RElugolix VErsus LeUprolide Cardiac Trial (REVELUTION)

Mechanism and Predictors of Cardiotoxicity After Prostate Cancer Treatment: A Parallel Cohort and Randomized Trial Comparing Radiation Alone, Radiation Plus Leuprolide, and Radiation Plus Relugolix

This clinical trial investigates the impact of prostate cancer treatment, specifically androgen deprivation therapy (ADT), on the heart and coronary vessels among men with localized, non-metastatic prostate cancer undergoing definitive radiation therapy and concomitant ADT. Recently, cardiovascular toxicity from hormone therapy that is routinely used for prostate cancer (e.g. leuprolide) has emerged as a concern, yet studies identifying who is at risk and the mechanism of cardiac damage are lacking. Additionally, a new hormone therapy drug, relugolix, has recently been Food and Drug Administration (FDA)-approved and may reduce toxicity to the heart. This trial intends to investigate the mechanism of cardiovascular toxicity from ADT, investigate the mechanism by which relugolix reduces cardiovascular toxicity, and identify predictive biomarkers to improve individualized risk-assessment for cardiovascular toxicity from ADT.

Study Overview

• Status: Active, not recruiting
• Conditions: Biochemically Recurrent Prostate Carcinoma; Localized Prostate Carcinoma; Stage I Prostate Cancer AJCC v8; Stage II Prostate Cancer AJCC v8; Stage IIIA Prostate Cancer AJCC v8; Stage IIIB Prostate Cancer AJCC v8; Stage IIC Prostate Cancer AJCC v8; Stage III Prostate Cancer AJCC v8; Stage IIIC Prostate Cancer AJCC v8; Stage IIA Prostate Cancer AJCC v8; Stage IIB Prostate Cancer AJCC v8
• Intervention / Treatment: Radiation: Radiation therapy; Drug: Leuprolide; Drug: Relugolix

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Emory University Hospital Midtown
    • Atlanta, Georgia, United States, 30342
      • Emory Saint Joseph's Hospital
    • Atlanta, Georgia, United States, 30322
      • Emory University/Winship Cancer Institute
    • Atlanta, Georgia, United States, 30308
      • Emory Proton Therapy Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men >= 18 years old
• Non-metastatic prostate cancer
• Non-metastatic, biochemically recurrent prostate cancer
• Plan to undergo curative-intent pelvic radiation therapy with or without ADT

Exclusion Criteria:

• Metastatic prostate cancer requiring > 24 months of ADT
• Prior exposure to androgen deprivation therapy
• Prior exposure to chemotherapy or immunotherapy
• History of cardiac bypass surgery or percutaneous coronary intervention

