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Context In addition to genetic alterations, epigenetic alterations play a crucial role during prostate cancer progression. A better understanding of the epigenetic factors that promote prostate cancer progression may lead to the design of rational therapeutic strategies to target prostate cancer more effectively. Objective To systematically review recent literature on the role of epigenetic factors in prostate cancer and highlight key preclinical and translational data with epigenetic therapies. Evidence acquisition We performed a systemic literature search in PubMed. At the request of the editors, we limited our search to articles published between January 2015 and August 2020 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Clinical trials targeting epigenetic factors were retrieved from clinicaltrials.gov. Evidence synthesis We retrieved 1451 articles, and 62 were finally selected for review. Twelve additional foundational studies outside this time frame were also included. Findings from both preclinical and clinical studies were reviewed and summarized. We also discuss 12 ongoing clinical studies with epigenetic targeted therapies. Conclusions Epigenetic mechanisms impact prostate cancer progression. Understanding the role of specific epigenetic factors is critical to determine how we may improve prostate cancer treatment and modulate resistance to standard therapies. Recent preclinical studies and ongoing or completed clinical studies with epigenetic therapies provide a useful roadmap for how to best deploy epigenetic therapies clinically to target prostate cancer. Patient summary Epigenetics is a process by which gene expression is regulated without changes in the DNA sequence itself. Oftentimes, epigenetic changes influence cellular behavior and contribute to cancer development or progression. Understanding how epigenetic changes occur in prostate cancer is the first step toward therapeutic targeting in patients. Importantly, laboratory-based studies and recently completed and ongoing clinical trials suggest that drugs targeting epigenetic factors are promising. More work is necessary to determine whether this class of drugs will add to our existing treatment arsenal in prostate cancer.

Summary Background The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. Methods For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. Findings 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7–10·6). Biochemical failure (R2 0·38 [95% CI 0·11–0·64]), biochemical failure-free survival (R2 0·12 [0·0030–0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045–0·65]), and local failure (R2 0·085 [0·00–0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22–0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59–0·89]) correlated strongly. Interpretation Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. Funding Prostate Cancer Foundation and National Institutes of Health.

Neuroendocrine prostate cancer (NEPC) is the most virulent form of prostate cancer. Importantly, our recent work examining metastatic biopsy samples demonstrates NEPC is increasing in frequency. In contrast to prostate adenocarcinomas that express a luminal gene expression program, NEPC tumors express a neuronal gene expression program. Despite this distinction, the diagnosis of NEPC is often challenging, demonstrating an urgent need to identify new biomarkers and therapeutic targets. Our prior work demonstrated that the histone demethylase LSD1 (KDM1A) is important for survival of prostate adenocarcinomas, but little was known about LSD1’s role in NEPC. Recently, a neural-specific transcript variant of LSD1—LSD1+8a—was discovered and demonstrated to activate neuronal gene expression in neural cells. The splicing factor SRRM4 was previously shown to promote LSD1+8a splicing in neuronal cells, and SRRM4 promotes NEPC differentiation and cell survival. Therefore, we sought to determine if LSD1+8a might play a role in NEPC and whether LSD1+8a splicing was linked to SRRM4. To investigate a potential role for LSD1+8a in NEPC, we examined a panel of prostate adenocarcinoma and NEPC patient-derived xenografts and metastatic biopsies. LSD1+8a was expressed exclusively in NEPC samples and correlated significantly with elevated expression of SRRM4. Using SRRM4-overexpressing cell lines, we determined that SRRM4 mediates alternative splicing of LSD1+8a. Finally, using gain of function studies, we confirmed that LSD1+8a and SRRM4 co-regulate target genes distinct from canonical LSD1. Our findings suggest further study of the interplay between SRRM4 and LSD1+8a and mechanisms by which LSD1+8a regulates gene expression in NEPC is warranted.

