ARN-509 in Men with Metastatic Castration-Resistant Prostate Cancer (CRPC)

ABSTRACT 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.