By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

The FDA approved the first oral, nonpeptide, gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone release hormone (LHRH), antagonist to treat advanced prostate cancer. Relugolix is a small molecule antagonist that suppresses the production and secretion of testosterone by blocking GnRH receptors in the anterior pituitary gland.1 The FDA gave the drug priority review and orphan status. Relugolix is manufactured by Bushu Pharmaceuticals in Japan and distributed by Myovant Sciences as Orgovyx.


Relugolix should be prescribed to adults with advanced prostate cancer.1


Administer a loading dose of 360 mg on the first day, followed by 120 mg daily at approximately the same time each day without regard to meals.1 Usually, relugolix is continued upon development of nonmetastatic or metastatic, castration-resistant prostate cancer.1 Relugolix is available as 120 mg tablets.


Relugolix is the first oral drug in this therapeutic class, as current therapies (e.g., GnRH agonists and antagonists) are injectables. GnRH antagonists do not produce the transient increase in serum testosterone and accompanying worsening of symptoms or new signs and symptoms associated with GnRH agonists. There are more patients with testosterone recovery on relugolix after discontinuation of treatment. In contrast to leuprolide, relugolix does not carry a warning in the prescribing information for higher risk of cardiovascular events.


Androgen deprivation, such as with relugolix, may prolong the QT/QTc interval.1 Animal studies suggest relugolix may cause embryo-fetal toxicity. Female partners of reproductive potential should use effective contraception during and for two weeks after the last dose of relugolix. Avoid coadministration of relugolix and combined P-gp and strong CYP3A inducers, since the combination may hinder efficacy.1 Concomitant administration of P-gp inhibitor may increase the risk of adverse reactions.1 Some patients may not properly adhere to the schedule with an oral medication vs. periodic injections.


Researchers evaluated the efficacy and safety of relugolix in a randomized, open-label study of men with advanced prostate cancer requiring at least one year of androgen deprivation.1,2 These subjects experienced biochemical or clinical relapse following local primary intervention, newly diagnosed castration-sensitive metastatic disease, or advanced localized disease.1 Subjects were randomized in a 2:1 ratio to relugolix (n = 622) or leuprolide acetate 22.5 mg or 11.25 mg (Japan and Taiwan; n = 308) administered subcutaneously every three months for 48 weeks. The median baseline testosterone level was recorded at 408 ng/dL. The primary efficacy endpoint was achieving and maintaining serum testosterone to castrate levels (< 50 ng/dL) by day 29 through 48 weeks. Results were 96.7% for relugolix compared to 88.8% for leuprolide. The decline in levels were more rapid with relugolix (99% achieved < 50 ng/dL by day 15 vs. 95% at day 29 for leuprolide). This happened because of initial upregulation of GnRH agonists, such as leuprolide, resulting in a sharp rise in hormones released by the pituitary, including follicular-stimulating hormone (FSH) and luteinizing hormones (LH) and resultant transient increase in testosterone levels. Continual administration results in suppression of FSH and LH and testosterone suppression. The sponsor reported noninferiority and superiority of relugolix over leuprolide, but the FDA reviewer did not accept this.2,3 Overall, the adverse reaction profiles were similar between the two groups (e.g., hot flush, musculoskeletal pain, fatigue, and laboratory abnormalities such as glucose, triglyceride, ALT/AST increases, and hemoglobin decreases).1 Diarrhea, mainly mild or moderate, was more common with relugolix (12% vs. 7%). The risk for major adverse cardiovascular events (MACE) appears to be lower with relugolix (2.8% vs. 6.2%), particularly in those with a history of MACE (3/84 [3.6%] vs. 8/45 [17.8%]).2 There was a 54% reduction in cumulative incidence at the end week 48. In this trial, more than 92% of subjects presented with cardiovascular risk factors.


There were an estimated 190,000 cases of prostate cancer and 33,000 deaths in the United States in 2020.3,4 Androgens (i.e., testosterone) have been shown to stimulate prostate cancer growth.3,4 Therefore, castration (orchiectomy) or chemical castration with GnRH agonists or antagonist are standard therapies for advanced prostate cancer.3 The National Comprehensive Cancer Network Guidelines (Version 3.2020) consider GnRH agonists or antagonists to be equally effective. The benefit of no initial increase in serum testosterone and perhaps lower risk of MACE may be potential benefits with an antagonist such as relugolix. The latter may be particularly relevant for those with cardiovascular risk factors, which is common in this population. Most deaths among prostate cancer patients happen because of cardiovascular disease rather than from index-cancer mortality.5 The cost for relugolix was unavailable at the time of this review.


  1. Myovant Sciences. Orgovyx prescribing information. December 2020.
  2. Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med 2020;382:2187-2196.
  3. Center for Drug Evaluation and Research. NDA/BLA multi-disciplinary review and evaluation: NDA 214, 621 relugolix. January 2020.
  4. U.S. Food & Drug Administration. FDA approves relugolix for advanced prostate cancer. Dec. 18, 2020.
  5. Sturgeon KM, Deng L, Bluethmann SM, et al. A population-based study of cardiovascular disease mortality risk in US cancer patients. Eur Heart J 2019;40:3889-3897.