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Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1
Matthew Smith1, Johann De Bono2, Cora Sternberg2
1Matthew Smith, Massachusetts General Hospital, Boston, MA; Johann De Bono, Royal Marsden Hospital, Sutton; Syed Hussain, University of Liverpool, Liverpool, United Kingdom; Cora Sternberg, San Camillo and Forlanini Hospitals, Rome; Ugo De Giorgi, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-Istituto di Ricovero e Cura a Carattere Scientifico, Meldola; Giorgio Cruciani, Istituto Tumori Romagna, Lugo di Romagna, Italy; Sylvestre Le Moulec, Hôpital d'Instruction des Armées Val-de-Grâce; Stéphane Oudard, European Hospital Georges Pompidou and Paris Descartes University, Paris; Antoine Thiery-Vuillemin, Jean Minjoz Hospital, Besançon; Nadine Houédé, Institut de Cancérologie du Gard-Centre Hospitalier Universitaire Caremeau, Nîmes; Karim Fizazi, Institute Gustave Roussy, University of Paris Sud, Villejuif, France; Michael Krainer, Medical University of Vienna, Vienna, Austria; Andries Bergman, Netherlands Cancer Institute, Amsterdam; Ronald De Wit, Erasmus University Medical Center and Cancer Institute, Rotterdam, the Netherlands; Wolfgang Hoelzer, Praxis für Urologie; Kurt Miller, Charité-Universitätsmedizin Berlin, Berlin; Martin Bögemann, University of Muenster Medical Center, Muenster; Susan Feyerabend, Studienpraxis Urologie, Nürtingen; Arnulf Stenzl, University Hospital, Tübingen, Germany; Fred Saad, Centre Hospitalier de I'Université de Montréal, Montreal, Quebec, Canada; Elaine Lam, University of Colorado Anschutz Medical Campus, Aurora, CO; Jonathan Polikoff, Kaiser Permanente Medical Group, San Diego; David Ramies, Colin Hessel, and Aaron Weitzman, Exelixis, South San Francisco, CA; and Paul Mainwaring, Hematology and Oncology Clinics of Australia, Brisbane, Queensland, Australia. smith.matthew@mgh.harvard.edu.
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.
Insights
Cabozantinib did not significantly improve overall survival in men with metastatic castration-resistant prostate cancer. However, it showed activity in improving bone scan response and radiographic progression-free survival.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) is a challenging diagnosis.
- Cabozantinib is a kinase inhibitor with potential activity in mCRPC.
Purpose of the Study:
- To compare the efficacy of cabozantinib versus prednisone in patients with previously treated mCRPC.
- To evaluate overall survival (OS) as the primary endpoint.
Main Methods:
- A phase III, blinded trial randomly assigned 1,028 patients with progressive mCRPC after docetaxel and abiraterone/enzalutamide to cabozantinib or prednisone.
- Primary endpoint was OS; secondary endpoints included bone scan response (BSR); exploratory endpoints included radiographic progression-free survival (rPFS), circulating tumor cells (CTCs), bone biomarkers, prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs).
Main Results:
- Median OS was 11.0 months for cabozantinib versus 9.8 months for prednisone (P = .213).
- Cabozantinib significantly improved BSR (42% vs 3%, P < .001) and rPFS (median 5.6 vs 2.8 months, P < .001).
- Improvements were noted in CTC conversion, bone biomarkers, and SSEs, but not PSA outcomes. Higher rates of grade 3-4 adverse events and discontinuations were observed with cabozantinib.
Conclusions:
- Cabozantinib did not significantly improve OS in heavily pre-treated mCRPC patients.
- Cabozantinib demonstrated activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers, but not PSA outcomes.
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