On December 18, 2020, relugolix was approved for the treatment of adult patients with advanced prostate cancer. Relugolix is the first oral gonadotropin-releasing hormone (GnRH) receptor antagonist to be approved in this setting.^1,2

Supporting Efficacy Data

Approval was based on findings in the open-label, phase III HERO trial (ClinicalTrials.gov identifier NCT03085095).^2,3 In the trial, 930 men requiring at least 1 year of androgen-deprivation therapy who had either recurrent disease following radiation therapy or surgery or newly diagnosed castration-sensitive advanced disease were randomly assigned 2:1 to receive relugolix at a loading dose of 360 mg, followed by daily doses of 120 mg (n = 622) of leuprolide acetate via subcutaneous injection every 3 months (n = 308) at 22.5 mg (n = 264) or 11.25 mg (n = 44) per local guidelines for 48 weeks. The 11.25-mg dose is not approved in the United States in this setting.

Among all patients, median age was 71 years (range = 47–97 years), and 68% were White, 21% were Asian, and 5% were Black. Disease stage was metastatic (M1) in 32%, locally advanced (T3/4 NX M0 or any T N1 M0) in 31%, localized (T1 or T2 N0 M0) in 28%, and not classifiable in 10%. Median testosterone concentration at baseline was 408 ng/dL.

The main efficacy outcome measure was a medical castration rate defined as achieving and maintaining serum testosterone suppression to castrate levels (< 50 ng/dL) by day 29 through 48 weeks of treatment. The medical castration rate was 96.7% (95% confidence interval [CI] = 94.9%–97.9%) in the relugolix group vs 88.8% (95% CI = 84.6%–91.8%) in the leuprolide acetate group. Among the 264 patients receiving leuprolide acetate at 22.5 mg, the medical castration rate was 88.0% (95% CI = 83.4%–91.4%). Among all patients, testosterone levels < 50 ng/dL and < 20 ng/dL were achieved at day 15 in 99% vs 12% and in 78% vs 1% and at day 29 in 99% vs 82% and in 95% vs 57%.

How It Works

Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors. Binding to the receptors reduces release of luteinizing hormone and follicle-stimulating hormone, resulting in reduced release of testosterone.

How It Is Used

The recommended dosage of relugolix is a loading dose of 360 mg on the first day followed by 120 mg daily at approximately the same time each day. If treatment is interrupted for at least 7 days, treatment should be restarted with a loading dose of 360 mg on the first day followed by 120 mg daily.

Coadministration of relugolix with P-glycoprotein inhibitors and with combined P-glycoprotein and strong CYP3A inducers (eg, ketoconazole, clarithromycin, nefazodone) should be avoided. Prescribing information provides instructions on relugolix dosage modifications if concomitant use cannot be avoided.

Safety Profile

Among patients receiving relugolix in the HERO trial, 91% were exposed for at least 48 weeks. The most common adverse events of any grade in the relugolix group were hot flush (54% vs 52% in leuprolide acetate group), musculoskeletal pain (30% vs 29%), fatigue (26% vs 24%), diarrhea (12% vs 7%), and constipation (12% vs 10%). The most common grade 3 or 4 adverse events included musculoskeletal pain (1.1% vs 1.6%) and hot flush (0.6% vs 0%). The most common laboratory abnormalities of any grade were increased glucose (44% vs 54%, grade 3 or 4 in 2.9% vs 6%), increased triglycerides (35% vs 36%, grade 3 or 4 in 2% vs 0.7%), decreased hemoglobin (28% vs 29%, grade 3 or 4 in 0.5% vs 0.7%), increased alanine aminotransferase (27% vs 28%, grade 3 or 4 in 0.3% vs 0%), and increased aspartate aminotransferase (18% vs 19%, grade 3 or 4 in 0% vs 0.3%).

Serious adverse events occurred in 12% of patients in the relugolix group, the most common being myocardial infarction (0.8%), acute kidney injury (0.6%), arrhythmia (0.6%), hemorrhage (0.6%), and urinary tract infection (0.5%). Fatal and nonfatal myocardial infarction and stroke occurred in 2.7% of patients. Adverse events led to dosage interruption in 2.7% of patients, the most common cause being fracture (0.3%). Adverse events led to permanent treatment discontinuation in 3.5%, the most common causes being atrioventricular block (0.3%), cardiac failure (0.3%), hemorrhage (0.3%), increased transaminases (0.3%), abdominal pain (0.3%), and pneumonia (0.3%). Fatal adverse events occurred in 0.8% of patients, including metastatic lung cancer (0.3%), myocardial infarction (0.3%), and acute kidney injury (0.2%).

Relugolix has warnings/precautions for QT/QTc interval prolongation and embryofetal toxicity. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves relugolix for advanced prostate cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-relugolix-advanced-prostate-cancer. Accessed January 7, 2021.

2. Orgovyx (relugolix) tablets prescribing information, December 2020, Myovant Sciences, Inc. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214621s000lbl.pdf. Accessed January 7, 2021.

3. Shore ND, Saad F, Cookson MS, et al: Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med 382:2187-2196, 2020.