Regulatory Decision Summary for Orgovyx

This New Drug Submission was filed to obtain market authorization for Orgovyx (relugolix) 120 mg tablet indicated for the treatment of adult patients with advanced prostate cancer.

The safety and efficacy of Orgovyx (relugolix) for the treatment of adult patients with advanced prostate cancer were supported by the pivotal study HERO. This phase 3, randomized, open-label study evaluated the efficacy and safety of relugolix 120 mg once daily (following a loading dose of 360 mg on Day 1) in 930 randomized patients who received relugolix or leuprolide injections every 3 months for 48 weeks.

There were two separate evaluation criteria for the primary efficacy endpoint. Evaluation criterion 1 was to determine whether the sustained castration rate, defined as achieving and maintaining serum testosterone suppression to castrate levels (< 50 ng/dL) by day 29 through 48 weeks of treatment, for relugolix in ≥ 90% of treated patients. Evaluation Criterion 2 was to establish the noninferiority of relugolix compared with leuprolide 3-month depot injection, as assessed by the cumulative probability of sustained testosterone suppression.

Biostatistical consultation concluded that the pre-specified 10% noninferiority margin for the comparison of relugolix versus leuprorelin was acceptable. However, given that Health Canada does not require a comparative trial for the androgen deprivation therapy (ADT) drug approval and products with similar indications have been approved based solely on the demonstration of sustained testosterone suppression, the comparative trial data were accepted as an supportive information only, without any comparative labeling claims in relation to leuprolide.

A total of 96.7% of patients who received relugolix met the study primary endpoint, i.e., achieved and maintained sustained testosterone suppression below castrate levels (< 50 ng/dL) from Week 5 Day 1 (Day 29) to Week 49 Day 1 (Day 337) (95% Confidence Interval [CI]: 94.9%, 97.9%) with the lower bound of the 95% CI exceeding 90%.

In addition to achieving sustained testosterone suppression below castrate levels (< 50 ng/dL), sustained profound castration (< 20 ng/dL) rate from Week 5 Day 1 (Day 29) through 48 weeks was higher in the relugolix group (81.6%) compared with the leuprolide group (68.6%).

Testosterone reduction by relugolix was not associated with initial testosterone surge, avoiding hormonal or clinical flare and the need for coadministration of an antiandrogen.

The potential risks of relugolix as a gonadotropic-releasing hormone (GnRH) receptor antagonist that lowers testosterone, include hepatic transaminase elevations, carbohydrate and lipid metabolic effects, adverse cardiovascular events, QT prolongation and mood disorders.

The most commonly reported adverse events included hot flushes, fatigue, constipation, diarrhea, arthralgia, and hypertension. The safety profile of relugolix was similar to leuprolide and other products used for ADT in general.

Adverse events leading to the drug withdrawal and interruption, adverse events related to the study drug, and serious adverse events leading to treatment discontinuation were reported at higher incidences in the relugolix group relative to the leuprolide group. This difference was also seen in the proportion of patients with serious adverse events leading to study drug discontinuation, 1.6% in the relugolix group and 0.3% in the leuprolide group.

The most common laboratory abnormalities included hepatic transaminase elevations, hemoglobin levels decreased, glucose increased, triglycerides increased, cholesterol increased.

The incidence of major cardiovascular events (MACE) (defined as all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke) after 48 weeks of ADT was 2.9% in the relugolix group compared with 6.2% in the leuprolide group.

It was identified by the comparative bioavailability review that Area Under the Curve (AUC) and C_max of relugolix decreased by 19% and 21%, respectively, after a high fat high-calorie meal. The observed effect of food was not considered to be clinically relevant. In addition, the population pharmacokinetic-pharmacodynamic (PopPK/PD) modelling predicted that with a 2-fold clearance and a 50% reduction in relugolix plasma concentrations more than 90% of the patients still maintained testosterone concentrations at castration levels. Therefore, Orgovyx can be taken with or without food.

Warnings regarding the potential for QTc prolongation, embryo-fetal toxicity and drug interactions with P-gp inhibitors have been included in the labeling.

Overall, the benefit/risk ratio of Orgovyx is considered positive when used as outlined in the approved Orgovyx Product Monograph. The European Union (EU) Risk Management Plan (RMP) version 1.0 and the associated Canadian Addendum, were reviewed and found acceptable.

For further details about Orgovyx, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.