The net oncogenic effect of β2-adrenergic receptor ADRB2, whose downstream elements induce neuroendocrine differentiation and whose expression is regulated by EZH2, is unclear. ADRB2 expression and associated clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) are unknown.This was a retrospective analysis of a multi-center, prospectively enrolled cohort of mCRPC patients. Metastatic biopsies were obtained at progression, and specimens underwent laser capture microdissection and RNA-seq. ADRB2 expression was stratified by histology and clustering based on unsupervised hierarchical transcriptome analysis and correlated with EZH2 expression; an external dataset was used for validation. The association between ADRB2 expression and overall survival (OS) was assessed by log-rank test and a multivariable Cox proportional hazard model.One hundred and twenty-seven patients with progressive mCRPC had sufficient metastatic tumor for RNA-seq. ADRB2 expression was lowest in the small cell-enriched transcriptional cluster (P0.01) and correlated inversely with EZH2 expression (r = -0.28, P0.01). These findings were validated in an external cohort enriched for neuroendocrine differentiation. Patients with tumors harboring low ADRB2 expression (lowest quartile) had a shorter median OS than those with higher (9.5 vs. 20.5 months, P = 0.02). In multivariable analysis, low ADRB2 expression was associated with a trend toward shorter OS (HR for death = 1.54, 95%CI 0.98-2.44). Conversely, higher expression of upstream transcriptional regulator EZH2 was associated with shortened OS (HR for death = 3.01, 95%CI 1.12-8.09).Low ADRB2 expression is associated with neuroendocrine differentiation and is associated with shortened survival. EZH2 is a potential therapeutic target for preventing neuroendocrine transdifferentiation and improving outcomes in mCRPC. Further studies of agents targeting β-adrenergic signaling are warranted.

Background Immunotherapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), an agent that previously demonstrated antitumor activity, was evaluated within an intermittent chemotherapy framework of docetaxel with prednisone (D+P) in metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods mCRPC patients with ≥ 50% prostate-specific antigen (PSA) decline after 6 cycles of D+P were randomized to either GM-CSF or observation (Obs). At disease progression (PD), D+P was reinitiated for 6 cycles followed by the same “off chemotherapy” regimen in patients eligible for chemotherapy interruption. The sequence was repeated until PD during chemotherapy, lack of PSA response to chemotherapy, or unacceptable toxicity. The primary end point was time to chemotherapy resistance (TTCR). Results Of 125 patients enrolled, 52 (42%) experienced ≥ 50% PSA decline on induction D+P and were randomized to GM-CSF (n = 27) or Obs (n = 25). The median time to PD was 3.3 months (95% confidence interval [CI], 2.4-3.5) and 1.5 months (95% CI, 1.5-2.4) during the initial course of GM-CSF and Obs, respectively. Twelve of 26 (46%) patients responded to a second course of D+P. Eleven randomized patients (21%) experienced PD during chemotherapy, precluding accurate assessment of TTCR. The remaining 41 randomized patients discontinued study for lack of PSA response to chemotherapy (n = 8), patient choice to not restart chemotherapy with PSA PD (n = 13), toxicity (n = 7), or study withdrawal (n = 13). Conclusion Conducting a prospective study in mCRPC with maintenance immunotherapy within the framework of intermittent chemotherapy was feasible. The use of PSA instead of radiographic end points limited the number of evaluable patients. This study provides important insight into designing contemporary intermittent chemotherapy trials with maintenance immunotherapy in patients with advanced prostate cancer.

