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NCT Number: NCT06650579

REVELUTION-2: Relugolix+Abiraterone Acetate (AA) Versus Leuprolide+AA Cardiac Trial

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.

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Key information

Conditions

Recurrent Prostate Carcinoma Genital Diseases Genital Diseases, Male Genital Neoplasms, Male Male Urogenital Diseases Neoplasms Neoplasms by Site Prostatic Diseases Prostatic Neoplasms Stage III Prostate Cancer AJCC v8 Stage IVA Prostate Cancer AJCC v8 Urogenital Diseases Urogenital Neoplasms

Age range

18 year and older

Sex eligibility

Male

Study type

Interventional

Phase

Phase 3

Primary location

Emory Proton Therapy Center, Atlanta, Georgia, United States

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About this study

PRIMARY OBJECTIVE:

I. Measure cardiovascular outcomes between combination gonadotropin releasing hormone agonist (GNRHa, i.e. leuprolide) plus abiraterone acetate (AA) versus gonadotropin releasing hormone antagonist (GNRH-antagonist, i.e. relugolix) plus AA in men with advanced prostate cancer receiving definitive radiation therapy.

SECONDARY OBJECTIVES:

I. Identify genomic alterations that predispose an individual to enhanced cardiovascular (CV) toxicity following hormone therapy with leuprolide or relugolix in combination with abiraterone acetate.

II. Evaluate serum testosterone kinetics during and after treatment with combination leuprolide+AA versus relugolix+AA.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive leuprolide intramuscularly (IM) or subcutaneously (SC) injection every 3 to 6 months plus oral AA with prednisone daily for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo standard of care radiation therapy. Patients may also receive bicalutamide orally (PO) once daily (QD) on days 21-30 with first injection of leuprolide at the discretion of the treating provider. All patients undergo pre-treatment and 12-month coronary computed tomography angiography (CCTA) and blood sample collection.

ARM II: Patients receive oral relugolix PO daily plus oral AA with prednisone daily for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo standard of care radiation therapy. All patients undergo pre-treatment and 12-month CCTA and blood sample collection.

After completion of study treatment, patients are followed up at 30 and 60 days for serum testosterone measurement.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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
  • Plan to undergo up to 24 months of combination androgen deprivation therapy (ADT) plus AA and prednisone

Exclusion criteria

  • 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
  • History of cardiac pacemaker or defibrillator

Treatment and study plan

Abiraterone Acetate

Drug

Given abiraterone acetate

Other names: BR9004, BR9004-1, CB 7630, CB-7630, CB7630, JNJ-212082, Yonsa, Zytiga

bicalutamide

Drug

Given PO

Other names: Casodex, Cassotide, Cosudex, ICI 176,334, ICI 176334, Utamide

Biospecimen Collection

Procedure

Undergo blood sample collection

Other names: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Computed Tomography Angiography

Procedure

Undergo CCTA

Other names: CT ANGIOGRAPHY, CT Scan Angiography, CTA

Leuprolide

Drug

Given IM or SC

Other names: Leuprorelin

Prednisone

Drug

Given prednisone

Other names: .delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-Prednisone

radiation therapy

Radiation

Undergo standard of care radiation therapy

Other names: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Relugolix

Drug

Given PO

Other names: N-(4-(1-((2,6-Difluorophenyl)methyl)-5-((dimethylamino)methyl)-1,2,3,4-tetrahydro-3-(6-methoxy-3-pyridazinyl)-2,4-dioxothieno(2,3-d)pyrimidin-6-yl)phenyl)-N'-methoxyurea, Orgovyx, Relumina, TAK 385, TAK-385, TAK385

Primary outcomes

  1. Incidence of ambulatory systolic blood pressure (BP) > 140 or diastolic > 90 (measurement on 2 separate days)

    Time frame: At baseline and up to 12 months

    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.

  2. Need for new or escalated anti-hypertensive medication

    Time frame: At baseline and up to 12 months

    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.

  3. Incidence of moderate-to-severe atherosclerosis of major coronary vessels

    Time frame: From month 0 to month 12

    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.

Secondary outcomes

  1. Total plaque volume

    Time frame: From month 0 to month 12

    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.

  2. Pre-existing genomic alterations promoting inflammatory immunity and associated with cardiovascular disease

    Time frame: At baseline

    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.

  3. Castration rate

    Time frame: At study days 7, 30 and 90

    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

  4. Sustained castration

    Time frame: At months 6 and 12

    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

  5. Testosterone recovery

    Time frame: At day 30 and/or day 90 following completion of androgen deprivation therapy

    The probability of testosterone recovery > 50 ng/mL and 200 ng/mL 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

Study contacts

Contact information is provided by the study sponsor or research team.

Bill Zheng, BS

CONTACT

[email protected]

404-686-6856

Sponsors and collaborators

Lead sponsor

Emory University

Other

Collaborators

  • National Cancer Institute (NCI)
  • National Comprehensive Cancer Network
  • Pfizer
  • Sumitomo Pharma America, Inc.

Registry information

Official study title

Randomized Controlled Trial of Leuprolide Plus Abiraterone Acetate (AA) Versus Relugolix Plus AA for Advanced Prostate Cancer: The REVELUTION-2 Trial

Important dates

Study start
2025
Primary completion
2029
Study completion
2029
First posted
Oct 21, 2024
Registry last updated
Feb 24, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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