RElugolix VErsus LeUprolide Cardiac Trial

PRIMARY OBJECTIVES: I. Identify and compare the association of gonadotrophin releasing hormone (GNRH)-agonist leuprolide versus GNRH-antagonist relugolix with coronary atherosclerosis and progression in men with prostate cancer. II. Determine the relationship between leuprolide versus relugolix with downstream immune effector response that is implicated in atherosclerosis. II. Determine how pre-existing genomic alterations associated with proinflammatory immunity impact development of CV toxicity following GNRH-agonist (GNRHa) versus relugolix. III. Identify imaging biomarkers associated with increased risk of CV toxicity from ADT OUTLINE: Patients undergoing radiation therapy alone as part of their standard treatment are assigned to Arm I. Patients undergoing radiation therapy and ADT as part of their standard treatment are randomized to Arm II or Arm III. ARM I: Patients undergo definitive radiation therapy in the absence of disease progression or unacceptable toxicity. ARM II: Patients undergo radiation therapy as in Arm I and receive leuprolide subcutaneously (SC) or intramuscularly (IM) every 3 or 6 months. Treatment continues for 6 to 24 months (depending on cancer risk) in the absence of disease progression or unacceptable toxicity. ARM III: Patients undergo radiation therapy as in Arm I and receive relugolix orally (PO) once daily (QD) for 6 to 24 months (depending on risk) in the absence of disease progression or unacceptable toxicity.