Background PD-1 inhibition (α-PD-1) can lead to deep, durable responses in mCRPC, but only in a minority of patients (pts). We previously reported 5 (18%) responders among 28 pts. No marker has been shown to universally predict response. Analysis of fecal microbiota from pts with epithelial cancers showed an association between elevated Akkermansia muciniphila (A. muc) levels and response to α-PD-1. To evaluate predictive markers, we treated an additional 30 pts obtaining tumor biopsies, blood, and fecal specimens collected for analysis. Methods 30 pts with mCRPC progressing on Enz received α-PD-1 pembrolizumab 200 mg IV every 3 weeks for 4 doses with continued Enz. Prior chemotherapy for mCRPC was prohibited. The primary endpoint was the proportion of pts with a prostate-specific antigen (PSA) decline ≥ 50%. The secondary endpoints were objective response, PSA progression-free survival (PFS), radiographic PFS, overall survival (OS) and correlative studies. Results Four of 30 (13%) achieved a PSA reduction ≥ 50%. Six of 24 (25%) pts with measurable disease responded radiographically. After median follow up of 17.4 months (mos), median PSA PFS was 5.57 mos (95%CI: 3.48-8.06). Median OS was 17.25 mos (95% CI: 7.71-17.68). Of 27 pts evaluable for radiographic PFS, 17 (63%) have progressed; median radiographic PFS was 5.26 mos (95% CI: 2.6-11.2). Eight pts had immune related adverse events. Single cell analysis revealed that immune cells represent an average 0.5% of cells in tumor biopsies. Single cell transcriptomic analysis prior to α-PD-1 in 12 pts revealed enrichment in a CD8+ exhausted T cell population (p Conclusions Using single cell RNA sequencing, we reveal a T-cell signature associated with response, an observation not possible at the bulk transcriptome level. Responders had lower levels of fecal A. muc than non-responders, suggesting markers of α-PD-1 response in mCRPC may be different than in other cancer types. Clinical trial identification NCT02312557. Legal entity responsible for the study Julie N Graff. Funding Merck Sharp & Dohme. Disclosure J.N. Graff: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas/Pfizer. A.E. Moran: Research grant / Funding (institution): Merck Sharp & Dohme. J.J. Alumkal: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Janssen Biotech; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Zenith Epigenetics Ltd; Research grant / Funding (institution): Gilead Sciences Inc. R.C. Bergan: Leadership role, Licensing / Royalties, Full / Part-time employment: Third Coast Therapeutics. T.M. Beer: Research grant / Funding (institution): Alliance Foundation Trials; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Corcept Therapeutics; Research grant / Funding (institution): Endocyte Inc; Research grant / Funding (institution): Janssen Research & Development; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): OncoGenex; Research grant / Funding (institution): Sotio; Research grant / Funding (institution): Theraclone Sciences/OncoResponse; Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Janssen Biotech; Honoraria (self), Advisory / Consultancy: Janssen Japan; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.

We previously reported that higher serum concentrations of C-reactive protein (CRP) are associated with shorter survival in men with castration-resistant prostate cancer (CRPC). To confirm this finding in an independent data set, we used 119 CRPC patients enrolled in 6 phase II clinical trials and examined the relationship of CRP, alkaline phosphatase, hemoglobin, age, ECOG PS, and prostate specific antigen (PSA) with survival. Median follow-up was 19.7 months (0.9-98.5 months), and 89% have died. After analyzing the form of the risk function using the generalized additive model method, univariate and multivariate Cox proportional hazard models were used to assess associations between baseline individual categorical and continuous variables. Quartiles of CRP were: 0-1.0, 1.1-4.9, 5.0-17.0, and 17.1-311 mg/L. In a Cox multivariate model, log(2) (CRP) (HR 1.106, P = 0.013) as well as hemoglobin and alkaline phosphatase were independently associated with survival, confirming that higher CRP is associated with shorter survival in CRPC. Since CRP is a marker of inflammation, this finding suggests that inflammation may play an important role in the natural history of advanced prostate cancer. CRP is a readily measurable biomarker that has the potential to improve prognostic models and should be validated in a prospective clinical trial.

Background Abiraterone acetate (AA) inhibits androgen biosynthesis and prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) when combined with prednisone (P). Resistance to therapy remains incompletely understood. In this open-label, single-arm, multicenter phase II study we investigated the clinical benefit of increasing the dose of AA at the time of resistance to standard-dose therapy. Patients and Methods Eligible patients had progressive mCRPC and started AA 1000 mg daily and P 5 mg twice daily. Patients who achieved any prostate-specific antigen (PSA) decline after 12 weeks of therapy continued AA with P until PSA or radiographic progression. At progression, AA was increased to 1000 mg twice daily with unchanged P dosing. Patients were monitored for response to therapy for a minimum of 12 weeks or until PSA or radiographic progression. The primary end point was PSA decline of at least 30% after 12 weeks of therapy at the increased dose of AA. Results Forty-one patients were enrolled from March 2013 through March 2014. Thirteen men experienced disease progression during standard-dose therapy and were subsequently treated with AA 1000 mg twice per day. Therapy was well tolerated. No PSA declines ≥ 30% nor radiographic responses were observed after 12 weeks of dose-escalated therapy. Higher baseline dehydroepiandrosterone levels, lower circulating tumor cell burden, and higher pharmacokinetic levels of abiraterone and abiraterone metabolites were associated with response to standard-dose therapy. Conclusion Increasing the dose of abiraterone at the time of resistance has limited clinical utility and cannot be recommended. Lower baseline circulating androgen levels and interpatient pharmacokinetic variance appear to be associated with primary resistance to AA with P.

