ORLANDO—Compared with prednisone, cabozantinib does not improve overall survival (OS) rates for men with metastatic castration-resistant prostate cancer (mCRPC), reported authors of a final analysis of the randomized, double-blind, controlled COMET-1 phase 3 trial (Abstract 139) presented during the 2015 Genitourinary Cancers Symposium.1

However, OS was significantly improved among a subset of patients with visceral metastatic disease, the authors reported.

“Cabozantinib did not significantly improve OS in men with mCRPC and disease progression despite prior docetaxel and abiraterone and/or enzalutamide,” reported lead study author Matthew Raymond Smith, MD, PhD, of the Massachusetts General Hospital in Boston, MA. “Subgroup analyses suggest larger OS improvement in men with visceral metastases or prior cabazitaxel.”

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However, cabozantinib was associated with improved bone scan responses, progression-free survival, time to first skeletal related event (SRE), CTC conversion, and bone biomarkers, Dr. Smith said.

“The observed safety profile is consistent with prior studies,” he added.

Cabozantinib is a MET- and VEGFR-targeting tyrosine kinase inhibitor previously shown to improve bone scan outcomes, pain, measurable disease, and circulating tumor cells in men with mCRPC.

The COMET-1 trial compared overall survival among men previously treated with docetaxel and abiraterone and/or enzalutamide, and then treated with cabozantinib versus prednisone for progressive metastatic disease.

A total of 960 patients with mCRPC and progression after prior docetaxel and abiraterone and/or enzalutamide therapy were enrolled during 2012 and 2013, and were randomly assigned 2:1 to undergo therapy with cabozantinib (60 mg once daily; 640 patients) or prednisone (5 mg twice daily; 320 patients).

Patients were stratified by prior treatment with cabazitaxel, ECOG status, and presence of moderate to severe pain, Dr. Smith reported.

OS was the primary endpoint. Bone scan response at week 12 (30% or greater reduction in bone scan lesion area vs. baseline) was a secondary endpoint.

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“In the final analysis, the estimated median OS was 11.0 months for cabozantinib versus 9.8 months for prednisone (hazard ratio [HR]=0.90; 95% CI: 0.76,1.06; P=0.213, not significant),” Dr. Smith and coauthors reported. “The secondary endpoint of BSR [bone scan response at week 12] was 42% for cabozantinib versus 3% for prednisone (P<0.001).”

Skeletal-related event (SRE) rates were 14% among patients on cabozantinib and 21% in patients on prednisone (P<0.001), Dr. Smith noted.

Among 191 patients with visceral disease, median OS was 7.1 months versus 4.8 months for men treated with cabozantinib and prednisone, respectively (HR=0.65; P=0.0215)

Median progression-free survival, an exploratory endpoint, was 5.5 months vs. 2.8 months for cabozantinib versus prednisone (HR=0.50; P<0.001), the researchers reported.

Serious grade 3/4 adverse events affected 71% of patients receiving cabozantinib and 56% of patients receiving prednisone. A third of the patients on the cabozantinib discontinued participation in the study because of adverse events, compared to 12% of patients in the prednisone arm.

Frequent grade 3/4 adverse events included hypertension (20% of cabozantinib-arm patients vs. 7% of prednisone arm); fatigue (17% vs. 8.8%); anemia (16% vs. 18%); asathenia (12% vs. 6%), diarrhea (7.3% vs. 1.5%), nausea (6.9% vs. 2%), and hand-foot syndrome (5.7% vs. 0%). The observed safety profile “is consistent with prior studies,” Dr. Smith noted.


  1. Smith MR, De Bono JS, Sternberg CN, et al. Final analysis of COMET-1: Cabozantinib (Cabo) versus prednisone (Pred) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E). 2015 Genitourinary Cancers Symposium. Abstract 139.