What is Orgovyx (relugolix) used for in adult male patients with advanced prostate cancer?

What is Orgovyx (Relugolix)?

Orgovyx (relugolix) is an oral GnRH receptor antagonist indicated for the treatment of adult patients with advanced prostate cancer, providing androgen deprivation therapy without the testosterone flare associated with GnRH agonists. 1

Mechanism and Clinical Profile

• Relugolix is the first oral gonadotropin-releasing hormone (GnRH) receptor antagonist, distinguishing it from injectable GnRH agonists (like leuprolide) and other injectable GnRH antagonists. 2, 3

• The drug provides rapid testosterone suppression without an initial testosterone surge, a critical advantage over GnRH agonists that cause testosterone flare upon treatment initiation. 2, 4

• Testosterone recovery occurs rapidly after discontinuation, with 55% of patients achieving testosterone levels above 280 ng/dL or baseline at 90 days after stopping treatment. 1

Dosing and Administration

• Loading dose: 360 mg (three 120 mg tablets) on day 1, followed by 120 mg once daily thereafter. 5

• The medication can be taken with or without food, and tablets must be swallowed whole without crushing or chewing. 1

• If a dose is missed by more than 12 hours, skip that dose and resume the regular schedule the next day. 1

Efficacy Data from HERO Trial

• In the pivotal phase III HERO trial, relugolix achieved sustained castration rates >90% over 48 weeks, demonstrating non-inferiority and exploratory superiority compared to leuprolide depot injections every 3 months. 2

• Castration resistance-free survival at 48 weeks was 74.3% with relugolix versus 75.3% with leuprolide in metastatic disease populations (hazard ratio 1.03, not significantly different). 5

• Median prostate-specific antigen concentration reached 0.04 ng/mL at week 12 when combined with androgen receptor signaling inhibitors. 6

Cardiovascular Safety Advantage

• Relugolix demonstrated a 54% lower incidence of major adverse cardiovascular events compared to leuprolide acetate, representing a potentially significant safety advantage. 4

• This improved cardiovascular safety profile makes relugolix particularly valuable for patients with preexisting cardiovascular comorbidities, a common concern in the predominantly elderly prostate cancer population. 3

Combination Therapy

• Relugolix can be safely combined with abiraterone (1,000 mg once daily with corticosteroid) or apalutamide (240 mg once daily) for treatment of advanced prostate cancer, with safety profiles consistent with individual drugs. 6

• However, safety has not been established in combination with enzalutamide, cabazitaxel, or lutetium Lu 177 vipivotide tetraxetan, which precludes its use with these agents until further data emerge. 3

• In the HERO trial, very few patients received concomitant enzalutamide (2.7%) or docetaxel (1.3%), limiting evidence for these combinations. 3

Adverse Effects

• The most common side effects include hot flushes, increased blood sugar, increased triglycerides, muscle and joint pain, decreased hemoglobin, increased liver enzymes, fatigue, constipation, and diarrhea. 1

• Additional effects include weight gain, decreased sex drive, and erectile dysfunction, consistent with testosterone suppression from any androgen deprivation therapy. 1

• QT interval prolongation can occur, requiring monitoring of electrolytes and cardiac electrical activity during treatment, with patients advised to report dizziness, fainting, palpitations, or chest pain. 1

• Severe hypersensitivity reactions including angioedema are possible, and the drug is contraindicated in patients with prior severe allergic reactions to relugolix. 1

Special Populations and Warnings

• Relugolix can cause embryo-fetal toxicity and pregnancy loss, requiring males with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose. 1

• The medication may cause infertility in males, which should be discussed with patients concerned about future fertility. 1

• Medication adherence rates exceeded 97% in clinical trials, though as an oral medication, relugolix may face challenges with affordability, adherence, and compliance in elderly populations compared to injectable depot formulations. 3, 6

Clinical Positioning

• Relugolix is particularly suited for patients pursuing intermittent androgen deprivation therapy due to rapid testosterone recovery during "off-treatment" periods. 3

• The oral administration offers convenience advantages over injectable depot formulations, eliminating the need for clinic visits for injections. 2

• Current guidelines from ASCO, ESMO, and NCCN recommend ADT combined with novel hormone agents (abiraterone, enzalutamide, apalutamide, darolutamide) or docetaxel for metastatic hormone-sensitive prostate cancer, and relugolix serves as the ADT component in these regimens. 7, 8, 9