Efficacy and safety of zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: Results of CALGB 90202 (Alliance).

Abstract

27 Background: Zoledronic acid (ZA) decreases risk of skeletal-related events (SREs) in men with castration-resistant prostate cancer (CRPC) and bone metastases. This phase III study evaluated efficacy and safety of earlier treatment with ZA in men with castration-sensitive metastatic prostate cancer. Methods: CALGB 90202 was a randomized, double-blinded, placebo-controlled phase III trial in men with castration-sensitive prostate cancer and bone metastases who had initiated androgen deprivation therapy within six months of study entry. Subjects were randomized 1:1 in blinded manner to receive ZA (4 mg intravenously every 4 weeks) or placebo (P). After progression to CRPC, all patients crossed over to open-label ZA. The primary endpoint was time to first SRE. Target sample size was 680. Time to SRE was defined as interval between date of randomization and date of first SRE (radiation to bone, or clinical fracture, or surgery to bone, or death due to prostate cancer). With 470 SRE events, the log-rank test has 88% power to detect a 23% decrease in hazard rate of SRE event assuming a one-sided type I error rate of 0.05. The study was discontinued prematurely after the corporate supporter withdrew study drug supply. Primary analysis was based on the stratified log-rank statistic adjusting on the stratification factors following observation of 284 SREs (60% of total events). Results: Between June 2004 and April 2012, 645 patients were randomly assigned to ZA or P. Median time to first SRE was 32.5 months in the ZA group and 29.8 months in the P group (hazard ratio (HR) 0.96 [0.76-1.22]; stratified log-rank P=0.74). A total of 271 deaths were observed; median follow-up time for surviving patients was 24.4 months (20.6, 28.3). Overall survival was similar between groups (HR= 0.89 [0.70-1.14]; stratified P=0.34). Rates of grade 3 or higher adverse events were similar between groups (15% vs. 12% in ZA and P). Conclusions: In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs or death. Early termination limited statistical power of the study. Clinical trial information: NCT00079001.