Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial
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, PRONOUNCE Study Investigators, Mirjam Mol-Arts, Samreen Mansor-Lefebvre, Konstantin Zubovskiy, Allan Blemings, Klaus Dugi, Gerald Bloomfield, Chris Kontos, Adam DeVore, Dedrick Jordan, Bradley Kolls, Robin Matthews, Rajendra Mehta, Thomas J Povsic, Michael Morse, Kenneth W Mahaffey, Susan Halabi, Darryl Leong, Laurence Klotz, Neil Fleshner, Godfrey Jansz, Jonathan Giddens, Russell Egerdie, Joseph Chin, Joseph Zadra, Richard Casey, Jean Simard, Tamim Niazi, André-Guy Martin, Marek Babjuk, Jaroslav Hajek, Jiri Klecka, Jiri Kubes, Jan Schraml, Jitka Jakesova, Jaroslav Vanasek, Bohuslav Melichar, Heikki Seikkula, Manouar Samir Abdiche, Marc Colombel, Philippe Debourdeau, Gregoire Robert, Arnauld Villers, Guillaume Ploussard, Benjamin Pradere, Franck Bruyere, Jean-Luc Descotes, Idir Ouzaid, Alexander Winter, Herbert Hanitzsch, Herbert Sperling, Ralf Eckert, Peter Hammerer, Elke Stagge, Florian Seseke, Silvio Szymula, Aristotelis Bamias, Anastasios Thanos, Konstantinos Hatzimouratidis, Charalambos Mamoulakis, Haralabos Kalofonos, Elzbieta Oszukowska, Katarzyna Madziarska, Jacek Fijuth, Mateusz Obarzanowski, Boris Alekseev, Vagif Atduev, Dmitri Pushkar, Evgeniy Veliev, Alexander Zyryanov, Sergey Petrov, Evgeny Kopyltsov, Vadim Kozlov, Ladislav Macko, Jozef Dubravicky, Richard Polak, Obaidullah Mir, Marek Vargovcak, Ivan Mincik, Jan Kliment, Frederico Goncalves, Juraj Mikulas, Roman Sokol, Michal Korcek, Jozef Marko, Viktor Kovacik, Igor Milichovsky, Pavol Dubinsky, John Lazarus, Sanjay Dixit, Euan Green, Rajaguru Srinivasan, Danish Mazhar, Yeung Ng, Naveed Sarwar, Craig Herman, Frederick Snoy, Robert Given, Ronald Suh, David Lipsitz, James Bailen, Lawrence Gervasi, Idalia Acosta, Laurence Belkoff, Ning Wu, Jeffrey Frankel, Lawrence Karsh, Bryant Poole, David Lieber, Jason Engel, Mohamed Bidair, Steven Rosenberg, Paul Sieber, Adam Perzin, Susan Kalota, Amar Singh, Ralph Henderson, Jeffrey Wayne, Moben Mirza, Richard D'Anna, Fredrick Wolk, Osvaldo Padron, Kathryn Bylow, Jonathan Rubenstein, Benjamin Gartrell, Michael Schwartz, Kalpesh Patel, Ajit Maniam, Thomas Keane, Michael Goodman, Charles Bane, Michael Chung, Stephen Savage, Edward Uchio, Son Nguyen, William Aronson, Rakesh Khanna, Carlton Barnswell, 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, PRONOUNCE Study Investigators, Mirjam Mol-Arts, Samreen Mansor-Lefebvre, Konstantin Zubovskiy, Allan Blemings, Klaus Dugi, Gerald Bloomfield, Chris Kontos, Adam DeVore, Dedrick Jordan, Bradley Kolls, Robin Matthews, Rajendra Mehta, Thomas J Povsic, Michael Morse, Kenneth W Mahaffey, Susan Halabi, Darryl Leong, Laurence Klotz, Neil Fleshner, Godfrey Jansz, Jonathan Giddens, Russell Egerdie, Joseph Chin, Joseph Zadra, Richard Casey, Jean Simard, Tamim Niazi, André-Guy Martin, Marek Babjuk, Jaroslav Hajek, Jiri Klecka, Jiri Kubes, Jan Schraml, Jitka Jakesova, Jaroslav Vanasek, Bohuslav Melichar, Heikki Seikkula, Manouar Samir Abdiche, Marc Colombel, Philippe Debourdeau, Gregoire Robert, Arnauld Villers, Guillaume Ploussard, Benjamin Pradere, Franck Bruyere, Jean-Luc Descotes, Idir Ouzaid, Alexander Winter, Herbert Hanitzsch, Herbert Sperling, Ralf Eckert, Peter Hammerer, Elke Stagge, Florian Seseke, Silvio Szymula, Aristotelis Bamias, Anastasios Thanos, Konstantinos Hatzimouratidis, Charalambos Mamoulakis, Haralabos Kalofonos, Elzbieta Oszukowska, Katarzyna Madziarska, Jacek Fijuth, Mateusz Obarzanowski, Boris Alekseev, Vagif Atduev, Dmitri Pushkar, Evgeniy Veliev, Alexander Zyryanov, Sergey Petrov, Evgeny Kopyltsov, Vadim Kozlov, Ladislav Macko, Jozef Dubravicky, Richard Polak, Obaidullah Mir, Marek Vargovcak, Ivan Mincik, Jan Kliment, Frederico Goncalves, Juraj Mikulas, Roman Sokol, Michal Korcek, Jozef Marko, Viktor Kovacik, Igor Milichovsky, Pavol Dubinsky, John Lazarus, Sanjay Dixit, Euan Green, Rajaguru Srinivasan, Danish Mazhar, Yeung Ng, Naveed Sarwar, Craig Herman, Frederick Snoy, Robert Given, Ronald Suh, David Lipsitz, James Bailen, Lawrence Gervasi, Idalia Acosta, Laurence Belkoff, Ning Wu, Jeffrey Frankel, Lawrence Karsh, Bryant Poole, David Lieber, Jason Engel, Mohamed Bidair, Steven Rosenberg, Paul Sieber, Adam Perzin, Susan Kalota, Amar Singh, Ralph Henderson, Jeffrey Wayne, Moben Mirza, Richard D'Anna, Fredrick Wolk, Osvaldo Padron, Kathryn Bylow, Jonathan Rubenstein, Benjamin Gartrell, Michael Schwartz, Kalpesh Patel, Ajit Maniam, Thomas Keane, Michael Goodman, Charles Bane, Michael Chung, Stephen Savage, Edward Uchio, Son Nguyen, William Aronson, Rakesh Khanna, Carlton Barnswell
Abstract
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 remains controversial.
Methods: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 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 (composite of death, myocardial infarction, or stroke) through 12 months.
Results: Because of slower-than-projected enrollment and fewer-than-projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From May 3, 2016, to April 16, 2020, a total of 545 patients from 113 sites across 12 countries were randomly selected. 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. A major adverse cardiovascular event occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) patients assigned to leuprolide (hazard ratio, 1.28 [95% CI, 0.59-2.79]; P=0.53).
Conclusions: PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) 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 because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02663908.
Keywords: agonists; atherosclerosis; cardiotoxicity; drug therapy; gonadotropin-releasing hormone; prostatic neoplasms.
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Source: PubMed