What is the recommended dosing regimen of relugolix (oral GnRH antagonist) for treating advanced or metastatic prostate cancer in adult men?

Relugolix Dosing for Advanced Prostate Cancer

The recommended dosing regimen for relugolix in advanced prostate cancer is a 360 mg oral loading dose on day 1, followed by 120 mg once daily thereafter, taken at approximately the same time each day, with or without food. 1

Standard Dosing Regimen

• Loading dose: 360 mg orally on the first day of treatment 1
• Maintenance dose: 120 mg orally once daily, starting on day 2 1
• Timing: Take at approximately the same time each day 1
• Food: Can be taken with or without food (no clinically meaningful differences in pharmacokinetics) 1
• Administration: Swallow tablets whole; do not crush or chew 1

This regimen achieves rapid testosterone suppression, with 56% of patients reaching castrate levels (<50 ng/dL) by day 4 and 97% maintaining castration through 48 weeks. 1, 2

Dose Modifications for Drug Interactions

When combined P-gp and strong CYP3A inducers cannot be avoided, increase relugolix to 240 mg once daily. 1

• With P-gp inhibitors alone: Avoid coadministration if possible. If unavoidable, take relugolix first, separate dosing by at least 6 hours, and monitor more frequently for adverse reactions. 1
• With combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin): These increase relugolix exposure by 3.5-fold for AUC and 2-fold for Cmax, requiring careful monitoring. 1

Use with Androgen Receptor Pathway Inhibitors (ARPIs)

Relugolix can be safely combined with ARPIs (abiraterone, apalutamide, enzalutamide, darolutamide) at standard dosing without dose adjustment. 3, 4

• Clinical studies demonstrate maintained testosterone suppression when relugolix is combined with ARPIs at standard 120 mg daily dosing 3, 4
• A 52-week study showed relugolix 120 mg daily with abiraterone 1,000 mg daily plus corticosteroid was safe and effective 3
• When combined with apalutamide, relugolix 240 mg daily (double dose) was studied, though standard dosing appears adequate based on real-world data 3, 4
• No new safety concerns emerged with ARPI combinations 3

Use with Radiotherapy

For patients receiving radiotherapy, use the same standard dosing regimen (360 mg loading dose, then 120 mg daily). 5

• Short-term ADT (24 weeks): Relugolix achieved 95% castration rate 5
• Longer-term ADT (48 weeks): Relugolix achieved 97% castration rate 5
• No dose adjustments needed when combined with radiotherapy 5

Clinical Efficacy Benchmarks

The ESMO 2023 guidelines recognize relugolix for adult patients with advanced hormone-sensitive prostate cancer, noting non-inferior and superior castration rates compared to leuprolide, with significantly lower risk of major cardiovascular events (HR 0.46,95% CI 0.24-0.88). 6

The pivotal HERO trial demonstrated:

• Sustained castration rate: 96.7% through 48 weeks (vs. 88.8% with leuprolide) 2
• Rapid onset: 56% achieved castrate levels by day 4 (vs. 0% with leuprolide) 2
• Testosterone recovery: Mean testosterone 288.4 ng/dL at 90 days post-discontinuation (vs. 58.6 ng/dL with leuprolide) 2

Special Populations

No dose adjustments are required based on:

• Age (45-91 years) 1
• Body weight (41-193 kg) 1
• Race/ethnicity 1
• Mild to severe renal impairment (CrCl 15-89 mL/min) 1
• Mild to moderate hepatic impairment (Child-Pugh A or B) 1

Caution: Effects in end-stage renal disease with hemodialysis or severe hepatic impairment (Child-Pugh C) have not been evaluated. 1

Key Safety Considerations

• QT prolongation: Androgen deprivation therapy may prolong QT interval; however, relugolix showed no clinically significant QT prolongation in thorough QT studies 1
• Hypersensitivity: Can cause hypersensitivity reactions including angioedema; withhold for symptoms and discontinue for severe reactions 1
• Cardiovascular benefit: Relugolix demonstrated 54% lower risk of major adverse cardiovascular events compared to leuprolide (HR 0.46) 6, 2
• Contraception: Males with female partners of reproductive potential should use effective contraception due to embryo-fetal toxicity risk 1

Adherence and Persistence

Real-world data demonstrate superior adherence with relugolix compared to injectable ADT:

• 12-month adherence (PDC ≥80%): 60.8% for relugolix vs. 46.3% for GnRH agonists vs. 13.0% for degarelix 7
• Median time to discontinuation: 13.5 months for relugolix vs. 8.8 months for GnRH agonists vs. 3.1 months for degarelix 7