The first oral gonadotropin-releasing hormone (GnRH) receptor antagonist for adults with advanced prostate cancer is now available in clinical practice.

On December 18, 2020, the FDA approved relugolix for adults with advanced disease based on medical castration rate data from the phase 3 HERO study ( identifier: NCT03085095).1 The randomized controlled trial compared the safety and efficacy of relugolix with that of leuprolide acetate in 930 evaluable patients with advanced prostate cancer who were candidates for at least 1 year of continuous androgen deprivation therapy.

The primary end point was the medical castration rate, defined as achievement and sustainment of testosterone suppression to castrate levels (<50 ng/dL) by day 29 through 48 weeks of treatment. Relugolix was administered in a 360-mg loading dose, followed by daily oral doses of 120 mg. In the control arm, leuprolide acetate was subcutaneously injected at 22.5 mg every 3 months for 48 weeks.

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Among the 622 patients randomly assigned to receive relugolix, the medical castration rate was 96.7% (95% CI, 94.9%-97.9%). This compared with a medical castration rate of 88.8% (95% CI, 84.6%-91.8%) in the leuprolide acetate arm (n=308).

In an interview with Cancer Therapy Advisor, Daniel J. George, MD, a lead investigator on the HERO study, a professor of medicine and surgery in the department of medicine at the Duke University School of Medicine, and a member of the Duke Cancer Institute in Durham, North Carolina, discussed the approval of relugolix and its implications for the advanced prostate cancer paradigm.

Cancer Therapy Advisor: Please provide an overview of the efficacy data that led to the approval.

Dr. George: “The HERO study was a definitive, international phase 3 study with representation from Asia, North America, and Europe. HERO enrolled men with advanced prostate cancer, [specifically disease] that had recurred following prostatectomy, locally advanced high-risk disease that would require hormonal therapy for a prolonged period of time, or metastatic prostate cancer. All of these men would receive standard-of-care hormonal therapy in the form of androgen deprivation therapy, and that usually entails a GnRH agonist for at least 12 months.

Patients were randomized 2 to 1 to receive oral therapy with the novel GnRH antagonist relugolix, or a 3 month injection of leuprolide. Relugolix is a novel first-in-class oral GnRH antagonist that, in prior studies, had been shown to effectively and efficiently block GnRH signaling.

The study had a primary end point of demonstrating continuous testosterone suppression over 48 weeks, which was checked every 4 weeks. Patients had to maintain a testosterone level less than 50 ng/ml, and as a goal, had to have a continuous testosterone suppression rate for the population that was over 90% for the lower limit of the 95% competence interval. There had to be really clean data to show continuous testosterone suppression.

The results were really quite remarkable. Nearly 97% of patients had continuous testosterone suppression, and the bottom level and 95% confidence interval lower limit—which had to be above 90%—was 94%. Relugolix more than met its primary end point in being able to maintain a very high consistency of continuous testosterone suppression. The HERO trial was also set up as a noninferiority study, and for that, they set a boundary of a 95% confidence interval within 10%. So, relugolix had to be at least 90% as effective as leuprolide at the 95th confidence interval. For this key secondary end point, relugolix was not only noninferior to leuprolide, but actually superior.”