Since the advent of prostate-specific antigen testing, most prostate cancers are now detected in an early, organ-confined stage. Because of this, local therapies including radical prostatectomy and irradiation have become more common in the treatment of men with prostate cancer. Nonetheless, relapse of disease remains a major problem. In the past decade, many groups have studied the early use of chemotherapy with or without hormonal therapy after radical prostatectomy, specifically, and found it to be safe. In this article, we will summarize the data for neoadjuvant and adjuvant chemotherapy and chemohormonal therapy in conjunction with radical prostatectomy. We will also highlight more recent clinical trial designs, including a multicenter pilot study of adjuvant docetaxel therapy, which has several important distinctions when compared with previous studies, including the active chemotherapeutic agent docetaxel, better risk-adapted patient accrual, and higher statistical power. Although data for this study are not yet mature, these differences in clinical trial design make such studies in adjuvant chemotherapy for patients with high-risk prostate cancer novel and promising.

Aim: In the PREVAIL trial, enzalutamide, an androgen receptor signaling inhibitor, significantly improved overall survival (OS) (HR, 071; p Methods: PREVAIL was a Phase 3 multinational, double-blind study in chemotherapy-naive men with asymptomatic or mildly symptomatic mCRPC. Co-primary endpoints were OS and rPFS. Best soft tissue objective response, a secondary endpoint, was defined as partial or complete response (PR or CR) per RECIST 1.1 criteria in patients with measurable disease at baseline. Results: A total of 1717 men were randomized (1715 treated) including 1513 (88.1%) without and 204 (11.9%) with visceral disease at screening (139 lung, 74 liver and 9 both). Patients with visceral disease had higher baseline median PSA than those without visceral disease (72.5 ng/mL and 46.8 ng/mL, respectively), worse performance status (38.2% and 31.1% ECOG PS = 1), and higher rates of lymph node disease (57.8% and 49.8%), but similar rates of bone disease (80.4% and 83.7%). Adverse event rates were similar to the full study population. Conclusions: Visceral metastases were permitted in the PREVAIL trial of men with chemotherapy-naive mCRPC. Enzalutamide was active in this small group of patients; post-hoc analyses showed benefit vs placebo on OS, rPFS, and secondary endpoints. Response rates were higher for lung vs liver metastases. These results support androgen receptor signaling as an important target in prostate cancer with visceral metastases. Response Rates and Study Outcomes in PREVAIL Total Visceral Disease Cohort Lung and/or Liver (n = 204) Median (months) Enzalutamide/Placebo HR (95% CI) rPFS NYR/3.6 0.28 (0.16, 0.49) OS 27.8/22.8 0.82 (0.55, 1.23) Time to cytotoxic chemotherapy 22.6/6.6 0.30 (0.20, 0.45) Time to PSA progression (PCWG2 criteria) 11.1/2.9 0.16 (0.10, 0.26) Time to first skeletal-related event 29.5/NYR 0.69 (0.43, 1.11) Visceral Disease Cohort With Baseline Measurable Soft Tissue Disease * Liver Lung Enzalutamide (N= 31) Placebo (N= 28) Enzalutamide (N= 25) Placebo (N= 36) Best Objective Response (95% CI) 29.0% (14.2-48.0) 0.0 (0.0 - 12.3) 60.0% (38.7-78.9) 0.0% (0.0- 9.7) Complete Response 6.5% 0.0% 8.0% 0.0% Partial Response 22.6% 0.0% 52.0% 0.0% * Defined as at least one target lesion per RECIST 1.1. Disclosure: C. Higano: Consultant: Astellas/Medivation, Bayer, Dendreon, Johnson & Johnson Research Funding: Alegra, Aragon, Astellas/Medivation, Dendreon, Sanofi; S. Chowdhury: Advisory Board/Lectures: Astellas, Janssen Cilag, Sanofi-Aventis, Dendreon Speaker: GSK; Y. Loriot: Consultant/Advisory: Astellas Research Funding: Astellas Other: Sanofi, Cellgene, Bayer, Jansen; C.N. Sternberg: Honoraria: Astellas, Johnson & Johnson, Ipsen, Bayer, Millenium; J.S. de Bono: Astellas/Medivation; B. Tombal: Advisor: Medivation, Astellas, Ferring Speaker: Astellas, Ferring; F.G. Perabo: Employee: Astellas Pharma; D. Forer, S. Noonberg and H. Mansbach: Employee: Medivation; T. Beer: Research Funding: Astellas/Medivation, Janssen Consultant: Janssen. All other authors have declared no conflicts of interest.

