Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC) Results of phase III PREVAIL study

SUMMARY: Prostate Cancer is driven by androgens (primarily testosterone) and androgen signaling pathways. There is evidence to suggest that prostate cancer cells continue to depend on androgen receptor (AR) signaling even in an androgen-deprived environment. Therefore, targeting AR and AR signaling pathways remains a rational approach in the treatment of Castration Resistant Prostate Cancer (CRPC). The first generation anti-androgen agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. XTANDI® (Enzalutamide) is a second-generation anti-androgen with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway. XTANDI® was first approved by the FDA in 2012, for the treatment of patients with metastatic CRPC who have previously received TAXOTERE® (Docetaxel) based chemotherapy. The PREVAIL study is a double-blind, placebo-controlled, phase III trial in which 1,717 chemotherapy-naive patients with mCRPC (metastatic Castrate Resistant Prostate Cancer) were randomly assigned 1:1 to receive either XTANDI® 160 mg/day or placebo. Prior treatment with surgery or radiation therapy for their primary tumor, as well as hormonal intervention with a LHRH (Luteinizing Hormone Releasing Hormone) agonist or first-generation anti-androgen was allowed. The two co-primary endpoints were Overall Survival (OS) and radiographic Progression Free Survival (rPFS), as measured by bone scans and CT scans. At the time of preplanned interim analysis, XTANDI® demonstrated a statistically significant benefit over placebo with a 30% reduction in risk of death (OS: HR= 0.70; P< 0.0001) and an 81% reduction in risk of radiographic Progression Free Survival (rPFS: HR 0.19; P< 0.0001). Further, the response rates were meaningful with 20% complete responses and 39% partial responses (59% Response Rate) compared with 5% Response Rate in the placebo group (P<0.0001). XTANDI® also significantly delayed the median time to chemotherapy by 17 months compared with those who took placebo (P<0.0001). Based on the results of this interim analysis, the Independent Data Monitoring Committee recommended stopping the study and allowing patients in the placebo group to receive XTANDI®. XTANDI® was well tolerated and the most common side effects were hot flashes, weight gain, fatigue, constipation, back and joint pain. The authors concluded that XTANDI® significantly improves OS and rPFS in patients with chemotherapy-naive mCRPC and can significantly delay the need for chemotherapeutic intervention. Beer TM, Armstrong AJ, Sternberg CN, et al. J Clin Oncol 32, 2014 (suppl 4; abstr LBA1)