Prostate cancer survival not improved with anti-angiogenic agent

August 1, 2010

Preliminary results from a phase III trial do not support the research hypothesis that the addition of bevacizumab (Avastin) to a regimen combining docetaxel (Taxotere) and prednisone improves survival in patients with metastatic castration-resistant prostate cancer.

Key Points

Conducted in cooperation with the Eastern Cooperative Oncology Group (ECOG), CALGB (Cancer And Leukemia Group B) 90401 was a randomized, double-blind, placebo-controlled trial of 1,050 patients who had chemotherapy-naïve metastatic CRPC with evidence of disease progression despite castrate testosterone levels and anti-androgen withdrawal. Patients were randomized to receive intravenous docetaxel, 75 mg/m2 (day 1 and once every 21 days), with oral prednisone, 5 mg twice daily, and either intravenous bevacizumab, 15 mg/kg, or placebo following docetaxel. Overall survival was analyzed as the primary endpoint in an intention-to-treat analysis performed with adjustment for baseline stratification factors.

Both groups had received a median of eight treatment cycles at the time of the analysis, and the results showed median overall survival was increased from 21.6 months in the placebo group to 22.6 months in the bevacizumab-treated arm. The hazard ratio favoring bevacizumab (0.91) was not statistically significant (p=.181), but there were statistically significant differences favoring bevacizumab over placebo in analyses of median progression-free survival (9.9 months vs. 7.5 months), objective response rate (53.2% vs. 42.1%), and rate of ≥50% decrease in PSA (69.5% vs. 57.9%).

"The role of anti-angiogenic therapy in CRPC remains to be defined, and any possible clinical benefits from the addition of bevacizumab to docetaxel will need to be tempered by the increased toxicity observed in this trial," said first author William Kevin Kelly, DO, professor of medical oncology and urology at Thomas Jefferson University, Philadelphia. "However, this study represents one of the largest single experiences of elderly patients treated with bevacizumab and provides a unique opportunity to understand the reasons for increased morbidity and mortality so that we may embrace this treatment in the future in this population of patients."

Analyses of subpopulations under way

Multiple exploratory analyses are being performed to determine whether there are subpopulations of patients with an overall survival benefit from bevacizumab. So far, the data suggest a clinical benefit in men with various baseline features suggesting a poorer prognosis; ie, lower hemoglobin, elevated serum alkaline phosphatase, lower testosterone, and lower lactate dehydrogenase.

Discussing the failure to reach the primary endpoint, Dr. Kelly noted that longer-than-expected survival in the control group and the impact of subsequent therapy may have played a role. The control group's median overall survival was 2.3 months longer than the value used in the power calculation, and about 30% of patients received subsequent chemotherapy, he explained. However, the CALGB 90401 participants also represented a "good risk population," with nearly half having a >30% probability of being alive at 24 months and 96% having ECOG performance status of 0 or 1, Dr. Kelly noted.

Commenting on the study, William Dahut, MD, of the National Cancer Institute, Bethesda, MD, also highlighted the favorable baseline clinical characteristics of the CALGB 90401 participants and suggested that may have left CALGB 90401 underpowered to show a survival advantage.

"Perhaps a treatment benefit for bevacizumab could emerge with longer duration of therapy or in subgroups defined by certain clinical or molecular markers," Dr. Dahut said. "However, concerns remain about toxicity, which raises the question of whether bevacizumab would have a meaningful impact on survival even in the best possible scenario of a larger trial and longer duration of therapy."

Nevertheless, Dr. Dahut said that angiogenesis remains a target worthy of exploring in CRPC, and he pointed to some promising preliminary data of regimens combining multiple antiangiogenic agents.

"However, further study is needed, and bevacizumab combinations for men with CRPC cannot currently be recommended outside of a clinical trial," he concluded.

Dr. Kelly is a consultant to and receives research funding from Genentech and sanofi-aventis, and he receives honoraria from sanofi-aventis.