Aim: The mechanisms of resistance to androgen signaling inhibitors such as Abi or Enz are poorly understood. A growing proportion of these pts are developing treatment resistant NEPC. Progressive mCRPC has historically been challenging to biopsy and characterize on a molecular basis because of its bone tropism. As part of the WCDT project, which aims to identify genetic pathways underlying primary and acquired resistance to Abi and Enz, RNA sequencing (RNAseq) was used to develop a NEPC expression signature in mCRPC biopsies. Methods: Following central radiologic review, eligible mCRPC pts underwent a metastasis (met) biopsy at one of 5 WCDT clinical sites, using a uniform biopsy protocol. Tissue was both frozen, and formalin fixed/paraffin embedded (FFPE). Frozen specimens underwent laser capture micro-dissection, RNA isolation, library preparation and RNAseq. Machine learning was used to derive NEPC markers from mCRPC adenocarcinoma and met NEPC RNAseq data. FFPE tissue was evaluated histologically, including NEPC markers. Results: 85 of 300 planned mCRPC pts have undergone a met biopsy. To date, 53 specimens have been evaluated histologically. Histologically identified NEPC was present in 17 (32%) of biopsies overall, 12% of bone biopsies, 64% of lymph nodes, and 27% of liver biopsies. To date RNAseq data are available on 20 pts, including 6 with NEPC. A106 gene signature for met NEPC was developed from this learning set. Conclusions: Genomic sequencing and expression analysis can be accomplished in small bone and soft tissue mCRPC biopsies. The development of NEPC is a common event in mCRPC resistant to ABi or Enz. The majority of liver metastases are not NEPC. A 106 gene signature was derived from this met NEPC learning set and has identified a number of genes that provide insight into the biology and potential treatment of NEPC. Disclosure: All authors have declared no conflicts of interest.

Aim: ARN-509 selectively binds the androgen receptor and impairs its nuclear translocation and DNA binding to androgen response elements. Study ARN-509-001 evaluates ARN-509 activity in pts with high-risk M0 CRPC, chemotherapy-naive metastatic CRPC (mCRPC), and mCRPC post abiraterone acetate. We report the updated results for the M0 CRPC cohort as of February 2014. Methods: All pts had CRPC with no radiographic evidence of metastases (pelvic lymph nodes Results: M0 CRPC cohort enrolled 51 pts from Nov 2011 to Jun 2012; 4 pts had metastatic disease and were excluded from the efficacy analysis. Median age was 71 years (range 51–88). Baseline characteristics were: ECOG performance status, 0 (76%); Gleason score, ≤ 7 (57%); median PSA, 10.7 ng/mL (range 0.5-201.7); and PSADT, ≤ 10 mos (45%). All pts received prior treatment with a luteinizing hormone–releasing hormone analog with or without a first-generation antiandrogen. At median follow-up of 20.2 mos, 29 (57%) pts remain on study. Pts discontinued due to disease progression (n = 7), adverse events (AEs) (n = 7), or other reasons (n = 8). Most common treatment-emergent AEs: fatigue (57%), diarrhea (41%), nausea (29%), dysgeusia (20%), arthralgia (18%), and weight decreased (16%). No seizures were reported. Efficacy M0 CRPC N 47 PSA responsea,b, n (%) 12 wks 42/46 (91) 24 wks 40/46 (87) 36 wks 22/46 (48) Median time to PSA progression, wks (95% CI) NR (67, NR) Median MFS, wks (95% CI) NR (NR, NR) NR, not reached. a≥ 50% decline in PSA from baseline per PCWG2. b1 pt did not have postbaseline PSA results. Conclusions: ARN-509 is well tolerated in pts with high-risk M0 CRPC with robust activity based on durable PSA responses and disease control. Disclosure: M.R. Smith: has served as a consultant/advisor to and received research funding from Janssen; E.S. Antonarakis: has received honoraria and research funding from Janssen; C.J. Ryan: has received honoraria from Janssen;W. Berry: has served on a speaker bureau for Janssen;N.D. Shore: has served as a consultant/advisor to Astellas, Algeta, Bayer, Ferring, Dendreon, Janssen, Millennium, Sanofi, and BNIT;G. Liu: has received research funding from Aragon and Janssen;C. Higano: has served as a consultant/advisor to Astellas/Medivation, Bayer, Dendreon, and Johnson & Johnson, and has received research funding from Algeta, Aragon, Astellas/Medivation, Dendreon, and Sanofi;R. Bandekar, C. De Boer, M. Todd and M. Yu: is an employee of Janssen and holds stock in Johnson & Johnson;D.E. Rathkopf: has served as a consultant/advisor for Johnson & Johnson and has received research funding (uncompensated) from Celgene, Janssen/J&J, Medivation/Astellas, Millennium, and Novartis. All other authors have declared no conflicts of interest.

