Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1.

Abstract

PURPOSE:

Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC.

PATIENTS AND METHODS:

Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments.

RESULTS:

A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively).

CONCLUSION:

Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes.

• Authors: Matthew Smith, Johann De Bono, Cora Sternberg, Sylvestre Le Moulec, Stéphane Oudard, Ugo De Giorgi, Michael Krainer, Andries Bergman, Wolfgang Hoelzer, Ronald De Wit, Martin Bögemann, Fred Saad, Giorgio Cruciani, Antoine Thiery-Vuillemin, Susan Feyerabend, Kurt Miller, Nadine Houédé, Syed Hussain, Elaine Lam, Jonathan Polikoff, Arnulf Stenzl, Paul Mainwaring, David Ramies, Colin Hessel, Aaron Weitzman, Karim Fizazi
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 34 Issue 25 Pg. 3005-13 (09 01 2016) ISSN: 1527-7755 [Electronic] United States
• PMID: 27400947 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by American Society of Clinical Oncology.

Chemical References

• Anilides
• Antineoplastic Agents
• Biomarkers, Tumor
• Protein Kinase Inhibitors
• Pyridines
• cabozantinib
• Prednisone

Topics

• Adult
• Aged
• Aged, 80 and over
• Anilides (adverse effects, therapeutic use)
• Antineoplastic Agents (adverse effects, therapeutic use)
• Biomarkers, Tumor (metabolism)
• Disease-Free Survival
• Double-Blind Method
• Humans
• Male
• Middle Aged
• Neoplasm Metastasis
• Neoplastic Cells, Circulating (pathology)
• Prednisone (adverse effects, therapeutic use)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, pathology)
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Pyridines (adverse effects, therapeutic use)
• Survival Rate