How does Relugolix (gonadotropin-releasing hormone receptor antagonist) work in adult males with hormone-sensitive prostate cancer?

How Relugolix Works

Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors, blocking the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently suppresses testosterone production to castrate levels without causing an initial testosterone surge. 1

Mechanism of Action

Direct Receptor Blockade

• Relugolix competitively binds to gonadotropin-releasing hormone (GnRH) receptors in the pituitary gland, preventing natural GnRH from activating these receptors 1, 2
• This competitive antagonism immediately blocks the pituitary's ability to release LH and FSH into systemic circulation 1, 3
• Unlike GnRH agonists (leuprolide, goserelin), relugolix does not cause initial receptor overstimulation, thereby avoiding the dangerous testosterone "flare" phenomenon that can worsen symptoms in men with advanced disease 4

Hormonal Cascade Suppression

• The reduction in LH directly suppresses testicular Leydig cells from producing testosterone 1
• FSH suppression prevents spermatogenesis and further gonadal stimulation 1
• In the HERO trial, 56% of patients achieved castrate testosterone levels (<50 ng/dL) by day 4, and 97% maintained castration through 48 weeks 1

Pharmacodynamic Profile

Rapid Onset Without Flare

• Testosterone suppression begins immediately after the first dose, with median time to effect of 2.25 hours (range 0.5-5.0 hours) 1
• The 360 mg loading dose on day 1 followed by 120 mg daily maintenance achieves rapid castration without the 2-3 week testosterone surge seen with GnRH agonists 4, 1
• This makes relugolix particularly valuable in patients with impending spinal cord compression or other complications requiring urgent testosterone suppression 4

Reversible Suppression

• Upon discontinuation, testosterone recovery is rapid compared to depot GnRH agonists 1, 5
• In a substudy of 137 patients, 55% achieved testosterone concentrations above 280 ng/dL or baseline within 90 days after stopping relugolix 1
• This reversibility is clinically relevant for intermittent androgen deprivation therapy strategies 5

Clinical Advantages Over GnRH Agonists

Cardiovascular Safety

• Relugolix demonstrated 54% lower risk of major adverse cardiovascular events compared to leuprolide (HR 0.46,95% CI 0.24-0.88) in the HERO trial 4, 6
• This superior cardiovascular profile makes relugolix particularly appropriate for patients with preexisting cardiovascular disease 5, 7
• The mechanism for improved cardiovascular safety is not fully elucidated but may relate to avoiding the initial testosterone surge and different effects on vascular endothelium 2

Oral Administration Benefits

• Once-daily oral dosing eliminates the need for depot injections every 1-12 months required with GnRH agonists 4, 2
• Oral administration allows for immediate discontinuation if needed, unlike long-acting depot formulations 5
• However, oral administration requires attention to adherence and may present affordability challenges in elderly populations 5

Important Clinical Caveats

Drug Interactions

• Relugolix is a substrate for intestinal P-glycoprotein (P-gp), making it susceptible to interactions with P-gp inhibitors or inducers 1
• Food does not clinically affect absorption, allowing flexible dosing with or without meals 1
• Concomitant use with cardiovascular medications (antihypertensives, antithrombotics, lipid-lowering agents) does not affect efficacy or introduce new safety concerns 7

Combination Therapy Considerations

• Relugolix can be safely combined with novel hormonal therapies (abiraterone, apalutamide, enzalutamide) or docetaxel in advanced disease 6, 7, 8
• However, the HERO trial included very few patients receiving concomitant enzalutamide (n=17,2.7%) or docetaxel (n<10,1.3%), limiting safety data for these combinations 5
• Safety has not been established with cabazitaxel or lutetium Lu-177 vipivotide tetraxetan 5

Side Effect Profile

• Adverse events are consistent with testosterone suppression: hot flashes, fatigue, gynecomastia, decreased libido, weight gain, and cognitive changes 4
• Long-term castration causes osteopenia and increased fracture risk, requiring bone density monitoring and consideration of bisphosphonate therapy 4
• Hypercholesterolemia and metabolic changes occur with sustained testosterone suppression 4