Background ARN-509 is a novel second-generation anti-androgen that binds directly to the ligand-binding domain of the androgen receptor, impairing nuclear translocation and DNA binding. The Phase II portion of a multicenter Phase I/II study is evaluating the activity of ARN-509 in 3 distinct patient populations of men with CRPC (high risk non-metastatic CRPC, metastatic treatment-naive CRPC, and progressive disease after abiraterone acetate). Preliminary results for the cohort of patients with high-risk non-metastatic CRPC are presented here. Methods All patients had CRPC, no radiographic evidence of metastases (pelvic lymph nodes Results Fifty patients were enrolled between November 2011 and May 2012. The median age was 72 years (range 51 to 86) and at baseline, patients presented with ECOG performance status 0 (67%), Gleason Score 8-10 (38%), and median PSA of 11.5 ng/mL. All patients received prior treatment with a LHRH analog with or without a first-generation anti-androgen. At a median treatment duration of 8 weeks, only one patient discontinued the study (due to inability to comply with the protocol). The most common adverse events (AE) were fatigue (13%), diarrhea (9%), nausea (6%) and abdominal pain (6%). There were no Grade > 2 AEs and no patients required dose modifications. At 12 weeks, 17/19 patients (89.5%) of patients had a PSA response. The median decrease in PSA from baseline to week 12 was 83.3%. Conclusion In men with high-risk non-metastatic CRPC, ARN-509 is safe and well tolerated with promising preliminary activity based on high PSA response rates. Disclosure E. Chow-Maneval: As an employee of Aragon Pharmaceuticals, I have stock ownership in Aragon Pharmaceuticals.All other authors have declared no conflicts of interest.

Background ARN-509 is a novel second-generation anti-androgen that binds directly to the ligand-binding domain of the androgen receptor, impairing nuclear translocation and DNA binding. The Phase II portion of a multicenter Phase I/II study is evaluating the activity of ARN-509 in 3 distinct patient populations of men with CRPC: 1) non-metastatic treatment-naive CRPC; 2) mCRPC treatment-naive (tx-naive); and 3) mCRPC abiraterone acetate pre-treated (AA). Preliminary results for the 2 cohorts of patients with metastatic CRPC are presented here. Methods All patients had metastatic CRPC with progressive disease based on rising PSA and/or imaging. No prior chemotherapy for metastatic prostate cancer was allowed. Patients on the AA pre-treated cohort had to have been treated with AA for at least 6 months. All patients received ARN-509 at the recommended Phase II dose of 240 mg/day (Rathkopf et al, GU ASCO 2012). The primary endpoint was PSA response rate at 12 weeks according to the Prostate Cancer Working Group 2 Criteria in each of the treatment groups. Secondary endpoints included safety, time to PSA progression and objective response rates. PSA assessments were collected every 4 weeks and tumor imaging was performed every 16 weeks. Results To date, 32 patients have been enrolled: 25 on the tx-naive and 7 on the post-AA cohorts, respectively. The combined median age was 67 (range 51-91) and at baseline, patients presented with ECOG performance status 0 (55%), Gleason Score 8-10 (54%), and median PSA of 14.7 (tx-naive) and 69.6 (post-AA) ng/mL. All patients received prior treatment with a LHRH analog with or without a first-generation anti-androgen. At a median treatment duration of 16 weeks, 4 patients discontinued the study due to disease progression, 2 in each cohort. The most common treatment-related adverse events (AE) were abdominal pain (36%), diarrhea (19%), nausea (16%) and fatigue (10%). There was only 1 treatment-related Grade 3 AE of abdominal pain. At 12 weeks, the PSA response was 91% (tx-naive) and 60% (post-AA), respectively. Conclusion In men with CRPC, ARN-509 is safe and well tolerated with promising preliminary activity in metastatic, chemo-naive patients both before and after treatment with abiraterone. Disclosure E. Chow-Maneval: Dr. Chow Maneval is an employee of Aragon and holds stock in the company. All other authors have declared no conflicts of interest.

