NEW YORK (Reuters Health) – The addition of bevacizumab (Avastin; Genentech/Roche) to the standard docetaxel and prednisone in men with progressive metastatic castration-resistant prostate cancer (mCRPC) did not improve overall survival and was associated with greater toxicity in the CALGB 90401 study.
“There was hope that adding this agent to docetaxel and prednisone backbone would improve survival however to date no agent added to docetaxel and prednisone has shown an improved survival advantage,” Dr. William Kevin Kelly from Thomas Jefferson University in Philadelphia, Pennsylvania, told Reuters Health by email.
CALGB 90401was a randomized, double-blind, placebo-controlled phase 3 trial that enrolled patients with chemotherapy-naive progressive mCRPC with ECOG performance status of 2 or lower and adequate bone marrow, hepatic and renal function.
A total of 1050 patients were randomly allocated to receive docetaxel 75 mg/m2 intravenously (IV) over one hour for 21 days plus prednisone 5 mg orally twice per day with either bevacizumab 15 mg/kg IV every 3 weeks or placebo.
In a paper online March 26 in the Journal of Clinical Oncology, the study notes that the addition of bevacizumab had a statistically significant impact on three secondary study end points – progression-free survival (PFS), prostate-specific antigen (PSA) level and the objective response rate (ORR).
PFS was about two months longer with bevacizumab (median 9.9 vs 7.5 months; stratified log-rank p<0.001); the proportion of responders was higher (49.4% vs 35.5%; p=0.0013); and more patients treated with bevacizumab achieved a PSA decline of at least 50% (69.5% vs 57.9%;p<0.001). But the addition of bevacizumab didn't improve overall survival, the primary study end point; median OS was 22.6 months with bevacizumab and 21.5 months without it, yielding a hazard ratio of 0.91; stratified log-rank p=0.181). In addition, treatment-related toxicity of grade 3 or higher was more common in the bevacizumab arm (75.4% vs 56.2%; p≤0.001), as was the number of treatment-related deaths (4.0% vs 1.2%; p=0.005). Bevacizumab works by blocking vascular endothelial growth factor, or VEGF, which research suggests plays a role in prostate cancer progression. “The initial hypothesis of this trial was that inhibiting VEGF by adding bevacizumab to docetaxel and prednisone would provide a survival advantage to patients with mCRPC. The results of this study failed to support this hypothesis,” the authors say. Given the positive PFS and response data, they did exploratory analyses to see if they could pinpoint characteristics of those patients with CRPC more likely to benefit from this therapy. “These analyses,” they report, “have generated the hypothesis that a targeted subpopulation of poor-risk patients with mCRPC (defined by either high tumor burden or disease progression in the setting of low testosterone levels) would experience greater clinical benefit from VEGF inhibition. Other ongoing phase III trials with aflibercept and tasquinimod may help further define the clinical benefit of vascular targeting agents in patients with mCRPC,” they conclude. The study was supported in part by grants from the National Cancer Institute and by Roche-Genentech. Several of the authors have disclosed financial relationships with Genentech and other drug companies. SOURCE: Randomized, Double-Blind, Placebo-Controlled Phase III Trial Comparing Docetaxel and Prednisone With or Without Bevacizumab in Men With Metastatic Castration-Resistant Prostate Cancer: CALGB 90401
Published online March 26, 2012.
