Oral advanced prostate cancer agent shows safety, efficacy

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Myovant Sciences recently announced positive phase III trial results for its once-daily oral small molecule gonadotropin-releasing hormone (GnRH) antagonist relugolix, for the treatment of advanced prostate cancer.

If the FDA approves relugolix, it would be the first oral androgen deprivation therapy option for men with advanced prostate cancer, according to Neal Shore, MD, of the Carolina Urologic Research Center, Myrtle Beach, SC and steering committee member of the phase III HERO relugolix trial.

Dr. Shore was among the researchers to perform two successful phase II trials on oral relugolix for advanced prostate cancer.

“The first phase II trial compared oral relugolix once a day in comparison to 3 months treatment with a luteinizing hormone-releasing hormone (LHRH) agonist preparation for patients with advanced prostate cancer. The endpoints for that study were testosterone suppression, PSA declines, and numerous secondary endpoints,” Dr. Shore said. “The second phase II study was oral relugolix versus monthly degarelix for patients receiving radiation therapy who had intermediate-risk prostate cancer.”

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Based on the success of the two phase II studies, Dr. Shore and colleagues designed the phase III HERO trial protocol studying 934 men with advanced prostate cancer with metastatic disease, biochemical relapse, or patients with high-risk, locally advanced disease. Researchers randomized patients to either relugolix once-per-day pill or 3 months LHRH agonist therapy (leuprolide acetate).

The primary efficacy endpoint of the study was the ability of relugolix to achieve and maintain testosterone suppression to castrate levels, defined as testosterone suppression of less than or equal to 50 ng/dL from week 5 through 48 weeks. For the study to be successful, the lower bound of the 95% confidence interval of the response rate had to be at least 90%, according to Myovant.

“Essentially, the trial met its primary endpoint of noninferiority. With this hurdle passed, we were allowed to test for superiority and relugolix also achieved response rates for sustained testosterone suppression that achieved superiority over those in the LHRH agonist arm,” Dr. Shore said.

Next: Relugolix was superior to leuprolide acetate in multiple secondary endpointsRelugolix was superior to leuprolide acetate in multiple secondary endpoints, including rapid suppression of testosterone at day 4 and day 15, profound suppression of testosterone at day 15, rapid suppression of PSA at day 15, and suppression of follicle-stimulating hormone at week 24.

Relugolix demonstrated non-inferiority to leuprolide acetate on sustained testosterone suppression through 48 weeks.

Relugolix’s safety and tolerability profiles also were well tolerated, Dr. Shore said.

“When we evaluated major adverse cardiovascular events, or MACE, there was a 50% reduction in the proportion of patients who developed MACE events in the relugolix arm versus the LHRH agonist arm,” according to Dr. Shore.

Researchers studied testosterone recovery in a subset of 184 patients and found mean testosterone returned to normal levels within 90 days of relugolix treatment, according to a Nov. 19, 2019 Myovant analyst presentation.

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Relugolix, a GnRH antagonist and not an agonist, does not result in a testosterone surge. Rather, its mechanism of action is direct inhibition of the endocrine axis, and thus achieves rapid testosterone suppression with rapid PSA decline, according to Dr. Shore.

“We continue to monitor our trial population who had metastatic disease for the development of castration-resistant prostate cancer, and thus to further assess differences between the two arms,” Dr. Shore said. “We await those results.”

The phase III HERO trial is a potential pathway for regulatory approval. According to the company, approximately 1,100 patients are enrolled in the HERO study, including about 430 patients with metastatic prostate cancer for the analysis of a secondary endpoint of castration resistance-free survival, for which data are expected in the third quarter of 2020.

“We are planning a peer-reviewed presentation and publication submission in 2020,” he said.

The company plans to submit a New Drug Application to the FDA in 2020. If approved, many prostate cancer patients would enjoy the option of a daily oral medication versus a subcutaneous or intramuscular injection, according to Dr. Shore.

Dr. Shore conducts research and does consulting for AbbVie, Ferring Pharmaceuticals, Myovant, and Tolmar.