUSIONS: The goals of therapy with SHMs should be discussed with patients and their preferences considered. In men without clinical evidence of metastases, gonadal androgen suppression should be maintained and generally patients should be observed. There is no clear evidence that SHMs are of benefit in these patients. Abiraterone plus prednisone is of proven benefit in men with CRPC metastases who are without significant symptoms prior to chemotherapy. Based on emerging data, enzalutamide may be of similar benefit. Use of other SHMs should be based on patient preference and consideration of possible adverse effects; with the exception of low dose prednisone, there is little evidence of benefit supporting their use. For patients accepting these uncertainties, a trial of nonsteroidal antiandrogen may be considered as an adjunct to observation, followed by low dose corticosteroid with immediate or delayed addition of abiraterone (in men with metastases) as a reasonable next step.

Practical guide to the use of abiraterone in castration resistant prostate cancer.

INTRODUCTION: While androgen deprivation therapy remains the primary treatment modality for patients with metastatic prostate cancer, treatment is uniformly marked by progression to castration resistant prostate cancer (CRPC). Abiraterone is the first new drug to enter clinical practice in a series of novel agents designed to potently target adrenal and tumor androgen production. MATERIALS AND METHODS: Herein, we review the mechanism of action of abiraterone and the phase III data supporting its approval for patients with metastatic CRPC. We discuss practical treatment considerations, including the incidence and management of side effect and monitoring requirements, and conclude by discussing future directions in the use of abiraterone, including early data supporting an expanded role for abiraterone in castration sensitive disease. RESULTS: Accumulating data emphasize that "androgen independent" or "hormone refractory" tumors remain sensitive to hormonal activation and suggest that despite suppression of circulating testosterone (T), residual tumor androgens play a prominent role in mediating CRPC progression. CONCLUSIONS: Accordingly, therapeutic strategies such abiraterone that more effectively target production of intratumoral androgens are necessary.

Practical guide to the use of enzalutamide.

INTRODUCTION: We summarize the development, definitive trials, and practical use of enzalutamide for practicing urologists and medical oncologists. The care paradigm for patients with metastatic castration resistant prostate cancer (mCRPC) is a changing landscape, with the ongoing discovery of drivers of cancer progression yielding actionable targets for drug development. Since 2010, sipuleucel-T, cabazitaxel, abiraterone with prednisone, radium 223 and enzalutamide have been Food and Drug Administration approved based upon improvement in overall survival in men with mCRPC. MATERIALS AND METHODS: A MEDLINE search for "enzalutamide or MDV3100" yielded 258 results. Prospective trials were reviewed. Abstracts from ASCO (American Society of Clinical Oncology) meetings and press release information were included where applicable. RESULTS: Enzalutamide, an oral inhibitor of the androgen receptor pathway, was approved in 2012 based upon improvement in overall survival of 4.8 months in men with mCRPC following docetaxel versus placebo. Measures of prostate-specific antigen (PSA) and radiographic response, and clinically significant endpoints such as quality of life improvement and toxicity parameters favored enzalutamide. Toxicity is modest with asthenia and fatigue being most common, with a 1% incidence of seizure reported, though patients can be selected to decrease this risk. CONCLUSION: Enzalutamide is an effective oral therapy for mCRPC, with an overall survival benefit before and following chemotherapy. Toxicity is mild, and seizure risk can be mitigated by careful patient selection. Ongoing studies will help determine the best sequence of novel agents for prostate cancer, along with safe and effective combinations of therapies. Better understanding of tumor characteristics, particularly reliance on the androgen receptor pathway, will lead to personalized approaches to prostate cancer therapy.

[Abiraterone acetate(ZYTIGA®)-development and literature review].

Abiraterone acetate(AA)has been approved in more than 80 countries for the treatment of patients with metastatic castration-resistant prostate cancer(mCRPC). In July 2013, a marketing approval application for AA was submitted to the Japanese Ministry of Health, Labour, and Welfare. AA is a selective inhibitor of CYP17A1, a crucial enzyme for androgen biosynthesis. AA exerts its anti-tumor activity by directly inhibiting androgen production at all three sources, i. e., the testes, adrenal glands, and tumor itself. Data from international phase III studies and phase I and II studies in Japan have indicated that AA improves the overall survival and quality of life(QoL)of patients with mCRPC. Herein, we have summarized the development of AA and the results of important international and local clinical trials in Japan. In addition, the effect of food on AA bioavailability, concomitant steroid use, and liver function test abnormalities have been discussed regarding the appropriate use of AA.

[Clinical efficacy and safety of enzalutamide in metastatic castration-resistant prostate cancer: systematic review and meta-analysis]. / Az enzalutamid klinikai hatásossága és biztonságossága metasztatikus, kasztrációrezisztens prosztatarákban: szisztematikus irodalomkeresés és metaanalízis.

