Background: Prostate cancer disproportionately impacts Black men, with a higher incidence and worse outcomes relative to other races (Siegel DA, MMWR Morb Mortal Wkly Rep. 2020;69:1473). In the international phase 3 HERO study, relugolix, the once-daily oral GnRH receptor antagonist, demonstrated superior continuous suppression of testosterone to castrate levels through week 48 compared to leuprolide (96.7% for relugolix vs. 88.8% of men receiving leuprolide; Shore N, NEJM 2020; 382:2187) in men with advanced prostate cancer (APC). To further characterize the results from this trial in black men a subgroup analysis of HERO was undertaken. Methods: HERO was a phase 3 randomized, open-label, study to evaluate relugolix vs. leuprolide in 930 treated men with APC. The subgroup analyzed included all Black men enrolled in the HERO study. Assessments analyzed included sustained testosterone suppression to castrate levels (<50 ng/dL) from day 29 through 48 weeks, early testosterone suppression to castrate levels (day 4 and day 15), PSA response (>50% decrease) at day 15 with confirmation at day 29, profound castration rate (<20 ng/dL) at day 15, and FSH level at the end of week 24. Results: Of the 930 men (relugolix: 622; leuprolide: 308) randomized and treated in HERO, 30 (4.8%) and 16 (5.2%) Black men were enrolled in the relugolix and leuprolide groups, respectively. Most men in this subgroup were from North America (82.6%) and ≤75 years old (89.1%), with a median age of 66 years. More Black men in the relugolix group had metastatic disease at study entry (30% vs. 25%), prior androgen deprivation therapy (13.3% vs. 6.3%), and prior prostatectomy (53.3% vs. 18.8%). Median PSA (12.8 vs. 16.0 ng/ml) and median testosterone levels (375.2 vs. 419.2 ng/dL) were lower at baseline for relugolix vs leuprolide. Of the Black men who received relugolix, 93.3% (95% confidence interval [CI], 75.9% to 98.3%) maintained castration through 48 weeks, as compared with 93.3% (95% CI, 61.3 to 99.0) of men receiving leuprolide (difference: 0% [95% CI, -15.5% to 15.5]). Testosterone suppression to castrate levels at day 4 (53% vs 0%), castrate levels at day 15 (97% vs 13%), and profound castration rates on day 15 (67% vs 6%) were greater with relugolix vs leuprolide. PSA response at day 15 was 83.3% with relugolix and 6.3% with leuprolide. At the end of week 24, median FSH levels were 1.75 IU/L for relugolix and 3.72 IU/L for leuprolide. Incidence of all grade adverse events were 96.7% vs 87.5% and grade ≥3 adverse events were 16.7% vs 25.0% in the relugolix and leuprolide groups, respectively. Conclusions: In this HERO study subgroup analysis, relugolix was effective and generally well tolerated in a cohort of Black men, consistent with the relugolix results in the overall population. Given the limited size of the subgroup, additional research is warranted in this population. Clinical trial information: NCT03085095.