Aflibercept versus placebo in combination with docetaxel/prednisone for first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC): Results from the multinational phase III trial (VENICE).

Abstract

13 Background: Docetaxel/prednisone is standard first-line chemotherapy for mCRPC. Aflibercept (known as ziv-aflibercept in the US) is a recombinant human fusion protein that binds VEGF-A, VEGF-B and Placental Growth Factor (PlGF), thereby inhibiting angiogenesis. Methods: VENICE was a double-blind, randomized phase III study with overall survival (OS) as primary endpoint. Men with mCRPC, ECOG PS 0-2, adequate organ function and no prior cytotoxic therapy were treated with docetaxel (75 mg/m² iv q3w) and oral prednisone (5mg bid) and randomized double blind 1:1 to receive aflibercept (A) 6 mg/kg or placebo (Pbo), IV every 3 weeks. Pts were stratified by ECOG PS (0-1 vs 2). For final OS analysis, 873 deaths were required to detect a hazard ratio (HR) of 0.8 with 90% power (overall 2-sided α = 0.05). Results: From Aug 2007 to Feb 2010, 1224 patients (median age 68 yr, PS 0-1 96%) were randomized. Baseline characteristics were well balanced between arms. Median number of cycles was 8 (A) and 9 (Pbo). Median relative dose intensity was >0.93 for A, Pbo and docetaxel. At final cut-off, median follow-up was 35.4 mos and 873 pts had died. Results for primary and key secondary endpoints with confidence intervals are in the table. Higher incidence of all grade hypertension, stomatitis, appetite disorders, diarrhea, dehydration, epistaxis, dysphonia, cough, headache and infections was observed in the aflibercept arm. Conclusions: Aflibercept in combination with docetaxel/prednisone given as first line chemotherapy for mCRPC did not lead to a statistically significant improvement in OS and added toxicity. (NCT00519285 sponsored by Sanofi and Regeneron Pharmaceuticals, Inc.) Clinical trial information: NCT00519285. [Table: see text]

Exploitation of the Androgen Receptor to Overcome Taxane Resistance in Advanced Prostate Cancer

“…Antiangiogenic agents represent a realm of therapeutics that hold tremendous promise, but have failed to yield improvement in patient survival. Bevacizumab and Aflibercept in combination with Docetaxel did not confer any improvement in overall survival Tannock et al, 2013). Agents targeting the bone microenvironment have been tested in Phase II trials; Atrasentan, Zibotentan, and Dasatinib among them did not garner overall survival benefit when combined with Docetaxel compared to Docetaxel alone (Araujo et al, 2013;Kelly et al, 2012;Quinn et al, 2012).…”

Growth factor and signaling pathways and their relevance to prostate cancer therapeutics

“…Over 1,200 patients were randomized to receive docetaxel plus either aflibercept or placebo. In this trial, there were no significant differences in progression-free or overall survival, and toxicities were higher in the aflibercept arm [7]. The increase in toxicities in the interventional arm mimicked the higher rate of adverse events with the docetaxel-bevacizumab combination.…”

Evolving treatment approaches for the management of metastatic castration-resistant prostate cancer – role of radium-223

“…Despite promising signals in Phase II studies, attempts to combine docetaxel with novel therapeutics have been unsuccessful to date. Negative results have been announced for large Phase III trials combining docetaxel with the endothelin receptor antagonist atrasentan,12 the tyrosine kinase inhibitor dasatinib,13 and the antiangiogenic agents bevacizumab,14 lenalidomide,15 and aflibercept 16…”

“…Negative results have been announced for large Phase III trials combining docetaxel with the endothelin receptor antagonist atrasentan, 12 the tyrosine kinase inhibitor dasatinib, 13 and the antiangiogenic agents bevacizumab, 14 lenalidomide, 15 and aflibercept. 16 …”