Background Androgen deprivation therapy (ADT) is the standard treatment of hormone-sensitive metastatic prostate cancer (HSMPC). We performed a phase III multicentre trial to compare ADT alone with ADT plus docetaxel (D) in HNMPC. Methods Patients (pts) with HSMPC were randomly assigned to either arm A (ADT + D: 75mg/m q3w, up to 9 cycles) or arm B (ADT). The primary endpoint was overall survival (OS). The planned number of pts was 378 to detect an improvement in OS with a hazard ratio (HR) of 0.62, a power of 80% and an alpha risk of 0.05 (two-sided test). Secondary endpoints were biological progression-free survival (PFS) and clinical PFS. Data on toxicity and quality of life have been previously presented. Results From October 2004 to December 2008, 385pts were included. Baseline characteristics were well balanced between the two arms. Median age was 63 years (43-84), median PSA was 26.4 ng/ml (0.1-11900), Gleason score was ≥ 8 in 57%. Prognostic classification was as follows: good prognosis (49%), intermediate (29%) and poor (22%). The majority of pts had metastases at the time of diagnosis (72%), 28% developed metastases after local treatment failure. Median number of D cycles was 8 (range 0-9). The median follow-up was 50 months (mo) [95%CI: 49-54]. At 6 mo, a higher PSA response (≥ 50%) in arm A (94% vs 85%, p = 0.0096) and a higher PSA progression (≥ 25%) in arm B (10% vs 1%, p = 0.0015) were observed. Biological PFS was significantly longer in arm A: 22.9 vs 12.9 mo, HR; 0.72 [95%CI: 0.57-0.91] (p = 0.005). Clinical PFS was increase in arm A: 23.46 vs 15.44 mo, HR: 0.75 [95CI: 0.59-0.94] (0.015). OS was not significantly different (median: 58.9 mo in arm A and 54.2 mo in arm B, HR: 1.01 [95%CI: 0.75-1.36]. The median OS for each prognostic group was 69.1 [95%CI: 60.9-NR], 46.5 [95%CI: 37.7-NR] and 36.6 [95%CI9: 28.5-58.9] mo respectively in the good, intermediate, and poor prognosis groups (p = 0.001), with no difference between the two arms. At the cut-off time, 65% of pts from the ADT arm had received docetaxel since they developed castrate-resistant prostate cancer. Conclusion Combining docetaxel and ADT improves PFS over ADT alone in pts with HSMPC. However, no difference in OS was observed between the two arms. Disclosure G. Gravis: I have expert testimony to disclose: Sanofi Aventis, uncompensated. K. Fizazi: Participation to advisory boards and speaker for Sanofi-Aventis. F. Joly Lobbedez: advisory board/board of directors position: Sanofi, Roche, Pfizer, Novartis, Ferring; compensated consultant relationship: Roche, Novartis; honoraria: Sanofi, Roche, Pfizer, Novartis, Ferring, Ipsen,Takeda; travel remuneration: ASCO by Novartis, ESMO by Janssen. S. Oudard: I have an advisory relationship and honoraria to disclose: Pfizer Oncology, Bayer-Schering Pharma, Hoffman La Roche, Glaxo SmithKline, Novartis Pharma, Sanofi Aventis. D. Pouessel: Consultant role and honoraria: Sanofi, P. Beuzeboc: Presentations: Avantis, All other authors have declared no conflicts of interest.