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Background We report secondary and exploratory analysis with 18F-NaF PET/CT and CTCs to determine how tumour burden and RNA expression of androgen receptor (AR) splice variants and neuroendocrine (NE) features predict duration of treatment (DoTx) with ENZA. Methods Men with progressive mCRPC with ≥ 2 lesions on bone scintigraphy were enrolled and treated with ENZA 160 mg daily at 3 US sites. 18F-NaF PET/CT scans were obtained at baseline (BL) (PET1), week 13 (PET2), and at the time of PSA progression (per PCWG2 criteria), standard radiographic or clinical progression, or at 2 years without progression (PET3) using QTBI. CTCs were obtained at BL and at PET3. PSA decline and DoTx were compared with BL QTBI, CTC metrics, and change in QTBI. Results 23 men (median age, 72 years [range, 51-93]; median PSA, 20.5 ng/mL [range, 3.9-133.6]) were enrolled; 22 of which completed planned imaging. The mean number of bone lesions on PET1 was 58 (range 9-168), with a median total standardized uptake value (SUVtotal) of 3886.5 (range 506.7-22852.8). DoTx ranged from 1.4 to 31.8+ mo. In general, SUV metrics decreased while on ENZA (PET2) and increased by PET3. Change in lesion heterogeneity (PET1 to PET3) was the most significant predictor of time to PSA progression (hazard ratio, 3.88; 95% confidence interval, 1.24-12.1). ARV7/9 was found in CTCs in 3/20 men and NE features were found in 4/20 men at BL and in 4/19 and in 11/19 men, respectively, at PET3. Conclusions Although PSA response with ENZA is high, DoTx is variable. SUVtotal at BL did not correlate with DoTx; however, decrease in SUVtotal/mean was associated with increased DoTx, with less heterogeneity correlating with a longer time to PSA progression. ARV7/9 or NE expression in CTCs did not predict lack of benefit from ENZA; however, at the time of progression, the observed increase in ARV7/9 and NE expression are consistent with tumor evolution to more aggressive phenotypes. While BL heterogeneity may be prognostic, it may not predict response or DoTx. Assessing response heterogeneity may predict response duration, thus, should be explored as a possible surrogate of benefit in future studies. Clinical trial identification NCT02384382. Editorial acknowledgement Medical writing and editorial assistance funded by Pfizer Inc. and Astellas Pharma, Inc. was provided by Stephanie Vadasz, PhD, and Michele Salernitano from Ashfield Healthcare Communications. Legal entity responsible for the study Pfizer Inc. and Astellas Pharma, Inc. Funding Pfizer Inc. and Astellas Pharma, Inc. Disclosure G. Liu: Leadership role, Shareholder / Stockholder / Stock options, Employee: AIQ Solutions; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): TRACON Pharma; Research grant / Funding (self), Research grant / Funding (institution): Madison Vaccines Inc.; Research grant / Funding (self), Research grant / Funding (institution): Pfizer Inc. C.E. Kyriakopoulos: Advisory / Consultancy, Travel / Accommodation / Expenses: Exelixis; Speaker Bureau / Expert testimony: The France Foundation; Research grant / Funding (self), Research grant / Funding (institution): Sanofi. J.M. Lang: Shareholder / Stockholder / Stock options, Licensing / Royalties, I am listed on the patent on a technology for rare cell capture and analysis. This technology has been licensed by Salus Discovery, LLC though no commercial products are available: Salus Discovery; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Pfizer Inc.; Research grant / Funding (institution): Novartis. E.I. Heath: Advisory / Consultancy, Research grant / Funding (institution): Agensys; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Honoraria (self): Bayer; Honoraria (self), Research grant / Funding (institution): Dendreon; Honoraria (self), Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Tokai Pharmaceuticals; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Inovio Pharmaceuticals; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Zenith Epigenetics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Esanik; Research grant / Funding (institution): Oncolys BioPharma; Research grant / Funding (institution): CureMeta; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): eFFECTOR Therapeutics; Research grant / Funding (institution): Fortis. S. Perlman: Research grant / Funding (institution): GE Healthcare Progenics; Advisory / Consultancy: Pfizer Inc. T. Mayer: Advisory / Consultancy: Beacon Biosciences/ICON Medical; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Research grant / Funding (institution): Sotio; Research grant / Funding (institution): Merck; Research grant / Funding (self): Pfizer Inc. K. Modelska: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. A. Porcari: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. W. Duggan: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Employee: Pfizer Inc. R. Jeraj: Licensing / Royalties, Patents: Wisconsin Alumni Research Foundation; Shareholder / Stockholder / Stock options: AIQ Solutions; Research grant / Funding (institution): GE Healthcare. All other authors have declared no conflicts of interest.

