For men diagnosed with prostate cancer, the leading cause of death is cardiovascular (CV) disease rather than the cancer itself. Around a third of patients with prostate cancer have pre-existing CV disease, and many have other co-morbidities, including obesity, diabetes, hypertension and hyperlipidemia. Androgen deprivation therapy (ADT) with either injectable long acting luteinizing hormone-releasing hormone (LHRH) receptor agonists or gonadotropin-releasing hormone (GnRH) antagonists is the mainstay of treatment for patients with advanced prostate cancer, with the main goal of lowering testosterone levels to <50 ng/dL. However, LHRH agonists, such as the commonly used leuprolide acetate, cause an initial surge of testosterone with a flare of symptoms and a possible delay of therapeutic effect. In addition, they fail to fully suppress follicle-stimulating hormone (FSH), a potential mitogenic growth factor for prostate cancer cells. Conversely, the GnRH antagonist degarelix results in a rapid suppression of testosterone levels without an initial testosterone surge; however, frequent injection-site reactions have probably limited its clinical use. Evidence also suggests a possible link between ADT and an increased risk of cardiovascular disease. Relugolix is a novel, oral, highly selective GnRH receptor antagonist that achieves hormone suppression by a direct inhibitory effect on the pituitary GnRH receptors.

The multi-national, randomized, open-label, phase III HERO trial was designed to evaluate the efficacy and safety of relugolix in men with androgen sensitive advanced prostate cancer. The results from this study were presented at the ASCO 2020 virtual meeting by Neal Shore, MD, FACS (Carolina Urologic Research Center, South Carolina, USA) and were simultaneously published in the New England Journal of Medicine. A total of 934 eligible men were randomly assigned in a 2:1 ratio to receive either oral relugolix (120 mg daily after one loading dose of 360 mg) or standard dose injection of leuprolide acetate (every 3 months) for 48 weeks. The primary endpoint was sustained testosterone suppression to castrate levels (<50ng/dL) through 48 weeks; key secondary endpoints included non-inferiority to leuprolide, castrate testosterone levels on day 4 and 15, profound castration levels (<20ng/dL) on day 15, prostate-specific antigen (PSA) response (a decrease of >50%) at day 15, and FSH levels at the end of week 24. In addition, testosterone recovery to normal levels within 90 days after drug discontinuation was evaluated in a subgroup of patients. The median follow-up was 52 weeks.

The primary endpoint of the trial was met with 96.7% of men achieving sustained testosterone suppression with relugolix compared with 88.8% for leuprolide. Notably, relugolix was shown to be both non-inferior and superior to leuprolide in sustaining castration rates (P < 0.0001); superiority was also shown in all key secondary endpoints (P < 0.0001). By day 4, testosterone levels were <50ng/dL with relugolix, which was maintained throughout the study; in contrast, leuprolide administration led to a surge in testosterone on day 4, decreasing to castrate levels by day 29. Testosterone recovery occurred in 54% and 3% of patients treated with relugolix and leuprolide, respectively. The overall incidence of adverse events (AEs) was comparable between the treatment groups, with ≥ grade 3 treatment-related AEs occurring in 3.4% and 2.6% of patients in the relugolix and leuprolide groups, respectively, and treatment-related deaths occurred in 1.1% versus 2.9% of patients. Notably, the incidence of major adverse cardiovascular events (MACE) after 48 weeks of treatment was lower with relugolix than leuprolide (2.9% versus 6.2%, respectively), and among 129 men who had a history of MACE (> 6 months before entering the trial), the incidence of MACE was 3.6% versus 17.8%, respectively. Overall, the risk of MACE was 54% lower with relugolix compared with leuprolide (hazard ratio 0.46).

Dr Shore concluded that the HERO trial achieved the primary and all key secondary endpoints, and that relugolix “has the potential to become a new standard of care for ADT for patients with advanced prostate cancer”. A discussant for the trial, Elahe A Mostaghel, MD, PhD (University of Washington, Seattle, Washington, USA) commented on the clear significance of the “more rapid onset of castration, lack of flare response, and decrease in MACE” with relugolix treatment.

Reference

Shore ND, et al. J Clin Oncol. 2020; 38 (suppl; abstract 5602).