Men with prostate cancer on androgen-deprivation therapy are usually treated with leuprolide, a long-acting injectable luteinizing hormone-releasing hormone (LHRH) agonist requiring an every-3-month injection, but it may be possible for ADT to be delivered by a daily oral treatment, pending regulatory approval. In the phase III HERO study, oral relugolix, given daily, was superior to leuprolide for achieving testosterone suppression in men with advanced prostate cancer who required androgen-deprivation therapy, as reported during the ASCO20 Virtual Scientific Program by Neal D. Shore, MD, FACS, of Carolina Urologic Research Center, Myrtle Beach, South Carolina, and published online in The New England Journal of Medicine to coincide with the presentation.^1,2

Neal D. Shore, MD, FACS

The study met the primary endpoint of sustained castration levels of testosterone at 48 weeks. Almost all men treated with relugolix (96.7%) maintained castration levels of testosterone through 48 weeks vs 88% of men treated with leuprolide (P < .001 for superiority). In addition, the risk of developing a major adverse cardiovascular event was 54% lower with relugolix.

“Prescribing information for leuprolide and other LHRH agonists already contains warnings about increased risk of myocardial infarction, sudden cardiac death, and stroke. In the HERO trial, the oral GnRH antagonist relugolix showed sustained testosterone suppression superior to that of leuprolide [an LHRH agonist],” stated Dr. Shore.

“Relugolix is a novel, oral GnRH antagonist that has the potential to become a new standard for androgen-deprivation therapy in advanced prostate cancer,” he added.

Practice-Changing Results?

This abstract was one of three prostate cancer abstracts selected for the Genitourinary Highlights session at this year’s ASCO meeting. David Wise, MD, of Perlmutter Cancer Center at NYU Langone Health in New York, who discussed the highlights, agreed that relugolix is a new standard of care. “Is this practice-changing? Yes, for a subset of patients with a history of significant cardiovascular disease and without gastrointestinal malabsorption problems,” Dr. Wise stated. “I will use this drug to avoid injection-site reactions commonly experienced with degarelix [another GnRH antagonist]. The concern for noncompliance with an oral drug will necessitate more frequent serum testosterone checks, particularly for monotherapy,” he added.

Relugolix is practice-changing for a subset of patients with a history of significant cardiovascular disease and without gastrointestinal malabsorption problems.

— David Wise, MD

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Dr. Shore explained that the reduced incidence of major adverse cardiovascular events with relugolix is noteworthy, because men with prostate cancer have an increased risk of cardiovascular events. “Cardiovascular events are the leading cause of death in men with prostate cancer, now accounting for up to one-third of deaths. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more have risk factors such as obesity, diabetes, hypertension, and hyperlipidemia. In the HERO trial, more than 90% of men had cardiovascular risk factors.”

Study Details

The global trial randomly assigned 930 men with advanced prostate cancer in a 2:1 ratio to receive oral relugolix at 120 mg/d (n = 622) or leuprolide injections (n = 308) every 3 months, for a total of 48 weeks. To be eligible for the trial, men had to be 18 years or older, have histologically confirmed adenocarcinoma of the prostate, and be candidates for at least 1 year of continuous androgen-deprivation therapy. Eligible patients had to have one of the following: evidence of biochemical or clinical relapse after primary therapy with curative intent, newly diagnosed hormone-sensitive metastatic disease, or advanced localized disease unlikely to be cured. Patients who experienced major adverse cardiovascular events within 6 months of enrollment were excluded.

At baseline, the median patient age was 71 years, and 28.6% were older than age 75. About 31% had metastatic disease, 43% had Gleason 8 to 10 disease, 11.9% had previous androgen-deprivation therapy, and 30.3% had previous radiotherapy. The median prostate-specific antigen (PSA) level at baseline was 10.8 ng/mL. The mean testosterone level at baseline was 427.5 ng/dL. More than 90% of men had at least one cardiovascular risk factor, and the percentage of men with risk factors was well balanced in the two arms. Treatment adherence was more than 99% in both groups. The median time to follow-up, including safety, was 52 weeks.

Key Results

In addition to superiority for the primary endpoint of maintained castration levels of testosterone over 48 weeks, relugolix was superior to leuprolide for all key secondary endpoints (P < .001). These endpoints included the cumulative probability of castrate levels on day 4 (56% vs 0%) and on day 15 (98.7% vs 12%) and of testosterone suppression to profound levels (ie, < 20 ng/dL). The percentage of patients with a confirmed PSA response at day 15 was 79.4% with relugolix and 19.8% with leuprolide (P < .001).

Men treated with relugolix achieved castration levels of testosterone more rapidly than leuprolide, and this response was maintained throughout treatment. On the other hand, patients who discontinued relugolix treatment had faster testosterone recovery to normal levels.

“Another clinical advantage of oral relugolix over leuprolide is a higher percentage of men achieved testosterone recovery to normal levels within 90 days after treatment discontinuation (54% vs 3%),” Dr. Shore noted. “This should be particularly relevant for men receiving intermittent androgen-deprivation therapy, short-course androgen-deprivation therapy, or stopping treatment to recover from serious and debilitating testosterone suppression adverse effects,” he explained.

Safety

The overall incidence of adverse events was consistent across the two treatment arms. Hot flash was the most common adverse event in both arms: 54.3% for relugolix and 51.6% for leuprolide. Moderate or mild diarrhea was reported in more patients in the relugolix group (12.2%) than in the leuprolide group (6.8%). There were no treatment withdrawals due to diarrhea.

Fatal events occurred in 1.1% of the relugolix group and 2.9% of the leuprolide group. A prespecified analysis after 48 weeks of treatment found the incidence of major adverse cardiovascular events was 2.9% with relugolix compared with 6.2% with leuprolide—a rate 54% lower with the oral androgen-deprivation therapy.

In a subgroup of patients with a reported history of major adverse cardiovascular events, the incidence of such events during treatment was 3.6% for relugolix and 17.8% for leuprolide. “The odds ratio was 5.8 times higher with leuprolide in comparison to relugolix in men with a history of major adverse cardiovascular events,” Dr. Shore stated. 

DISCLOSURE: The HERO study was funded by Myovant Sciences. Dr. Shore has reported consulting relationships with Myovant Sciences, Amgen, Astellas Pharma, AstraZeneca, Bayer, BMS, Dendreon, Ferring, Genentech/Roche, Janssen, Medivation/Astellas, Merck, Pfizer, and Tolmar. Dr. Wise has received honoraria from OncLive; consulting fees from AlphaSights, Foundation Medicine, GLG Pharma, Guidant Global, Leap Therapeutics, Pfizer, and Silverlight; and reimbursement for travel expenses from Pfizer.

REFERENCES

1. Shore ND, George DJ, Saad F, et al: HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer. ASCO20 Virtual Scientific Program. Abstract 5602.

2. Shore ND, Saad F, Cookson MS, et al: Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med 382:2187-2196, 2020.