This phase III/IV trial compares the impact of leuprolide and abiraterone acetate (AA) versus relugolix and AA on the heart in hormone-naive patients with advanced prostate cancer receiving pelvic radiation therapy. Leuprolide is in a class of medications called gonadotropin-releasing hormone agonists (GNRHa). It prevents the body from making luteinizing hormone-releasing hormone (LHRH) and luteinizing hormone (LH). This causes the testicles to stop making testosterone (a male hormone) in men and may stop the growth of prostate tumor cells that need testosterone to grow. Abiraterone acetate, an androgen biosynthesis inhibitor, works by decreasing the amount of certain hormones in the body. Relugolix, a GNRH antagonist, works by decreasing the amount of testosterone produced by the body. This may slow or stop the spread of prostate tumor cells that need testosterone to grow. The use of hormone therapy with radiation therapy has been shown to improve survival, however, studies have suggested that the addition of hormone therapy may worsen heart (cardiac) disease and high blood pressure. In fact, studies have shown that the most common cause of death in prostate cancer patients is due to heart disease or heart attacks. Computed tomography (CT) scans create a series of detailed pictures of areas inside the body; the pictures are created by a computer linked to an x-ray machine. In this study, sophisticated cardiac CT images are used to take pictures of patients' heart and coronary arteries to help assess damage to the heart. Using cardiac CT and blood tests, this trial may help doctors determine which patients are at risk of cardiac disease when treated with combination hormone therapy, as well as the differential risk of leuprolide versus relugolix in combination with abiraterone acetate.
Men ≥ 18 years old
Non-metastatic prostate cancer
Non-metastatic, biochemically recurrent prostate cancer
Plan to undergo curative-intent pelvic radiation therapy (photons or protons) with or without brachytherapy
Metastatic prostate cancer requiring indefinitive ADT or chemotherapy
Prior exposure to androgen deprivation therapy
Prior exposure to chemotherapy, immunotherapy, or radiation therapy
History of cardiac bypass surgery or percutaneous coronary intervention
Parallel
Abiraterone Acetate
DrugGiven abiraterone acetate
Bicalutamide
DrugGiven PO
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Computed Tomography Angiography
Procedure/SurgeryUndergo CCTA
Leuprolide
DrugGiven IM or SC
Prednisone
DrugGiven prednisone
Radiation Therapy
RadiationUndergo standard of care radiation therapy
Relugolix
DrugGiven PO
Incidence of ambulatory systolic blood pressure (BP) > 140 or diastolic > 90 (measurement on 2 separate days)
The change will be estimated and tested using paired tests (Wilcoxon signed rank test or McNemar test). The difference at each interval for the two groups will be tested using Fisher's exact test for binary endpoints or Wilcoxon rank-sum test for continuous. Data transformation to fit statistical assumptions will be done as needed. Multivariable models that control for potential confounders will be implemented using general linear and logistic regression.
Need for new or escalated anti-hypertensive medication
The change will be estimated and tested using paired tests (Wilcoxon signed rank test or McNemar test). The difference at each interval for the two groups will be tested using Fisher's exact test for binary endpoints or Wilcoxon rank-sum test for continuous. Data transformation to fit statistical assumptions will be done as needed. Multivariable models that control for potential confounders will be implemented using general linear and logistic regression.
Incidence of moderate-to-severe atherosclerosis of major coronary vessels
Defined as \> 50% luminal stenosis per the Society of Cardiac Computed Tomography. Change will be tested using paired tests (Wilcoxon signed rank test or McNemar test). Luminal stenosis will be measured on a per-vessel basis. Proportion of patients achieving \> 50% luminal stenosis of a major coronary vessel between each arm will be compared using Fisher's exact test. The percent change of maximal stenosis between the two arms will be tested using Wilcoxon signed rank test.
Total plaque volume
Total plaque volume (per-patient and per-vessel basis, respectively) will be measured. Adjusted mean difference will be calculated from baseline to month 12 between arms. Multivariable adjustment will be utilized that control age and statin using logistic regression.
Pre-existing genomic alterations promoting inflammatory immunity and associated with cardiovascular disease
Pre-treatment samples will be subjected to whole exome sequencing to determine alterations to the protein-coding regions of the genome, specifically those associated with clonal hematopoiesis of indeterminate potential (CHIP). The association of CHIP mutations with development of cardiovascular toxicity following therapy will be measured.
Castration rate
The cumulative probability of testosterone suppression to ≤ 50 ng/dL will be summarized using the Kaplan-Meier method. Confidence intervals will be calculated using the exponential Greenwood formulation via log-log transformation of the survival function
Sustained castration
The probability of testosterone suppression ≤ 50 ng/mL will be summarized using Kaplan-Meier. Confidence intervals will be calculated using the exponential Greenwood formulation via log-log transformation of the survival function
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Emory University
Lead sponsor
Pfizer
Collaborator
Sumitomo Pharma America, Inc.
Collaborator
National Comprehensive Cancer Network
Collaborator
National Cancer Institute (NCI)
Collaborator
