An Oral Gonadotropin-Releasing Hormone Antagonist for Advanced Prostate Cancer

Injectable depot formulations of luteinizing hormone–releasing hormone (LHRH) agonists are the standard method of attaining androgen deprivation in men with advanced prostate cancer. However, these agents can cause an initial spike of testosterone (“testosterone flare”). Gonadotropin-releasing hormone (GnRH) antagonists provide rapid achievement of testosterone suppression without causing a testosterone flare.

To compare the efficacy and safety of an oral GnRH antagonist (relugolix) with that of an LHRH agonist (leuprolide) in this setting, investigators conducted an industry-sponsored, multinational, randomized, phase III study (HERO) of 930 patients with advanced prostate cancer; of these, >90% had excess risk for cardiovascular events. Patients were assigned 2:1 to receive relugolix daily or leuprolide every 3 months.

Through 48 weeks, the primary endpoint of sustained suppression of testosterone to castrate levels (<50 ng/dL) was achieved by a greater proportion of relugolix recipients than leuprolide recipients (96.7% vs. 88.8%), demonstrating superiority of relugolix (P<0.001). In a subgroup analysis of 184 patients, recovery of testosterone to normal levels (≥280 ng/dL) after discontinuation of therapy was achieved by more relugolix recipients than leuprolide recipients (54% vs. 3%; P=0.002). The incidence of major adverse cardiovascular events was lower with relugolix than with leuprolide among all patients (2.9% vs. 6.2%) and among a subset of patients with a history of cardiovascular events (3.6% vs. 17.8%).