A phase II study of the androgen signaling inhibitor ARN-509 in patients with castration-resistant prostate cancer (CRPC).

TPS4697 Background: ARN-509 is a novel small molecule androgen signaling inhibitor that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. Preclinical data suggests that the maximal therapeutic index of ARN-509 can be achieved at low steady state plasma levels with minimal toxicity (Clegg et al, 2012). Enrollment in the Phase 1 dose escalation study of ARN-509 in patients with progressive CRPC with and without prior chemotherapy was completed in January 2012. The recommended Phase 2 dose of 240 mg was determined based on safety, PSA kinetics, and pharmacokinetic and pharmacodynamic analysis (Rathkopf et al, GU ASCO, 2012). Methods: The primary objective of this Phase 2 study is to determine the PSA response at 12 weeks according to Prostate Cancer Working Group 2 (PCWG2) Criteria (Scher et al, 2008). Three expansion cohorts will enroll a total of 80-90 patients for treatment with 240 mg continuous oral ARN-509 daily. These cohorts include: 1) non-metastatic treatment-naïve CRPC (50 patients); 2) chemotherapy-naïve metastatic (m) CRPC (20 patients); and 3) chemotherapy-naïve, post abiraterone mCRPC (10-20 patients). The effect of food on the PK of ARN-509 and the effect of ARN-509 on ventricular repolarization will also be evaluated. Phase 2 enrollment is ongoing. DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals. NCT01171898.