Doctor talking a with patient in hospital exam room. Photo courtesy: 2019 Fotolia
Doctor talking a with patient in hospital exam room. Photo courtesy: 2019 Fotolia

Results of the Phase III HERO study (NCT03085095), a randomized, open-label, parallel-group, multinational clinical study, designed to determine the benefit and safety of once daily 120 mg relugolix (Relumina, Myovant Sciences) for 48 weeks on maintaining serum testosterone suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L] in participants with androgen-sensitive advanced prostate cancer confirm that the trial met its primary efficacy endpoint and all six key secondary endpoints in men with advanced prostate cancer.

Patient’s enrolled in the Phase III HERO study were randomized 2:1 to receive a single loading dose of relugolix 360 mg followed by relugolix 120 mg once daily, or to treatment with leuprolide acetate 3-month depot injection, respectively.

Prostate cancer
Prostate cancer is the second most prevalent form of cancer in men and the second leading cause of death due to cancer in men in the U.S. Approximately three million men in the U.S. are currently living with prostate cancer, and approximately 170,000 men are estimated to be newly diagnosed in 2019.

Treatment for advanced prostate cancer typically involves androgen deprivation therapy, which reduces testosterone to very low levels, commonly referred to as castrate levels.

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GnRH agonists, such as leuprolide acetate, a synthetic gonadotropin-releasing hormone, are the current standard of care for medical castration. However, GnRH agonists may be associated with mechanism-of-action limitations, including the potentially detrimental initial rise in testosterone levels that can exacerbate clinical symptoms, which is known as clinical or hormonal flare, and delayed testosterone recovery if the drug is discontinued.

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Alternative
Relugolix, available as Relumina®, is a once-daily, oral gonadotropin-releasing hormone (GnRH) receptor antagonist that reduces testicular testosterone production, the hormone primarily responsible for stimulating prostate cancer, and ovarian estradiol production, a hormone known to stimulate the growth of uterine fibroids and endometriosis.

Myovant is developing a relugolix monotherapy tablet (120 mg) for men with advanced prostate cancer and relugolix combination tablet (relugolix 40 mg plus estradiol 1.0 mg and norethindrone acetate 0.5 mg) for women with heavy menstrual bleeding associated with uterine fibroids and for women with endometriosis-associated pain.

New Drug Application
These results of the Phase III HERO study support a New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) in the second quarter of 2020 and future regulatory submissions in Europe and Japan.

“An oral gonadotropin-releasing hormone, or GnRH, antagonist for advanced prostate cancer has been an aspiration for many years,” said Neal Shore, M.D., Medical Director of the Carolina Urologic Research Center and HERO Program Steering Committee Member.

“If approved, relugolix would become the first-of-its-kind oral option for men with advanced prostate cancer,” Shore added.

Analysis
In the primary endpoint responder analysis, 96.7% (95% CI: 94.9%, 97.9%) of men receiving once-daily, oral relugolix achieved sustained testosterone suppression to castrate levels.

A responder was defined as achieving and maintaining testosterone suppression to less than or equal to 50 ng/dL from Week 5 through Week 48. For the study to be successful, the lower bound of the 95% confidence interval of the response rate had to be at least 90%.

Superior results
Five key secondary endpoints demonstrated superiority to leuprolide acetate (Eligard®; Tolmar Pharmaceuticals and Lupron Depot®; AbbVie), including rapid suppression of testosterone at Day 4 and Day 15, profound suppression of testosterone at Day 15, rapid suppression of prostate-specific antigen (PSA) at Day 15, and suppression of follicle-stimulating hormone (FSH) at Week 24 (all p-values < 0.0001).

In addition, relugolix demonstrated non-inferiority to leuprolide acetate on sustained testosterone suppression through 48 weeks (96.7% vs. 88.8%, respectively) with a between-group difference of 7.9% (95% CI: 4.1%,11.8%), the primary endpoint required for regulatory submissions outside of the U.S. In addition, the pharmacodynamic results showed no testosterone flare after initiation of relugolix and mean testosterone levels returned to normal levels within 90 days after treatment discontinuation.

“With the exciting results from the HERO study demonstrating the potential of relugolix to provide unique benefits compared to leuprolide, we look forward to submitting an NDA to the FDA,” said Lynn Seely, M.D., President and CEO of Myovant Sciences.

“We are now closer to our goal of bringing a precision oral medicine to the broad spectrum of men with advanced prostate cancer,” Seely added.

The overall incidence of adverse events in the relugolix and leuprolide acetate groups was comparable (92.9% vs. 93.5%, respectively). In the relugolix group, 3.5% of men discontinued the study early due to adverse events compared with 2.6% of men in the leuprolide acetate group.

The most frequently reported adverse events, reported in at least 10% of men in the relugolix group, were hot flashes, fatigue, constipation, diarrhea, and arthralgia. Unadjudicated major adverse cardiovascular events were reported in 2.9% of men in the relugolix group versus 6.2% of men in the leuprolide acetate group. These events included non-fatal myocardial infarction, non-fatal stroke, and all-cause mortality.

Approximately 1,100 patients are planned to be enrolled in this study, including approximately 430 patients with metastatic prostate cancer to support the analysis of a secondary endpoint of castration resistance-free survival, data which are expected in the third quarter of 2020, and 138 Chinese patients (enrolled in China and Taiwan) to support registration in China.

Other studies
Earlier this year, Myovant announced positive top-line data from two Phase III studies, LIBERTY 1 and LIBERTY 2, evaluating relugolix combination therapy for uterine fibroids, as well as positive results from a separate bioequivalence study supporting a potential one tablet, once-daily dosing regimen. Myovant expects to submit an NDA to the FDA for uterine fibroids in April 2020. Myovant also expects to announce top-line results from two Phase 3 studies, SPIRIT 2 and SPIRIT 1, evaluating relugolix combination therapy for endometriosis-associated pain in the first and second quarters of 2020, respectively.

Clinical trials
A Study to Evaluate the Safety and Efficacy of Relugolix in Men With Advanced Prostate Cancer (HERO) – NCT03085095

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