NDA submitted for first oral GnRH receptor antagonist for prostate Ca

After meeting the primary endpoint in a phase 3 study, Myovant Sciences submitted a New Drug Application to the FDA seeking approval of relugolix, an oral nonpeptide gonadotropin-releasing hormone (GnRH) receptor antagonist, as a once-daily treatment for men with advanced prostate cancer.

Recruitment is ongoing in the phase 3 study, which is known as HERO. It is a multinational, randomized, open-label trial enrolling men with androgen-sensitive advanced prostate cancer who required at least 1 year of continuous androgen deprivation therapy (NCT03085095).

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Eligible patients are randomized 2:1 to receive oral relugolix or the GnRH receptor agonist, leuprolide acetate depot suspension. Relugolix is administered with a single 360 mg loading dose followed by 120 mg once daily. Leuprolide 22.5 mg (11.25 mg in some Asian countries) is being administered every 3 months by subcutaneous or intramuscular injection. Patients are followed at monthly visits with assessments of serum testosterone, prostate-specific antigen, gonadotropins, and safety outcomes.

The study has a planned enrollment of approximately 1,100 men and includes a subgroup of patients with metastatic prostate cancer to support the analysis of a secondary endpoint of castration resistance-free survival. Data on castration resistance-free survival are expected to be reported in the third quarter of 2020.

The primary outcome measure in the study is sustained castration rate, which is defined as the cumulative probability of testosterone suppression to ≤50 ng/dL while on study treatment from week 5 through week 48. Among men treated with relugolix, 96.7% (95% confidence interval: 94.9%, 97.9%) achieved sustained suppression of testosterone to castrate levels. Success in meeting the primary endpoint required that the lower bound of the 95% confidence interval be at least 90%.

Continue to the next page for more.In a press release, Myovant Sciences reported that relugolix also showed statistical superiority (P<.0001) over leuprolide in six key secondary endpoints, including sustained testosterone suppression to castrate levels through 48 weeks, rapid suppression of testosterone at Day 4 and at Day 15, profound suppression of testosterone (<20 ng/dL) at Day 15, rapid suppression of PSA at Day 15, and suppression of follicle-stimulating hormone at Week 24. Myovant Sciences previously reported pharmacodynamic results that showed absence of testosterone flare after starting relugolix and a return of mean testosterone levels to normal within 90 days after stopping the treatment.

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In HERO, approximately 93% of men in both the relugolix and leuprolide groups experienced at least one adverse event. The incidence of major adverse cardiovascular events, which includes non-fatal myocardial infarction, non-fatal stroke, and all-cause mortality, was approximately 50% lower in the relugolix group compared with the leuprolide group, 2.9% versus 6.2%, respectively.

The rate of adverse event-related study discontinuation was 3.5% in the relugolix group and 2.6% for the control group. Adverse events reported in ≥10% of men receiving relugolix included hot flashes, fatigue, constipation, diarrhea, and arthralgia.

The phase 2 program investigating relugolix for treatment of prostate cancer included a trial comparing it with the depot peptide GnRH antagonist degarelix in patients with localized prostate cancer and a study comparing relugolix with subcutaneous leuprorelin in men who are candidates for androgen deprivation therapy for the management of hormone-sensitive prostate cancer.