Background The investigational agent TAK-700 (orteronel) is a selective 17,20-lyase inhibitor that blocks androgen production. Since DP is currently standard chemotherapy in mCRPC, this phase 1/2 study examined TAK-700 + DP in men with mCRPC. Methods The primary phase 2 objective is tolerability of TAK-700 400 mg BID + D (75 mg/m q3w) + P (5 mg BID) in castrate men (testosterone [T] Results 24 men were treated: median age was 66 yrs (range 53–87), ECOG PS 0/1 (88%/12%). At baseline, median PSA was 47 ng/mL (4.5–813) and T was 7.2 ng/dL (3.2–13.8). At data cutoff, 15/24 men remained on study treatment. 22/24 men experienced a treatment-related AE. 3 men discontinued due to AEs (ALT increase, arthralgia, pneumonitis). 21 men (88%) had at least 1 Gr ≥3 AE (19 were drug-related). Drug-related Gr ≥3 AEs ≥10% were WBC decreased (29%); neutropenia (25%); decreased neutrophil count (25%); fatigue, and febrile neutropenia (each 13%). The most common drug-related SAE was febrile neutropenia (13%). As of cutoff, there were no on-study deaths. At 3 mo, PSA30, PSA50, and PSA90 rates in the PSA evaluable population were 59%, 50%, and 18%, respectively. Best PSA decline (median) was -76% (n = 22; -99 to +144%). Median T at 3 mo decreased to ≤0.2 ng/dL (0.3–10.6). Best ORR 50% (n = 10; 80% CI: 27,73; partial response in 5 of 10 evaluable men). Median time to PSA progression was 6.1 mo (95% CI: 4.6, not reached) and median time to radiologic progression was not reached. The Cmax of DP + TAK-700 was similar to that of DP alone. Conclusions TAK-700 400 mg BID + DP appears tolerable and shows androgen-lowering activity and strong PSA and partial tumor response in mCRPC. Plasma levels of D administered with TAK-700 + P were similar to published data on DP without TAK-700. Disclosure D.P. Petrylak: Consultant/Advisor: Amgen, Bayer, Pfizer, Ferring, Millennium, Novartis, Dendreon, Johnson & Johnson, Glaxo Smith Kline Research funding: Celgene, Dendreon, Sanofi, Pfizer, AstraZenca, Glaxo Smith Kline, Rogosen institute, Boehringer Ingelheim, W.R. Clark: Investigator for BMS, Millenium, Lily, Watson, Roll International, Astellas, E.I. Heath: Research funding: Millennium Pharmaceuticals, Ltd. W.K. Oh: Advisor/consultant: Amgen, Pfizer, Sanofi, Dendreon, Bellicum, and Medivation, D.B. Agus: Millenium Pharmaceuticals, Inc./Takeda Advisory Board, S. Moran: Employment: Millennium Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

Aim: Androgen deprivation therapy (ADT) is standard therapy for metastatic PrCa and although most respond, many develop castration resistant prostate cancer (CRPC). Patients with high volume disease have poorer outcomes compared with low volume patients. Docetaxel (D) prolongs the overall survival of men with CRPC and we aimed to see if D improves overall survival when given at time of starting ADT. Methods: 1:1 randomization to ADT alone or ADT + D at 75mg/m2 every 3 weeks for 6 cycles within 4 mos of ADT. Stratification factors: high volume (HV) vs. low volume (LV) disease (HV: visceral metastases and/or 4 or more bone metastases with at least one outside of the vertebral column and pelvis); Anti-androgen use beyond 30 days; Age ≥70 vs. 12 vs. ≤ 12 mos (mos); FDA approved drug for delaying skeletal related events. Key eligibility criteria: suitable organ and neurological function for D; adjuvant ADT ≤ 24 mos and no progression within 12 mos of adjuvant ADT. Overall survival was the primary endpoint with an improvement in median OS of 33.3% (80% power and 1-sided alpha = 2.5%). Projected median OS for ADT alone: HV-33 mos; LV - 67 mos. Results: 790 men were accrued from 7/28/06 to 11/21/2012: ADT n = 393; ADT + D: 397; balanced for demographic, stratification and disease factors. Median age: 63 years (range: 36 to 91); 99% ECOG PS 0 or 1; 89% Caucasian; 24% prior prostatectomy; HV 64% on ADT and 67% on ADT + D. ADT + D: Gde 3/4 Neutropenic fever: 4/2%; Gde 3 neuropathy: 1% sensory, 1% motor; 1 death due to treatment was in the LV subset (no death on ADT alone). Efficacy data for high volume subset of pts in table 1. Conclusions: ADT + D improves disease control and OS over ADT alone in men with HV disease. NCT00309985 Disclosure: C. Sweeney: Consultant with compensation: Sanofi; M. Carducci: Compensated consultant; M. Eisenberger: Compensated consultant. All other authors have declared no conflicts of interest. Intent to treat Analysis High Volume Pts ADT N = 253 ADT + D N = 265 p-value Hazard Ratio (95%CI * ) PSA 6.3% 15.5% 0.0011 N with PSA or clinical PD 137 113 Time to PSA or clinical PD 8.8 mos 15.0 mos 0.55(0.42-0.71) N with clinical PD 112 70 Time to clinical PD 14.1 mos 29.5 mos 0.43 (0.32-0.59) N with docetaxel for CRPC 98 38 Median OS 32.2 mos 49.2 mos 0.0013 0.62 (0.46, 0.83) * CI: confidence intervals; #PD: progressive disease in months; N = number of patients

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.