Myovant’s Relugolix Retains Strong Probability of FDA Approval Despite Equivalence for Castration Resistance-Free Survival

Myovant is a healthcare company developing innovative treatments for women’s health and prostate cancer. Myovant is currently evaluating their lead gonadotropin-releasing hormone (GnRH) receptor antagonist, relugolix, in late-stage clinical programs for uterine fibroids, endometriosis, and prostate cancer.
Prostate cancer remains the second leading cause of cancer mortality in men in the US. With over three million cases currently in the US and another 190,000 expected to be diagnosed in 2020. 210,000 patients are treated with GnRH antagonist or agonist therapy each year. Patients with advanced prostate cancer currently have very few therapeutic options.
Prostate cancer is unique in that tumor growth may be stimulated by testosterone. In these cases, androgen suppression therapy can function to inhibit tumor growth by reducing testosterone production, referred to as medical castration or androgen suppression therapy.
Medical castration my be achieved by use gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists. These drugs work by signaling to the testes to produce less testosterone. GnRH agonists may be delivered via injection or delivered over time via sub-dermal implant. Leuprolide (Lupron) is a commonly prescribed LHRH agonist.
GnRH antagonists achieve similar results to agonists, but often with fewer side-effects. These drugs require monthly injection by a medical professional. For this reason, leuprolide may be preferred as injection is only required once up to every six months.
Relugolix is a GnRH antagonist already approved to treat uterine fibroids in Japan and is available as a once-daily oral tablet. Approval of relugolix for the treatment of castration-sensitive advanced prostate cancer in the US would be the first new GnRH antagonist for this indication since approval of degarelix in 2008 and would be the first ever orally available androgen suppression therapy for prostate cancer, offering simpler compliance than current treatments delivered via injection.
 The ongoing Phase 3 HERO clinical trial for relugolix has demonstrated noninferiority in the primary endpoint of sustained castration rate (<50 ng/L testosterone) through 48 weeks versus active comparator leuprolide (96.7% vs. 88.8%, respectively). Leuprolide is the most commonly prescribed injectable luteinizing hormone–releasing hormone agonist used for androgen suppression therapy in prostate cancer. Furthermore, relugolix showed increased potency with a profound castration rate (<20 ng/L testosterone) at Day 15 of 78.4% vs. 1% from leuprolide. These data strongly support the efficacy of relugolix for use in androgen-sensitive prostate cancer.
Additionally, relugolix showed improvement in three other secondary endpoints. Specifically, significant improvement (p < 0.0001) over leuprolide was observed in rapid suppression of testosterone at Days 4 (56% vs. 0%) and Day 15 (98.7% vs.12%), rapid suppression of prostate-specific antigen (PSA) at Day 15 and confirmed at Day 29 (79.4% vs. 19.8%), and follicle-stimulating hormone (FSH) suppression at Week 24 (1.72 vs.5.95).
Relugolix however did not demonstrate statistical improvement in the secondary endpoint of castration resistance-free survival compared to leuprolide (74% vs. 75%, respectively) [1]. Given the high mortality rate among advanced prostate cancer patients, improvement in survival is of ultimate importance. The equivalence in survival results with relugolix compared to leuprolide is not surprising however given that the mechanism of relugolix is not novel.
In comparing safety profile, relugolix did not induce testosterone flare that is often observed with the used of LHRH agonists. Upon discontinuation of relugolix, testosterone returned to pre-treatment levels within 90 days. And most importantly, there was a 54% reduced incidence of major adverse cardiovascular events compared to leuprolide (2.9% with relugolix versus 6.2% with leuprolide). The overall incidence of adverse events was equivalent between relugolix and leuprolide (92.9% vs. 93.5%, respectively).
Androgen suppression therapy has been correlated with increased risk of cardiovascular risk in some studies and cardiovascular disease remains the most common cause of death in men with early-stage prostate cancer [2-5]. While androgen suppression therapy has not been proven as a causative factor for cardiovascular disease, this
remains a key area of interest in this indication. A reduction in cardiovascular morbidity in patients could be of significant benefit in addition to castration rate.
Based on the clinical outcomes data for relugolix in advanced prostate cancer, including sustained castration rate, profound castration rat, reduced incidence of major adverse cardiovascular events, and being the first orally available GnRH antagonist for advanced prostate cancer, Biopharma Insights Group predicts a 76% probability of FDA approval. Although there was great anticipation for improved survival outcomes, the significant improvements in efficacy, reduced risk of CVD, and ease of compliance provide strong support for approval of relugolix in this indication. This probability score is based on a quantitative statistical model built on clinical outcomes data from hundreds of clinical trials.
About Biopharma Insights Group
Biopharma Insights Group is an investment research company providing insights on clinical trial approval probability using advanced statistical methods.
1. Myovant Sciences. Myovant Sciences Announces Results of Additional Secondary Endpoint of Castration Resistance-Free Survival from Phase 3 HERO Study of Relugolix in Advanced Prostate Cancer. September 29, 2020 at 8:30 AM EDT.
2. Levine GN, D'Amico AV, Berger P, et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. CA Cancer J Clin. 2010;60(3):194-201.
3. Collier A, Ghosh S, McGlynn B, Hollins G. Prostate cancer, androgen deprivation therapy, obesity, the metabolic syndrome, type 2 diabetes, and cardiovascular disease: a review. J Clin Oncol. 2012;35(5):504-509.
4. Conteduca V, Di Lorenzo G, Tartarone A, Aieta M. The cardiovascular risk of gonadotropin releasing hormone agonists in men with prostate cancer: an unresolved controversy. Critical reviews in oncology/hematology. 2013;86(1):42-51.
5. Albertsen PC, Moore DF, Shih W, Lin Y, Li H, Lu-Yao GL. Impact of comorbidity on survival among men with localized prostate cancer. J Clin Oncol. 2011;29(10):1335-1341.

Back to news