“GnRH antagonists have several advantages over GnRH agonists,” explained David Wise, MD, of Perlmutter Cancer Center at NYU Langone Health in New York. “There is no testosterone flare on initiation [as there is with leuprolide], no increase in cardiac toxicity, and faster onset of action. Currently available GnRH antagonists [ie, degarelix] require monthly subcutaneous injections, which can be uncomfortable,” he added. “To date, conventional androgen-deprivation therapy has been with GnRH agonists such as leuprolide.”

“The HERO study met its preset endpoint, with relugolix achieving castration levels of testosterone more rapidly and in a higher percentage of patients than leuprolide. A clear advantage was seen in cardiovascular events,” Dr. Wise continued. “The reduction in major adverse cardiovascular events is impressive, especially in patients with a history of such events—3.6% vs 17.8% with leuprolide.”

Additional Commentary

In an accompanying editorial in The New England Journal of Medicine,¹Celestia S. “Tia” Higano, MD, FACP, of the Seattle Cancer Care Alliance Hospital at the University of Washington Medical Center, Seattle, agreed that relugolix could be a good choice for men with preexisting cardiovascular disease.

Celestia S. “Tia” Higano, MD, FACP

“This and other trials raise the question of whether the use of a GnRH antagonist, either oral or subcutaneous, might result in improved cardiovascular outcome, especially for those at highest risk,” Dr. Higano stated. “To that end, it might be time to consider treating men who have preexisting cardiovascular risk factors with a GnRH antagonist, rather than an agonist. Even though no level 1 outcome data exist for the superiority of a GnRH antagonist over a GnRH agonist with respect to cardiovascular events or death from cardiovascular causes, the testosterone suppression data for GnRH antagonists, oral or subcutaneous, are level 1. Therefore, it is likely the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting.” 

DISCLOSURE: Dr. Wise has received honoraria from OncLive; consulting fees from AlphaSights, Foundation Medicine, GLG Pharma, Guidant Global, Leap Therapeutics, Pfizer, and Silverlight; and reimbursement for travel expenses from Pfizer. Dr. Higano has received honoraria from Astellas Pharma; has served as a consultant or advisor to AstraZeneca, Bayer, Blue Earth Diagnostics, Carrick Therapeutics, Clovis Oncology, Ferring, Hinova, Janssen, Merck Sharp & Dohme, Novartis, and Pfizer; has received institutional research funding from Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Effector Therapeutics, Emergent BioSolutions, Ferring Pharmaceuticals, Medivation, Pfizer, and Roche; and has been reimbursed for travel, accommodations, or other expenses by Bayer, Blue Earth Diagnostics, Carrick Therapeutics, Clovis Oncology, Ferring, Hinova Pharmaceuticals, Janssen Oncology, Merck Sharp & Dohme, Novartis, and Pfizer.

REFERENCE

1. Higano CS: Cardiovascular disease and androgen axis-targeted drugs for prostate cancer. N Engl J Med 382:2257-2259, 2020.