Enzalutamide, abiraterone-acetate, and cabazitaxel are licensed post-docetaxel treatments of metastatic castration-resistant prostate cancer (mCRPC) in Hungary. The objectives of the study were to assess the efficacy and safety of post-docetaxel enzalutamide treatment and to compare it with abiraterone and with cabazitaxel, using Medline-based systematic literature search, and meta-analysis of randomised controlled trials (RCT). Overall 3 RCTs were included, one for each substance. Compared to placebo, enzalutamide proved significant efficacy in each primary and secondary endpoint. Enzalutamide extended median overall survival by 4.8 months. Due to lack of a common comparator in the cabazitaxel trial, only enzalutamide and abiraterone were involved in an indirect comparison. No significant difference was identified either in the primary endpoint (overall survival) (HR: 0.97, 95% CI: 0.75-1.25) or in frequencies of adverse events between these two treatments. However, enzalutamide was significantly more efficacious than abiraterone in 3 secondary endpoints: time to prostate-specific antigen (PSA) progression (HR: 0.43, 95% CI: 0.31-0.59), radiographic progression-free survival (HR: 0.6, 95% CI: 0.5-0.72), and PSA response rate (RR: 7.48, 95% CI: 2.83-19.72). Enzalutamide therapy proved clinical efficacy and safety in patients with post-docetaxel mCRPC. In the indirect comparison, efficacy and safety of abiraterone and enzalutamide were found to be similar.

Antitumour activity of abiraterone and diethylstilboestrol when administered sequentially to men with castration-resistant prostate cancer.

BACKGROUND: Abiraterone is a standard treatment for men with castration-resistant prostate cancer (CRPC). We evaluated the antitumour activity of abiraterone following the synthetic oestrogen diethylstilboestrol (DES). METHODS: Castration-resistant prostate cancer patients treated with abiraterone were identified. Demographics, response variables and survival data were recorded. RESULTS: Two-hundred and seventy-four patients received abiraterone, 114 (41.6%) after DES. Pre-chemotherapy abiraterone resulted in ≥50% PSA declines in 35/41 (85.4%) DES-naïve and 20/27 (74.1%) DES-treated patients. Post-docetaxel abiraterone resulted in ≥50% PSA declines in 40/113 (35.4%) DES-naïve and 23/81 (28.4%) DES-treated patients. Time to PSA progression was similar regardless of prior DES. CONCLUSION: Abiraterone has important antitumour activity in men with CRPC even after DES exposure.

The European medicines agency review of abiraterone for the treatment of metastatic castration-resistant prostate cancer in adult men after docetaxel chemotherapy and in chemotherapy-naive disease: summary of the scientific assessment of the committee for medicinal products for human use.

On September 5, 2011, abiraterone was approved in the European Union in combination with prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer (CRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. On December 18, 2012, the therapeutic indication was extended to include the use of abiraterone in combination with prednisone or prednisolone for the treatment of metastatic CRPC in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Abiraterone is a selective, irreversible inhibitor of cytochrome P450 17α, an enzyme that is key in the production of androgens. Inhibition of androgen biosynthesis deprives prostate cancer cells from important signals for growth, even in cases of resistance to castration. At the time of European Union approval and in a phase III trial in CRPC patients who had failed at least one docetaxel-based chemotherapy regimen, median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for those receiving placebo (hazard ratio, 0.65; 95% confidence interval 0.54-0.77; p < .0001). In a subsequent phase III trial in a similar but chemotherapy-naïve patient population, median radiographic progression-free survival was 16.5 months for patients in the abiraterone treatment arm versus 8.3 months for patients in the placebo arm (hazard ratio, 0.53; 95% confidence interval, 0.45-0.62; p < .0001). Abiraterone was most commonly associated with adverse reactions resulting from increased or excessive mineralocorticoid activity. These were generally manageable with basic medical interventions. The most common side effects (affecting more than 10% of patients) were urinary tract infection, hypokalemia, hypertension, and peripheral edema.

Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide.

BACKGROUND: Abiraterone acetate and enzalutamide both improve outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Optimal sequencing for these agents and whether cross-resistance occurs is unknown. METHODS: Multicentre review of patients with mCRPC treated with abiraterone acetate and prednisone after progressing on enzalutamide. Primary objective was to determine abiraterone acetate response. RESULTS: Thirty patients identified from four North American centres. At abiraterone initiation, median age was 70 years (56-84 years); 70% had ECOG performance status of 0-1; all had prior docetaxel. Median prior enzalutamide treatment duration was 41 weeks (6-95 weeks), with 70% (21 of 30) having a ≥30% prostate-specific antigen (PSA) decline. Median abiraterone acetate treatment duration was 13 weeks (1-52). No objective radiographic responses were observed. Median abiraterone time to progression (PSA, objective or symptomatic) was 15.4 weeks [95% confidence interval (CI) 10.7-20.2]. Median overall survival was 50.1 weeks (95% CI 28.3-72.0). Three patients had a ≥30% PSA decline with abiraterone. Two of these patients had PSA progression as best response with prior enzalutamide. CONCLUSIONS: In this study of patients progressing after enzalutamide, treatment with abiraterone was associated with a modest response rate and brief duration of effect. Primary progression on enzalutamide may not preclude a response to abiraterone.

New agents in the arsenal to fight castrate-resistant prostate cancer.

Prior to 2010, the treatment options for castrate-resistant prostate cancer (CRPC) were limited. In the past 3 years, four new agents have been approved by the US Food and Drug Administration for use in CRPC. These four agents differ in their mechanisms of action and highlight the progress made in our understanding of CRPC, and more importantly, provide options with proven clinical benefit. This review examines the development, investigational evolution, adverse events, and future direction of: 1) the androgen receptor inhibitor, enzalutamide, 2) androgen biosynthesis inhibitor, abiraterone, 3) novel taxane chemotherapy, cabazitaxel, and 4) autologous immunotherapeutic agent, sipuleucel-T.