Matthew Smith1, Johann De Bono2, Cora Sternberg2, Sylvestre Le Moulec2, Stéphane Oudard2, Ugo De Giorgi2, Michael Krainer2, Andries Bergman2, Wolfgang Hoelzer2, Ronald De Wit2, Martin Bögemann2, Fred Saad2, Giorgio Cruciani2, Antoine Thiery-Vuillemin2, Susan Feyerabend2, Kurt Miller2, Nadine Houédé2, Syed Hussain2, Elaine Lam2, Jonathan Polikoff2, Arnulf Stenzl2, Paul Mainwaring2, David Ramies2, Colin Hessel2, Aaron Weitzman2, Karim Fizazi2. 1. Matthew 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. 2. Matthew 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.
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 afterdocetaxel 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.
RCT Entities:
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: Lipika Goyal; Hui Zheng; Matthew B Yurgelun; Thomas A Abrams; Jill N Allen; James M Cleary; Michelle Knowles; Eileen Regan; Amanda Reardon; Anna Khachatryan; Rakesh K Jain; Valentina Nardi; Darrell R Borger; Dan G Duda; Andrew X Zhu Journal: Cancer Date: 2017-02-13 Impact factor: 6.860
Authors: Bernard Escudier; Thomas Powles; Robert J Motzer; Thomas Olencki; Osvaldo Arén Frontera; Stephane Oudard; Frederic Rolland; Piotr Tomczak; Daniel Castellano; Leonard J Appleman; Harry Drabkin; Daniel Vaena; Steven Milwee; Jillian Youkstetter; Julie C Lougheed; Sergio Bracarda; Toni K Choueiri Journal: J Clin Oncol Date: 2018-01-08 Impact factor: 44.544
Authors: Akash Patnaik; Kenneth D Swanson; Eva Csizmadia; Aniruddh Solanki; Natalie Landon-Brace; Marina P Gehring; Katja Helenius; Brian M Olson; Athalia R Pyzer; Lily C Wang; Olivier Elemento; Jesse Novak; Thomas B Thornley; John M Asara; Laleh Montaser; Joshua J Timmons; Todd M Morgan; Yugang Wang; Elena Levantini; John G Clohessy; Kathleen Kelly; Pier Paolo Pandolfi; Jacalyn M Rosenblatt; David E Avigan; Huihui Ye; Jeffrey M Karp; Sabina Signoretti; Steven P Balk; Lewis C Cantley Journal: Cancer Discov Date: 2017-03-08 Impact factor: 39.397
Authors: Halena R VanDeusen; Johnny R Ramroop; Katherine L Morel; Song Yi Bae; Anjali V Sheahan; Zoi Sychev; Nathan A Lau; Larry C Cheng; Victor M Tan; Zhen Li; Ashley Petersen; John K Lee; Jung Wook Park; Rendong Yang; Justin H Hwang; Ilsa Coleman; Owen N Witte; Colm Morrissey; Eva Corey; Peter S Nelson; Leigh Ellis; Justin M Drake Journal: Mol Cancer Res Date: 2020-05-27 Impact factor: 5.852