Relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, is superior to leuprolide, the commonly used injectable luteinizing hormone-releasing hormone (LHRH) agonist, in suppressing testosterone production in patients with advanced prostate cancer (PCa), and with possibly less cardiovascular risk, according to new study findings reported at the American Society of Clinical Oncology 2020 Virtual Scientific Program and published concurrently in the New England Journal of Medicine.

In the international phase 3 HERO trial, 930 men with PCa who had biochemical or clinical recurrence, new hormone-sensitive metastatic disease, or advanced localized disease not amenable to definitive treatment were randomly assigned 2:1 to relugolix (120 mg once daily after a loading dose) or leuprolide (22.5 mg every 3 months) for 48 weeks. A significantly greater proportion of relugolix recipients – 96.7% vs 88.8% – achieved the primary end point of sustained testosterone suppression to castration levels of less than 50 ng/dL. The less than 10 percentage point difference between treatment arms demonstrated both the noninferiority and superiority of relugolix over leuprolide, Neal D. Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, South Carolina and colleagues reported. Relugolix also proved superior in key secondary end points, such as castration levels of testosterone on day 4 (56% vs 0%); profound castrate levels of less than 20 ng/dL on day 15 (78.4% vs 1.0%); and suppression of follicle-stimulating hormone (FSH) at week 24 (mean FSH 1.72 vs 5.95 IU/L, respectively).

Notably, Relugolix patients were a significant 54% less likely to experience major adverse cardiovascular events (MACE), including nonfatal myocardial infarction or stroke or death from any cause: 2.9% vs 6.2%, respectively. Among men with a history of MACE (but no MACE in the 6 months before trial, which was an exclusion criterion), the investigators found a nearly 5-fold difference in MACE between groups: 3.6% of the relugolix group vs 17.8%, of the leuprolide group, respectively.

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The team also examined testosterone recovery. Mean testosterone levels at 90 days after treatment discontinuation were 288.4 vs 58.6 ng/dL in the relugolix and leuprolide subgroups, respectively. The rapid recovery of testosterone after relugolix use may be clinically relevant for patients receiving intermittent therapy or a short course of androgen deprivation therapy or patients who want to recover after a complication, according to the investigators.

In an accompanying editorial, Celestia S. Higano, MD, of the University of Washington in Seattle, commented that “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.”

Disclosure: This clinical trial was supported by Myovant Sciences, the developers of relugolix. Please see the original reference for a full list of authors’ disclosures.


Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer [published online May 29, 2020]. N Engl J Med. doi: 10.1056/NEJMoa2004325

Higano CS. Cardiovascular disease and androgen axis-targeted drugs for prostate cancer [published online May 29, 2020]. N Engl J Med. doi: 10.1056/NEJMe2016433