COMET-1

Cabozantinib inhibits MET and vascular endothelial growth factor receptors, and in phase 2 it produced bone scan resolutions in men with castration-resistant prostate cancer that were unlike anything the field had seen. COMET-1 tested whether that translated.

It randomised 1,028 heavily pretreated men 2:1 to cabozantinib 60 mg daily (682) or prednisone 5 mg twice daily (346). Median overall survival was 11.0 months with cabozantinib and 9.8 months with prednisone, hazard ratio 0.90 (95 percent confidence interval 0.76 to 1.06, stratified log-rank p=0.213). The primary endpoint was not met.

Bone scan response at week 12 favoured cabozantinib overwhelmingly, 42 against 3 percent (stratified Cochran-Mantel-Haenszel p<0.001), and radiographic progression-free survival was 5.6 against 2.8 months, hazard ratio 0.48 (0.40 to 0.57, p<0.001). Circulating tumour cell conversion, bone biomarkers and symptomatic skeletal events all improved. PSA outcomes did not.

Grade 3 to 4 adverse events occurred in 71 percent with cabozantinib against 56 percent, and discontinuation for adverse events in 33 against 12 percent. The companion trial COMET-2, in men with bone pain, was also negative. Exelixis stopped developing cabozantinib in prostate cancer.

The dissociation between the bone scan and survival is the reason bone scan response is not accepted as a registrational endpoint. Cabozantinib changes what the isotope does in bone; it does not change what the cancer does to the man.