Does relugolix (generic name) have a lower cardiovascular risk compared to goserelin (generic name) in a patient with prostate cancer?

Relugolix Has Lower Cardiovascular Risk Than Goserelin in Prostate Cancer

Relugolix demonstrates significantly lower cardiovascular risk compared to GnRH agonists like goserelin, with a 54% reduction in major adverse cardiovascular events (HR 0.46,95% CI 0.24-0.88) based on the HERO trial, and this cardiovascular safety advantage is the primary reason to prefer relugolix over traditional GnRH agonists in patients with advanced prostate cancer, particularly those with pre-existing cardiovascular disease or risk factors. 1

Evidence for Cardiovascular Safety Advantage

Direct Comparison Data

• The HERO trial directly compared relugolix (an oral GnRH antagonist) to leuprolide (a GnRH agonist similar to goserelin) and demonstrated a 54% lower incidence of major adverse cardiovascular events with relugolix (HR 0.46,95% CI 0.24-0.88) 1, 2

• A systematic review pooling data from 10 randomized controlled trials (including both degarelix and relugolix as GnRH antagonists versus leuprolide and goserelin as GnRH agonists) found that GnRH antagonists reduced adverse cardiovascular events by 43% (pooled risk ratio 0.57,95% CI 0.39-0.81), cardiovascular death by 51% (risk ratio 0.49,95% CI 0.25-0.96), and all-cause mortality by 52% (risk ratio 0.48,95% CI 0.28-0.83) 3

Mechanism of Cardiovascular Benefit

• GnRH antagonists like relugolix avoid the initial testosterone surge that occurs with GnRH agonists (leuprolide, goserelin), which may contribute to cardiovascular instability and acute cardiac events 2, 4, 5

• Relugolix achieves rapid testosterone suppression without the flare phenomenon, eliminating the need for concomitant anti-androgen therapy to prevent tumor flare and its associated cardiovascular stress 4, 5

Clinical Efficacy Equivalence

Castration Achievement

• Relugolix achieved sustained castration rates (testosterone <50 ng/dL) of >90% over 48 weeks, which was non-inferior and exploratory analysis suggested superior to leuprolide 1, 2

• The between-group difference in castration rate favored relugolix by 7.9% (95% CI 4.1% to 11.8%) 1

Efficacy in Patients on Cardiovascular Medications

• In subgroup analysis from HERO, relugolix maintained consistent sustained castration rates in men taking antihypertensives (52.7% of patients), antithrombotics (39.1%), and lipid-modifying therapies (39.6%) 6

• Specific castration rates for relugolix versus leuprolide in men on common cardiovascular agents: losartan (95.4% vs 80.6%), amlodipine (97.2% vs 85.5%), metoprolol (95.7% vs 86.9%), aspirin (97.0% vs 92.1%), clopidogrel (96.4% vs 86.7%), and simvastatin (98.0% vs 87.3%) 6

Guideline Recognition

• The 2023 ESMO Clinical Practice Guidelines include relugolix in their treatment recommendations for advanced hormone-sensitive prostate cancer, specifically noting the "significantly lower risk of major CV events (HR 0.46,95% CI 0.24-0.88)" and assigning it an ESMO-MCBS score of 4 1

• The guideline explicitly documents relugolix's "reduced toxicity" profile compared to leuprolide 1

Clinical Decision Algorithm

When to Strongly Prefer Relugolix Over Goserelin

1. Patients with pre-existing cardiovascular disease (prior MI, stroke, heart failure, or coronary artery disease) - the 54% reduction in major adverse cardiovascular events makes relugolix the clear choice 1, 3

2. Patients with multiple cardiovascular risk factors (hypertension, diabetes, hyperlipidemia) - the cardiovascular safety advantage is maintained even in patients on multiple cardiovascular medications 6

3. Patients already on antithrombotics or anticoagulants - relugolix demonstrated consistent efficacy and safety in this high-risk population 6

4. Patients requiring rapid testosterone suppression without flare risk - relugolix avoids the testosterone surge that can precipitate cardiovascular events 4, 5

Additional Advantages of Relugolix

• Oral administration provides convenience and eliminates injection-related complications 2, 4

• Rapid testosterone recovery after treatment discontinuation (median 90 days) may reduce long-term ADT-related adverse effects and enable intermittent therapy strategies 4, 5

• No requirement for concomitant anti-androgen therapy to prevent tumor flare, simplifying treatment regimens 4, 5

Important Caveats

Study Limitations

• The HERO trial had a median follow-up of only 48 weeks, which is relatively short for assessing long-term cardiovascular outcomes 3

• Most trials were unblinded and identified cardiovascular events through safety reporting rather than as pre-specified outcomes, though the consistency across multiple studies strengthens the findings 3

• The systematic review found no evidence of heterogeneity among studies, supporting the robustness of the cardiovascular benefit 3

Safety Profile

• Relugolix has an adverse event profile consistent with testosterone suppression (hot flashes, fatigue, musculoskeletal effects), similar to other ADT agents 2

• In patients on cardiovascular medications, there were some increases in grade ≥3 adverse events, though the overall safety profile remained acceptable 6

Cost Considerations

• While not addressed in the clinical evidence, relugolix as a newer oral agent may have different cost implications compared to injectable GnRH agonists, though the reduction in cardiovascular events may offset higher drug costs through reduced hospitalizations 2, 4