Relugolix Shows Acceptable Safety in Patients With Advanced Prostate Cancer Enrolled to HERO Trial


Results from a detailed safety analysis of the pivotal phase 3 HERO trial showed that relugolix, an oral gonadotropin-releasing hormone receptor antagonist, had an acceptable toxicity profile with favorable tolerability in patients with advanced prostate cancer.

Bryan Mehlhaff, MD

Bryan Mehlhaff, MD

Results from a detailed safety analysis of the pivotal phase 3 HERO trial (NCT03085095) presented during the 2022 American Urological Association (AUA) Annual Meeting showed that relugolix (Orgovyx), an oral gonadotropin-releasing hormone receptor (GnRH) antagonist, had an acceptable toxicity profile with favorable tolerability in patients with advanced prostate cancer.1

A lower percentage of patients who received relugolix experienced major adverse cardiovascular events (MACE) compared with those who were given leuprolide (Lupron), at 2.9% and 6.2%, respectively. Specifically, Kaplan-Meier estimates of incidence rate revealed a risk reduction of 54% with relugolix (HR, 0.46; 95% CI, 0.24-0.88).

Notably, in a subset of men who had a reported medical history of cardiovascular events, MACE rates on study drug treatment in the investigative and control arms were 3.6% and 17.8%, respectively; this translated to 5.8-fold higher odds of experiencing MACE with leuprolide vs relugolix.

“Relugolix, an oral nonpeptide GnRH receptor antagonist, was generally well tolerated in the phase 3 HERO study,” lead study author Bryan Mehlhaff, MD, of the Oregon Urology Institute, and colleagues, wrote in a poster on the data. “Adverse effects [AEs] occur with varying time of onset and duration depending on the type of event.”

HERO enrolled patients with histologically or cytologically confirmed adenocarcinoma of the prostate that needed at least 1 year of continuous androgen deprivation therapy.2 To be eligible for enrollment, patients needed to be at least 18 years of age, and have 1 of the following 3 clinical presentations: evidence of biochemical or clinical relapse after local primary intervention with curative intent, newly diagnosed hormone-sensitive metastatic disease, or advanced localized disease that is not likely to be cured by local primary intervention with curative intent.

If patients experienced MACE within 6 months of study start, they were excluded.

Study participants were randomized 2:1 to receive oral relugolix at a once-daily dose of 120 mg following a single loading dose of 360 mg, or leuprolide injections given every 12 weeks for 48 weeks. Stratification factors included geographic region, presence or absence of metastatic disease, and age.

The primary end point of the trial was sustained castration rate, and key secondary end points included noninferiority of relugolix to leuprolide regarding sustained castration rate with a noninferiority margin of -10 percentage points.

Other end points included cumulative probability of testosterone suppression to less than 50 ng per deciliter on day 4 and 15, the percentage of patients with a prostate-specific antigen (PSA) response at day 15 with confirmation at day 29, the profound castration rate on day 15, and the FSH level at the end of week 24.

In December 2020, the FDA approved relugolix for use in patients with advanced prostate cancer based on earlier findings from HERO.3 Data showed that 96.7% (95% CI, 94.9-97.9) of those who received relugolix (n = 622) maintained castration through 48 weeks vs 88.8% (95% CI, 84.6%-91.8%) of those who were given leuprolide (n = 308); the difference of 7.9 percentage points (95% CI, 4.1-11.8) was indicative of noninferiority and superiority of relugolix.2

Notably, all secondary end points showed superiority with relugolix over leuprolide (P < .001). The cumulative probability of castration on day 4 with relugolix was 56.0% vs 0% with leuprolide; on day 15, these rates were 98.7% and 12.0%, respectively. Moreover, the cumulative probability of testosterone suppression to profound castrate levels on day 15 was 78.4% with relugolix and 1.0% with leuprolide. More patients in the investigative arm had a confirmed PSA response at day 15 vs those in the control arm, at 79.4% and 19.8%, respectively (P < .001).

Updated data from the HERO trial shared at the 2021 AUA Annual Meeting showed that relugolix did not significantly delay onset of castration resistance vs leuoprolide.4 At 48 weeks, the castration resistance–free survival (CRFS) rate was 74.3% (95% CI, 68.6%-79.2%) with relugolix vs 75.3% (95% CI, 66.7%-81.9%) with leuprolide in the metastatic disease cohort (n = 434; HR, 1.03; 95% CI, 0.68-1.57; P = .84). Similar CRFS rates were reported in the modified intention-to-treat population (n = 1074).

At this year’s meeting, investigators shared a review of the safety findings from the trial, including an analysis of toxicity onset and duration. The safety population was comprised of 622 patients who received relugolix and 308 patients who were given leuprolide.

Data indicated that 92.9% of those in the investigative arm and 93.5% of those in the control arm experienced AEs. The AEs that occurred in more than 10% of patients in the relugolix and leuprolide arms, respectively, included hot flash (54.3% vs 51.6%), fatigue (21.5% vs 18.5%), constipation (12.2% vs 9.7%), diarrhea (12.2% vs 6.8%), and arthralgia (12.1% vs 9.1%).

Grade 3 or higher toxicities were experienced by 18.0% of those in the relugolix arm vs 20.5% of those in the leuprolide arm. Grade 3 or higher AEs reported in 1% or more of patients in the investigative and control arms, respectively, comprised hypertension (1.6% vs 0.6%), diabetes (1.0% vs 0.6%), and syncope (1.0% vs 1.0%). All other grade 3 or higher toxicities were reported with comparable incidence in both arms.

For the toxicities that were experienced by more than 10% of patients, the median time to onset ranged from 19.0 days to 142.0 days in the investigative arm and 41.0 days to 189 days in the control arm. The duration of these effects varied.

Notably, diarrhea was noted to have a short median duration compared with other toxicities; this AE had a median duration of 9 days (range, 1-370) in the relugolix arm vs 3 days (range, 1-224) in the leuprolide arm. Fatigue and hot flash were found to be more persistent. The median duration of fatigue in those who received relugolix was 289 days (range, 2-429) vs 274 days (range, 3-426) in those who were given leuprolide. Moreover, hot flash lasted for a median of 342 days (range, 15-477) with relugolix vs 331 days (range, 1-428) with leuprolide.

Regarding MACE, the median time to onset with relugolix was 177 days (range, 38-343) vs 132 days (range, 8-352) with leuprolide.

“MACE appeared to occur earlier and with a higher percentage in leuprolide vs relugolix groups, possibly supporting a different risk/mechanism between GnRH agonists and antagonists,” the authors concluded.


  1. Mehlhaff B, Shore ND, George DJ, et al. Oral relugolix for androgen deprivation therapy in advanced prostate cancer: detailed safety analysis from the randomized phase 3 HERO study. Presented at: 2022 American Urology Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract MP27-16.
  2. Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325
  3. FDA approves first oral hormone therapy for treating advanced prostate cancer. News release. FDA. December 18, 2020. Accessed May 14, 2022.
  4. Saad F, George DJ, Cookson MS, et al. Relugolix vs leuprolide effects on castration resistance-free survival from the phase 3 HERO study in men with advanced prostate cancer. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP24-07.
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