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

Matthew Smith , Johann de Bono , Cora Sternberg , Sylvestre Le Moulec (1) , Stéphane Oudard (2, 3) , Ugo de Giorgi , Michael Krainer , Andries Bergman , Wolfgang Hoelzer , Ronald de Wit , Martin Bögemann , Fred Saad , Giorgio Cruciani , Antoine Thiery-Vuillemin (4) , Susan Feyerabend , Kurt Miller , Nadine Houédé (5, 6) , Syed Hussain , Elaine Lam , Jonathan Polikoff , Arnulf Stenzl , Paul Mainwaring , David Ramies , Colin Hessel , Aaron Weitzman , Karim Fizazi (7, 8)

1 Hôpital d'Instruction des Armées du Val de Grâce
2 HEGP - Hôpital Européen Georges Pompidou [APHP]
3 UPD5 - Université Paris Descartes - Paris 5
4 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
5 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
6 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
7 UP11 - Université Paris-Sud - Paris 11
8 Oncologie génito-urinaire

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. TRIAL REGISTRATION: ClinicalTrials.gov NCT01605227.

Domaines: Cancer; Urologie et Néphrologie; Pharmacologie

Matthew Smith, Johann de Bono, Cora Sternberg, Sylvestre Le Moulec, Stéphane Oudard, et al.. Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1. Journal of Clinical Oncology, 2016, 34 (25), pp.3005 - 3013. ⟨10.1200/JCO.2015.65.5597⟩. ⟨hal-01903858⟩