ARN-509 in men with metastatic castration-resistant prostate cancer (mCRPC).

Abstract

48 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-naïve CRPC; 2) mCRPC treatment-naïve (tx-naïve); 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: A total of 46 patients were enrolled: 25 on the tx-naïve and 21 on the post-AA cohorts. The combined median age was 68 (range 48-91) and at baseline, patients presented with ECOG performance status 0 (57%), Gleason Score 8-10 (52%), and median PSA of 14.7 (tx-naïve) and 58.4 (post-AA) ng/mL. All patients received prior treatment with a LHRH analog with or without a first-generation anti-androgen. To date, 15 patients discontinued the study due to disease progression (11), adverse events (2) and consent withdrawn (2). The most common treatment-related adverse events (AE) were fatigue (30%), abdominal pain (24%), nausea (22%), and diarrhea (17). There was only 1 treatment-related Grade 3 AE of abdominal pain. At 12 weeks, the PSA response was 88% (tx-naïve) and 29% (post-AA). Conclusions: In men with mCRPC, ARN-509 is safe and well tolerated, with robust PSA response in the tx-naïve cohort. Post-AA data suggests that ARN-509 has activity in a subset of patients that developed resistance to abiraterone acetate. Clinical trial information: NCT01171898.