Background
Phase III open-label, multinational RCT; 934 men with advanced prostate cancer randomized 2:1 to oral GnRH antagonist versus injectable LHRH agonist for 48 weeks. Eligible: PSA relapse after curative-intent therapy, newly diagnosed hormone-sensitive metastatic disease, or advanced localized disease unlikely cured locally.
Interventions and follow up
Arm A: Relugolix 120mg PO daily after a 360mg loading dose.
Arm B: Leuprolide 22.5mg (11.25mg in Japan & Taiwan) IM every 3 months.
Primary endpoint: Sustained testosterone suppression to <50 ng/dL through 48 weeks.
mFollow up: 52 weeks.
Arm B: Leuprolide 22.5mg (11.25mg in Japan & Taiwan) IM every 3 months.
Primary endpoint: Sustained testosterone suppression to <50 ng/dL through 48 weeks.
mFollow up: 52 weeks.
Results
Sustained testosterone suppression: 96.7% vs 88.8%, arm A vs B; difference 7.9 points, 95%CI 4.1–11.8; P<.001 (superiority).
Cumulative castration by day 4 / day 15: 56.0% vs 0% and 98.7% vs 12.0%, arm A vs B.
Mean testosterone day 4: 38 ng/dL vs 625 ng/dL, arm A vs B.
Major adverse cardiovascular events: 2.9% vs 6.2%, arm A vs B (54% relative reduction).
Cumulative castration by day 4 / day 15: 56.0% vs 0% and 98.7% vs 12.0%, arm A vs B.
Mean testosterone day 4: 38 ng/dL vs 625 ng/dL, arm A vs B.
Major adverse cardiovascular events: 2.9% vs 6.2%, arm A vs B (54% relative reduction).
Adverse events
Overall: Grade 3–4 events 18.0% vs 20.5% (arm A vs B).
Common (any grade): Hot flashes 54.3% vs 51.6%; fatigue 21.5% vs 18.5%; constipation 12.2% vs 9.7%; hypertension 7.9% vs 11.7%.
Common (any grade): Hot flashes 54.3% vs 51.6%; fatigue 21.5% vs 18.5%; constipation 12.2% vs 9.7%; hypertension 7.9% vs 11.7%.
Conclusions
Oral relugolix achieved superior, more rapid sustained testosterone suppression with faster recovery than leuprolide and roughly halved major cardiovascular events, providing an oral ADT option for advanced prostate cancer.
Key Limitations
Open-label design; surrogate primary endpoint (testosterone) rather than oncologic outcomes; cardiovascular benefit was a secondary, hypothesis-generating finding requiring confirmation. Daily oral dosing depends on adherence.
Clinical Context
FDA approved relugolix (Orgovyx) for advanced prostate cancer in December 2020 based on HERO — the first oral GnRH antagonist. ASCO/ESMO recognize it as an ADT option, of particular interest in men with cardiovascular risk. Degarelix is an injectable GnRH antagonist alternative.