Background: MDV3100, a novel androgen receptor signaling inhibitor (ARSI), competitively inhibits binding of androgens to the androgen receptor (AR), inhibits AR nuclear translocation, and inhibits association of the AR with DNA (Tran et al, Science. 2009;324:787). MDV3100 was selected for development based on activity in prostate cancer model systems with overexpressed AR, and was active in a phase I-II trial enrolling pre- and post-chemotherapy treated patients with progressive castration resistant disease (CRPC) (Scher et al, Lancet. 2010;375:1437). The AFFIRM trial evaluated whether MDV3100 could prolong overall survival (OS) in men with CRPC who progressed following docetaxel-based chemotherapy. Methods: In this randomized, double-blind, placebo-controlled, multinational phase III study (NCT00974311), patients who had received ≤ 2 regimens of docetaxel-based chemotherapy were randomized 2:1 to MDV3100 160 mg/day or placebo. Treatment with corticosteroids was allowed but not required. Patients were stratified by baseline ECOG performance status and mean brief pain inventory score. The primary endpoint was OS. Other efficacy endpoints included radiographic progression-free survival (PFS), time to first skeletal-related event, time to prostate-specific antigen (PSA) progression, and circulating tumor cell count conversion rate. Results: 1,199 patients were randomized between Sep 2009 and Nov 2010. Based on a planned interim analysis at 520 death events, the Independent Data Monitoring Committee (IDMC) recommended the study be unblinded and placebo patients offered MDV3100 due to a significant OS benefit (p<0.0001; hazard ratio 0.631). The estimated median OS was 18.4 months for MDV3100 treated compared to 13.6 months for placebo treated men, a median OS difference of 4.8 months. Data to be available include PFS, time to PSA progression, and safety. Conclusions: MDV3100, a novel ARSI, significantly improves OS in men with postdocetaxel-treated CRPC reducing the risk of death by 37% relative to placebo. The IDMC determined the risk:benefit of MDV3100 was favorable and recommended the phase III AFFIRM trial be unblinded.