Importance: Androgen deprivation therapy (ADT) for men with prostate cancer (PCa) is associated with cardiovascular (CV) morbidity, yet the biological basis remains unclear. Recent studies have yielded conflicting results regarding the CV safety of gonadotropin-releasing hormone (GnRH) agonists vs antagonists.
Objective: To test the hypothesis that ADT is associated with accelerated coronary atherosclerosis and is more prominent with a GnRH agonist compared with a GnRH antagonist.
Design, setting, and participants: This open-label randomized clinical trial was conducted at 4 centers affiliated with a single academic institution in Atlanta, Georgia. Participants were men with nonmetastatic PCa without prior ADT exposure receiving pelvic radiotherapy with ADT of 6 months duration or longer. Patients were randomly assigned 1:1 to either the GnRH agonist leuprolide or the GnRH antagonist relugolix. Trial enrollment was completed between June 16, 2022, and March 6, 2024. Data analysis was completed between March 31, 2025, and June 23, 2025.
Intervention: Pelvic radiotherapy plus either GnRH agonist leuprolide or GnRH antagonist relugolix.
Main outcomes and measures: The primary end point was change in coronary artery total plaque volume (TPV), measured by coronary computed tomographic angiography completed at baseline and 12 months after ADT initiation. The secondary end point was change in coronary artery noncalcified plaque volume (NCPV). Other outcome measures included change in calcified plaque volume (CPV) and low-attenuation plaque volume (LAPV).
Results: Of 65 men enrolled, 62 (31 in each arm) completed all study procedures for analysis. Mean (SD) age was 68.5 (8.5) years, and 35 of 62 participants (56%) were taking statins. Compared with relugolix, leuprolide was associated with a significantly greater 12-month increase in TPV (estimated difference, +68.9 mm3; 95% CI, 23.2-114.5 mm3; P = .02) and NCPV (+64.5 mm3; 95% CI, 31.6-97.3 mm3; P = .004) after adjustment for baseline plaque volume, age, and statin use. There was no significant difference in 12-month change in CPV or LAPV between patients treated with leuprolide vs relugolix.
Conclusions and relevance: In this randomized clinical trial in men with localized PCa treated with radiation plus ADT, the GnRH agonist leuprolide was associated with greater coronary plaque progression within 12 months compared with the GnRH antagonist relugolix. This change was driven by an increase in noncalcified plaque volume and may be mediating ADT-associated CV risk.
Trial registration: ClinicalTrials.gov Identifier: NCT05320406.