As reported at the ASCO20 Virtual Scientific Program (Abstract 5602) and in The New England Journal of Medicine by Shore et al, the phase III HERO trial showed sustained castrate testosterone levels and lower risk of major cardiovascular events with the oral gonadotropin-releasing hormone antagonist relugolix given daily vs the injectable luteinizing hormone–releasing hormone agonist leuprolide given every 3 months in men with advanced prostate cancer.
The open-label trial included 934 patients with advanced prostate cancer from sites in North and South America, Europe, and the Asia-Pacific region. Patients were randomly assigned 2:1 between April 2017 and October 2018 to receive relugolix at 120 mg once daily after a single loading dose of 360 mg (n = 622 treated) or depot-injection leuprolide at 22.5 mg (11.25 mg in Japan and Taiwan) every 3 months (n = 308 treated) for 48 weeks. A total of 32% of patients had metastatic disease and 50% had biochemical recurrence after definitive treatment. The primary endpoint was sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks in the treated population (patients receiving at least one dose of study drug). If noninferiority of relugolix was shown, with a noninferiority margin of -10 percentage points, testing for superiority was performed.
Sustained Testosterone Suppression
Castrate levels of testosterone were maintained through 48 weeks in 96.7% (95% confidence interval [CI] = 94.9%–97.9%) of the relugolix group vs 88.8% (95% CI = 84.6%–91.8%) of the leuprolide group. The difference of 7.9 percentage points (95% CI = 4.1%–11.8%) established noninferiority; since the lower boundary of the 95% confidence interval for the difference was above zero, superiority was also established (P < .001 for superiority).
All key secondary endpoints showed superiority of relugolix over leuprolide (P < .001), including cumulative probability of castration on day 4 (56.0% vs 0%) and day 15 (98.7% vs 12.0%), testosterone suppression to profound castrate levels (< 20 ng/dL) on day 15 (78.4% vs 1.0%), and confirmed prostate-specific antigen response (> 50% decrease) at day 15 (79.4% vs 19.8%). In a subgroup of 184 patients followed for testosterone recovery, mean testosterone levels 90 days after treatment discontinuation were 288.4 ng/dL vs 58.6 ng/dL, with testosterone recovery to ≥ 280 ng/dL (lower limit of the normal range) observed in 54% vs 3% of patients (P = .002).
Grade 3 or 4 adverse events occurred in 18.0% of the relugolix group vs 20.5% of the leuprolide group. The most common adverse events of any grade reported in both groups were hot flash (54.3% vs 51.6%) and fatigue (21.5% vs 18.5%). Serious adverse events occurred in 12.2% vs 15.3% of patients. Major adverse cardiovascular events (defined as nonfatal myocardial infarction, nonfatal stroke, and death from any cause) occurred in 2.9% vs 6.2% of patients over 48 weeks (hazard ratio = 0.46, 95% CI = 0.24–0.88), including rates of 2.8% vs 4.2% in patients without history of a major adverse cardiovascular event and 3.6% vs 17.8% in 84 vs 45 patients with history of such an event. Adverse events led to death in seven (1.1%) vs nine patients (2.9%).
The investigators concluded, “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.”
Disclosure: The study was funded by Myovant Sciences. For full disclosures of the study authors, visit nejm.org.
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