Background: The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease (ASCVD) remains controversial. Methods: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant ASCVD were randomized 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (MACE) (composite of death, myocardial infarction, or stroke) through 12 months. Results: Due to slower than projected enrollment and fewer than projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From 3 May 2016 to 16 April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease and 20.4% had metastatic disease. MACE occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) assigned to leuprolide (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.59-2.79; p=0.53). Conclusions: PRONOUNCE is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely due to smaller than planned number of participants and events and no difference in MACE at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02663908.
Circulation. 2021 Aug 30 [Epub ahead of print]
Renato D Lopes, Celestia S Higano, Susan F Slovin, Adam J Nelson, Robert Bigelow, Per S Sørensen, Chiara Melloni, Shaun G Goodman, Christopher P Evans, Jan Nilsson, Deepak L Bhatt, Noel W Clarke, Tine K Olesen, Belinda T Doyle-Olsen, Henriette Kristensen, Lauren Arney, Matthew T Roe, John H Alexander
Department of Medicine, Division of Cardiology, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC., Division of Medical Oncology, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA., Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, NY., Ferring Pharmaceuticals A/S, Copenhagen, Denmark., Department of Medicine, Division of Cardiology, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC; IQVIA, Durham, NC., Division of Cardiology, St. Michael's Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada., Department of Urologic Surgery, University of California, Davis, Sacramento, CA., Department of Clinical Sciences Malmö, Lund University, Lund, Sweden., Division of Cardiovascular Medicine, Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA., Department of Urology, The Christie and Salford Royal Hospitals Manchester, United Kingdom., Department of Medicine, Division of Cardiology, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC; Verana Health, San Francisco, CA.