Abstract Body (Do not enter title and authors here): Purpose: Androgen deprivation therapy (ADT) for 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 versus antagonists. Relugolix Versus Leuprolide Cardiac Trial (REVELUTION, NCT05320406) was designed to test the hypothesis that ADT-associated CV risk is mediated by accelerated coronary atherosclerosis and is more prominent with the GnRH-agonist leuprolide compared with the GnRH-antagonist relugolix.

Methods: This prospective three-arm trial enrolled men with treatment-naïve, localized PCa pursuing pelvic radiotherapy (RT) alone or with concomitant ≥ 6 months ADT. Patients receiving ADT were randomized 1:1 to either leuprolide vs relugolix. Patients receiving RT alone without ADT served as a control. Primary endpoint was change in total coronary artery plaque volume (TPV), measured by prospective coronary CT angiography completed at baseline and 12 months after treatment initiation. Other outcome measures included change in non-calcified plaque volume (NCPV), calcified plaque volume (CPV), and low-attenuation plaque volume (LAPV), and incidence of major adverse CV events (MACE: stroke, myocardial infarction, coronary stent).

Results: Of the 94 men enrolled from 06/2022 to 03/2024, 90 (28 RT alone, 31 RT plus leuprolide, and 31 RT plus relugolix) completed study for analysis. Median change in TPV was higher (P=.02) with leuprolide (+52.0 [19.5-159.0] mm³) compared with relugolix (+25.0 [-6.0-46.0] mm³) and no ADT (+13.0 [-19.0-45.0] mm³). Compared with no ADT, leuprolide was associated with a significantly greater increase in TPV (estimated difference +79.1 mm³, P=.004), NCPV (+71.9 mm³, P=.001), CPV (CPV +19.9 mm³, P=.04), and LAPV (+5.1 mm³, P=.03) after adjusting for baseline plaque volume, age, and statin use. Compared with no ADT, relugolix did not result in a significant change in TPV (estimated difference +10.5 mm³, P=.69), NCPV (+7.2 mm³, P=.73), CPV (+8.9 mm³, P=.34), or LAPV (+1.3 mm³, P=.56). With a median follow-up of 23.3 (IQR 18.2-29.1) months, 3 patients (9.7%) in the leuprolide arm, 0 patients in the relugolix arm, and 1 patient (3.6%) in the no ADT arm experienced a MACE.

Conclusion: ADT for PCa is associated with accelerated coronary atherosclerosis within 12 months and is significantly higher with GnRH-agonist leuprolide compared with GnRH-antagonist relugolix.