Cabozantinib for Progressive Metastatic Castration-resistant Prostate Cancer Following Docetaxel: Combined Analysis of Two Phase 3 Trials

Two phase 3 trials, COMET-1 and COMET-2, have reported that cabozantinib did not significantly extend overall survival (OS) compared to prednisone and prednisone plus mitoxantrone, respectively, in post-docetaxel patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted a retrospective analysis of a combined data set from these trials to identify a benefit in subsets of patients according to prognostic risk factors. The prognostic ability of factors to predict survival was evaluated using Cox proportional hazards regression models. Evaluation of potential beneficial subsets was performed using interaction terms between factors and cabozantinib. All tests were two-sided and p≤0.05 was considered statistically significant. A total of 1147 post-docetaxel patients with mCRPC were available (1028 from COMET-1 and 119 from COMET-2). The following factors were prognostic for OS: age, disease-free interval, hemoglobin, prostate-specific antigen, alkaline phosphatase, albumin, bone scan lesion area, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, and pain (all p<0.05). There was no interaction effect on survival between cabozantinib versus comparator arms and any prognostic group. After adjusting for prognostic factors, cabozantinib was associated with better OS (hazard ratio 0.80, 95% confidence interval 0.67-0.95; p=0.012). Further investigation of cabozantinib in a better-powered trial or a rational patient population based on a molecular biomarker may be warranted. PATIENT SUMMARY: Two phase 3 trials have reported no survival benefit for cabozantinib, a multitarget oral drug, in metastatic castration-resistant prostate cancer. This analysis pooled 1147 patients from these trials to identify a survival benefit for cabozantinib. This study suggests that further rational development may be justified.