Double-blind randomized trial of aflibercept versus placebo with docetaxel and prednisone for treatment of metastatic castration-resistant prostate cancer (mCRPC).

Abstract

5002 Background: Docetaxel/prednisone is standard first-line chemotherapy for men with mCRPC. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of Vascular Endothelial Growth Factor and Placental-derived Growth Factors, thereby inhibiting angiogenesis. Methods: We performed an international double-blind randomized trial (known as VENICE) which recruited men with mCRPC, adequate organ function and no prior chemotherapy. Men were treated with docetaxel (75mg/m² intravenously every 3 weeks) and oral prednisone (5mg twice daily) and randomized 1:1 to receive aflibercept (6 mg/kg) or placebo, intravenously every 3 weeks. The primary endpoint was overall survival: 873 deaths were required to detect a hazard ratio (HR) of 0.8 with 90% power. Results: A total of 1,224 men were randomized, 612 in each arm. Median age was 68 years and baseline characteristics were well balanced between arms. Participants received a median of 8 (aflibercept) and 9 (placebo) cycles of therapy. Median relative dose intensity was >0.93 for aflibercept, placebo and docetaxel. At final analysis, median follow-up was 35 months and 873 pts had died. Median survival was 22.1 months (95.6% CI: 20.3-24.1 months) in the aflibercept arm and 21.2 months (95.6% CI: 19.6-23.8 months) in the placebo arm (stratified HR = 0.94; 95.6% CI: 0.82-1.08, p=0.38). Pre-defined secondary endpoints for aflibercept and placebo arms were similar, including PSA response rate (68.6% and 63.5%), time to first skeletal-related event (median: 15.3 and 15.0 months), and progression-free survival (median: 6.9 and 6.2 months). Quality of Life analysis using FACT-P and a trial-specific module will be reported. Higher incidence of grade 3-4 gastrointestinal disorders, hemorrhagic events, hypertension, fatigue, infections and fatal adverse events (5.6% vs. 3.3%) was observed in the aflibercept arm. Conclusions: Aflibercept in combination with docetaxel/prednisone given as first-line chemotherapy for men with mCRPC did not lead to an improvement in survival and added toxicity. Trial Registration: NCT00519285. Funding: Sanofi and Regeneron Pharmaceuticals, Inc. Clinical trial information: NCT00519285.