Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mCRPC pts, Cabo was associated with improvements in bone scans, pain, measurable disease, and circulating tumor cells. COMET-1 compared the effects of Cabo versus Pred on overall survival (OS) in men with progressive mCRPC and prior D and A and/or E. Methods: In this randomized, double-blind, controlled phase 3 study (NCT01605227), pts with mCRPC and prior D and A and/or E were randomized 2:1 to receive Cabo (60 mg qd) or Pred (5 mg bid). Pts were stratified by prior treatment with cabazitaxel, ECOG status, and presence of moderate to severe pain. The primary endpoint was OS. The study was designed to observe 578 deaths to provide 90% power to detect a hazard ratio (HR) of 0.75. A secondary endpoint was bone scan response at Week 12 (BSR) determined by central independent radiology committee, defined as a ≥30% decrease in the bone scan lesion area compared to baseline. Exploratory endpoints include PFS and OS subgroup analyses. Results: 1,028 pts were randomized between Jul 2012 and Nov 2013. In the final analysis after 614 deaths, the estimated median OS was 11.0 months for Cabo vs 9.8 months for Pred (HR 0.90; 95% CI: 0.0.76-1.06; P = 0.212). The secondary endpoint of BSR was 41% for Cabo vs 3% for Pred (P <0.001). Median PFS per investigator was 5.5 months for Cabo vs 2.8 months for Pred (HR 0.50; P <0.001). For 191 pts with visceral disease median OS was 7.1 months for Cabo vs 4.8 months for Pred (HR 0.65; P = 0.0215). 371 (54.4%) and 233 (67.3%) pts received salvage therapy in the Cabo and Pred arms, respectively. Subsequent cabazitaxel and/or D was reported in 107 (15.7%) and 104 (30.1%) Cabo and Pred pts, respectively. Serious adverse events of pulmonary embolism, nausea, dehydration and fatigue were more frequent with Cabo. Conclusions: Compared to prednisone, Cabo improved BSR and PFS but did not significantly increase OS. The improvement in OS was greatest in the subset of patients with visceral metastases. The activity and safety profile of Cabo was similar to that observed in phase 2 studies in mCRPC. Clinical trial information: NCT01605227