Although cabozantinib failed to improve survival, it did improve a number of endpoints.… The improvement was greatest in patients with visceral metastases.
—Matthew R. Smith, MD, PhD
Final results of the phase III, randomized double-blind, controlled COMET-1 trial were disappointing. Although the oral tyrosine kinase inhibitor cabozantinib (Cometriq) improved several secondary endpoints compared with prednisone, including bone scan response and progression-free survival, the drug failed to meet the primary endpoint of improved overall survival in men with pretreated metastatic castration-resistant prostate cancer,1 according to the final results presented at the 2015 Genitourinary Cancers Symposium.
“Although cabozantinib failed to improve survival, it did improve a number of endpoints,” said presenting author Matthew R. Smith, MD, PhD, of Massachusetts General Hospital, Boston. “The improvement was greatest in the patients with visceral metastases, which deserves further study.”
COMET-1 enrolled 1,028 patients with metastatic castration-resistant prostate cancer that progressed on previous treatment with docetaxel and abiraterone (Zytiga) and/or enzalutamide (Xtandi). The median age of patients was 69 years.
Patients were randomly assigned 2:1 to receive cabozantinib at 60 mg once daily plus placebo or prednisone at 5 mg twice daily plus placebo. Therapy was discontinued in 91% of the cabozantinib group and 95% of the prednisone group, mainly for progressive disease or side effects.
No Difference in Overall Survival
Cabozantinib showed excellent activity in a phase II trial of more than 300 heavily pretreated men with metastatic castration-resistant prostate cancer on a variety of metrics, including improvements in bone scan response, decreased pain, and reductions in circulating tumor cells.
However, the final overall survival analysis showed no significant difference between treatment arms, with a hazard ratio of 0.90 and overlapping confidence intervals. Median overall survival was 11 months with cabozantinib vs 9.8 months with prednisone.
In a prespecified subgroup analysis, the effect on overall survival appeared to be greater in patients treated previously with cabazitaxel (Jevtana) as well as in patients with visceral metastases (n = 191).
Salvage therapies after disease progression were used by 55% of the cabozantinib group and 68% of those assigned to prednisone.
Although there was no improvement in survival, cabozantinib significantly improved bone scan response (measured as a 30% reduction in lesion volume): 42% vs 3% with prednisone (P < .001).
In addition, cabozantinib significantly improved investigator-assessed progression-free survival: Median progression-free survival was 5.6 months vs 2.8 months, respectively (P < .001). Also, time to first on-study skeletal-related event was longer with cabozantinib. Circulating tumor cells normalized in 33% of the cabozantinib group vs 6% of the prednisone group.
However, the rates of grades 3 and 4 adverse events were higher in the cabozantinib arm (71% vs 56%, respectively), and treatment discontinuation due to adverse events was reported in 33% vs 12% of the prednisone-treated patients. The most common adverse events on cabozantinib were hypertension, fatigue, anemia, and decreased appetite. ■
Disclosure: Dr. Smith has served as a consultant or advisor to and received research funding from Exelixis.
1. Smith MR, De Bono JS, Sternberg CN, et al: Final analysis of COMET-1: Cabozantinib versus prednisone in metastatic castration-resistant prostate cancer patients previously treated with docetaxel and abiraterone and/or enzalutamide. 2015 Genitourinary Cancers Symposium. Abstract 139. Presented February 26, 2015.
Eric J. Small, MD, of the University of California at San Francisco, discussed what he thought went wrong for cabozantinib (Cometriq) in the COMET-1 trial, yet another example of a phase III trial that failed to deliver on the promise of phase II results.
“Although this was a negative study,...