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm I (radiation therapy alone); Patients undergo definitive radiation therapy alone (IMRT, SBRT, proton therapy, brachytherapy) in the absence of disease progression or unacceptable toxicity.	Radiation: Radiation therapy; Undergo radiation therapy; Other Names: Brachytherapy; External beam radiation therapy; Intensity modulated radiation therapy; Proton therapy; Stereotactic body radiotherapy
Experimental: Arm II (radiation therapy plus leuprolide); Patients undergo radiation therapy as in Arm I and receive leuprolide SC or IM every 3 or 6 months. Treatment continues for 6 to 12 months (depending on risk) in the absence of disease progression or unacceptable toxicity.	Radiation: Radiation therapy; Undergo radiation therapy; Other Names: Brachytherapy; External beam radiation therapy; Intensity modulated radiation therapy; Proton therapy; Stereotactic body radiotherapy; Drug: Leuprolide; Given IM or SC; Other Names: Lupron; Leuprolide acetate
Experimental: Arm III (radiation therapy plus relugolix); Patients undergo radiation therapy as in Arm I and receive relugolix PO QD. Treatment continues for 6 to 12 months (depending on risk) in the absence of disease progression or unacceptable toxicity.	Radiation: Radiation therapy; Undergo radiation therapy; Other Names: Brachytherapy; External beam radiation therapy; Intensity modulated radiation therapy; Proton therapy; Stereotactic body radiotherapy; Drug: Relugolix; Given PO; Other Names: TAK-385; Orgovyx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Coronary Plaque Volume in Major Coronary Arteries (i.e. Left Anterior Descending, Left Circumflex, Right Major Coronary Arteries)	Using cardiac computed tomography angiography (CCTA), total coronary plaque volume will be determined using an artificial intelligence-enabled quantitative coronary plaque analysis (AI-QCPA) through a commercially available and validated software service (HeartFlow, Inc). Each coronary artery (right coronary, left main, left anterior descending, and left circumflex) will be scored, and plaque volumes were summed over all segments.	From baseline to 12 months post-treatment initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-calcified Coronary Plaque Volume in Major Coronary Arteries (i.e. Left Anterior Descending, Left Circumflex, Right Major Coronary Arteries)	Using cardiac computed tomography angiography (CCTA), total coronary plaque volume will be determined using an artificial intelligence-enabled quantitative coronary plaque analysis (AI-QCPA) through a commercially available and validated software service (HeartFlow, Inc). Each coronary artery (right coronary, left main, left anterior descending, and left circumflex) will be scored, and plaque volumes were summed over all segments.	From baseline to 12 months post-treatment initiation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Calcified and Low-attenuation Coronary Plaque Volume in Major Coronary Arteries (i.e. Left Anterior Descending, Left Circumflex, Right Major Coronary Arteries)	Using cardiac computed tomography angiography (CCTA), total coronary plaque volume will be determined using an artificial intelligence-enabled quantitative coronary plaque analysis (AI-QCPA) through a commercially available and validated software service (HeartFlow, Inc). Each coronary artery (right coronary, left main, left anterior descending, and left circumflex) will be scored, and plaque volumes were summed over all segments.	From baseline to 12 months post-treatment initiation
Coronary Artery Calcium Score (CACS)	The CACS will be measured by the Agatston score (range 0-400, with higher scores indicating more coronary artery calcium) on precontrast cardiac computed tomography anigiography (CCTA) scans by two blinded, board-certified cardiologists.	From baseline to 12 months post-treatment initiation
Number of Participants With <30%, 30-49%, 50-69%, and >70% Maximum Coronary Vessel Stenosis at Baseline and Month 12	Coronary computed tomographic angiography post-contrast images were used for vessel stenosis, using an artificial intelligence-informed coronary stenosis quantification tool (AI-CSQ, Roadmap Analysis, Heart flow, Mountain View CA). Stenoses regions are defined in ranges of 0-29%, 30-49%, 50-69%, and >70%. The number of participants within each treatment meeting these stenosis thresholds were quantified at baseline and month 12.	From baseline to 12 months post-treatment initiation
Major Adverse Cardiovascular Events	Incidence of myocardial infarction, need for coronary revascularization, and/or sudden cardiac death will be measured for up to 2 years following enrollment.	From baseline to at least 2 years post-treatment initiation
Testosterone Kinetics	Change in total testosterone levels (ng/dL) will be measured at baseline and month 0, 3, 6, and 12 between treatment arms. Testosterone change over time will be summarized and plotted over time for each treatment arm.	Baseline and month 0, 3, 6, 12

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: National Cancer Institute (NCI); Prostate Cancer Foundation
• Investigators: Principal Investigator: Sagar A Patel, MD, Emory University Hospital/Winship Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2022
• Primary Completion (Actual): January 30, 2025
• Study Completion (Estimated): October 30, 2026

Study Registration Dates

• First Submitted: March 18, 2022
• First Submitted That Met QC Criteria: April 1, 2022
• First Posted (Actual): April 11, 2022

Study Record Updates

• Last Update Posted (Actual): February 12, 2026
• Last Update Submitted That Met QC Criteria: January 26, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Investigative Techniques; Therapeutics; Surgical Procedures, Operative; Stereotaxic Techniques; Neurosurgical Procedures; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Gonadotropin-Releasing Hormone; Heavy Ion Radiotherapy; Leuprolide; relugolix; Radiotherapy; Radiosurgery; Radiotherapy, Intensity-Modulated; Brachytherapy; Proton Therapy
• Other Study ID Numbers: STUDY00003654; P30CA138292 (U.S. NIH Grant/Contract); NCI-2022-00117 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); RAD5484-21 (Other Identifier: Emory University Hospital/Winship Cancer Institute); 22YOUN21 (Other Grant/Funding Number: Prostate Cancer foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes