What is Orgovyx (relugolix) and what is its indication for use?

Orgovyx (Relugolix): Drug Profile and Indication

What is Orgovyx?

Orgovyx (relugolix) is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the treatment of adult patients with advanced prostate cancer. 1

• Relugolix is the first and only oral GnRH antagonist approved for prostate cancer treatment, providing a mechanistic alternative to traditional LHRH agonists 2, 3
• It is a nonpeptide GnRH receptor antagonist that provides rapid testosterone suppression without the initial testosterone surge seen with LHRH agonists 2, 3

FDA-Approved Indication

The sole FDA-approved indication for Orgovyx is the treatment of adult patients with advanced prostate cancer. 1

• This includes patients with advanced hormone-sensitive prostate cancer requiring androgen deprivation therapy (ADT) 4, 2
• The drug is not approved for use in females or children 1

Mechanism and Clinical Rationale

Relugolix works by directly blocking GnRH receptors in the pituitary gland, leading to rapid suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently reduces testosterone production to castration levels. 2, 3

• Unlike LHRH agonists that initially cause a testosterone surge (requiring concomitant antiandrogen therapy), relugolix immediately suppresses testosterone without flare 2, 3
• In the pivotal HERO trial, relugolix achieved sustained castration rates >90% over 48 weeks, demonstrating non-inferiority and exploratory superiority compared to leuprolide depot 4, 2

Dosing Regimen

The recommended dosing is a loading dose of 360 mg (three 120 mg tablets) on day 1, followed by 120 mg once daily thereafter, taken at approximately the same time each day. 1

• Tablets should be swallowed whole and not crushed or chewed 1
• Can be taken with or without food 1

Key Clinical Advantages

Relugolix demonstrated a significantly lower risk of major adverse cardiovascular events compared to leuprolide (HR 0.46,95% CI 0.24-0.88), making it particularly valuable for patients with preexisting cardiovascular disease. 4, 3

• This cardiovascular safety advantage is clinically significant, as ADT increases cardiovascular risk and LHRH agonists carry FDA label warnings about cardiovascular disease 3
• Relugolix allows for rapid testosterone recovery upon discontinuation (55% of patients achieved testosterone >280 ng/dL at 90 days post-discontinuation), which may benefit patients pursuing intermittent ADT strategies 1, 5

Combination Therapy Data

Recent evidence supports the safety and tolerability of relugolix in combination with androgen receptor signaling inhibitors (ARSIs) such as abiraterone and apalutamide. 6

• A 52-week trial demonstrated that relugolix combined with abiraterone (plus corticosteroid) or apalutamide maintained castrate testosterone levels with a safety profile consistent with individual agents 6
• However, the HERO trial included very few patients receiving concomitant enzalutamide (n=17,2.7%) or docetaxel (n<10,1.3%), and safety has not been established with many other agents used in advanced prostate cancer 5

Important Safety Considerations

Orgovyx carries warnings for QT/QTc interval prolongation, hypersensitivity reactions including angioedema, and embryo-fetal toxicity. 1

• Males with female partners of reproductive potential must use effective contraception during treatment and for 2 weeks after the last dose 1
• The drug is contraindicated in patients with known severe hypersensitivity to relugolix or any product components 1
• Most common adverse reactions (≥10%) include hot flush, increased glucose, increased triglycerides, musculoskeletal pain, decreased hemoglobin, increased liver enzymes (ALT/AST), fatigue, constipation, and diarrhea 1

Clinical Context in Treatment Guidelines

Current ESMO guidelines recognize relugolix as an effective ADT option for advanced hormone-sensitive prostate cancer, with evidence supporting non-inferior castration rates and reduced cardiovascular toxicity compared to leuprolide. 4

• The ESMO-MCBS score for relugolix is 4 (Form 2c), reflecting its clinical benefit profile 4
• Relugolix represents an evolution in ADT delivery, offering oral administration convenience compared to injectable depot formulations 2, 3

Practical Limitations

As an oral medication, relugolix may present challenges with affordability, adherence, and compliance in the predominantly elderly prostate cancer population. 5

• Drug interactions require careful management: avoid co-administration with P-gp inhibitors (or separate dosing by ≥6 hours if unavoidable), and avoid combined P-gp and strong CYP3A inducers (or increase dose to 240 mg daily if unavoidable) 1
• Patients must be counseled on the importance of daily adherence, as missed doses can compromise testosterone suppression 1