Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer

Abstract

Injectable luteinizing hormone-releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect. The efficacy and safety of relugolix, an oral gonadotropin-releasing hormone antagonist, as compared with those of leuprolide are not known. METHODS In this phase 3 trial, we randomly assigned patients with advanced prostate cancer, in a 2:1 ratio, to receive relugolix (120 mg orally once daily) or leuprolide (injections every 3 months) for 48 weeks. The primary end point was sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks. Secondary end points included noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients. RESULTS A total of 622 patients received relugolix and 308 received leuprolide. Of men who received relugolix, 96.7% (95% confidence interval [CI], 94.9 to 97.9) maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6 to 91.8) of men receiving leuprolide. The difference of 7.9 percentage points (95% CI, 4.1 to 11.8) showed noninferiority and superiority of relugolix (P<0.001 for superiority). All other key secondary end points showed superiority of relugolix over leuprolide (P<0.001). The percentage of patients with castrate levels of testosterone on day 4 was 56.0% with relugolix and 0% with leuprolide. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group. Among all the patients, the incidence of major adverse cardiovascular events was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24 to 0.88). CONCLUSIONS In this trial involving men with advanced prostate cancer, relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events. (Funded by Myovant Sciences; HERO ClinicalTrials.gov number, NCT03085095.

Cardiovascular risk profiles of GnRH agonists and antagonists: real-world analysis from UK general practice

“…The findings of the current study are also in line with a recent Phase 3 trial which investigated CV risk as a prespecified safety analysis in 622 patients with advanced prostate cancer who received a GnRH antagonist (relugolix) compared with 308 patients who received a GnRH agonist (leuprolide), and suggested reduced CV risks with GnRH antagonists compared with agonists [46]. Among all patients, the incidence of major adverse CV events (defined as non-fatal MI, non-fatal stroke, and death from any cause) was 2.9% (exact 95% CI 1.7-4.5) in the relugolix group and 6.2% (exact 95% CI 3.8-9.5) in the leuprolide group (hazard ratio 0.46; 95% CI 0.24-0.88).…”

Effect of androgen deprivation therapy on cardiovascular function in Chinese patients with advanced prostate cancer: a prospective cohort study

“…These include awareness of the condition and patient education on diet, smoking and exercise, careful monitoring of blood pressure, blood sugar and lipid level for patients, appropriate patient referral to cardiological assessment and usage of pharmacological agents, including aspirin, for high risk patients. For patients with high cardiovascular risk, the usage of LHRH antagonist had shown to have less cardiovascular complications when compared to LHRH agonist 27,30 . All these measures would help to improve the overall standard of care and survival of patients.…”

Cardiac biomarkers in patients with prostate cancer and cardiovascular disease receiving gonadotrophin releasing hormone agonist vs antagonist

“…Evidence suggesting a differential ADT class effect between GnRH agonist and antagonist on cardiac outcomes is now accumulating [3,11,12]. Previous studies have shown that low testosterone levels are associated with an increased CV risk.…”

“…In this study, the GnRH antagonist, degarelix, was associated with an 18% reduction in the risk of CV events compared with a GnRH agonist over 1 year in patients with CVD comorbidities. In the HERO trial [12], which enrolled 934 men, the incidence of major adverse CV events after 48 weeks of treatment was 2.9% with relugolix (oral GnRH antagonist) and 6.2% with leuprolide (GnRH agonist). In the subgroup of men with a history of CV events, the incidence was 3.6% in the relugolix group and 17.8% in the leuprolide group, indicating that the risk differed by a factor of 4.8.…”