RElugolix VErsus LeUprolide Cardiac Trial

Study Overview
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Brief Summary
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This phase IV 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.

Detailed Description
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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.

Official Title
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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

Conditions
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Stage IIB Prostate Cancer AJCC v8, Stage IIC Prostate Cancer AJCC v8, Stage III Prostate Cancer AJCC v8, Stage IIIA Prostate Cancer AJCC v8, Stage IIIB Prostate Cancer AJCC v8, Biochemically Recurrent Prostate Carcinoma, Localized Prostate Carcinoma, Stage I Prostate Cancer AJCC v8, Stage II Prostate Cancer AJCC v8, Stage IIA Prostate Cancer AJCC v8, Stage IIIC Prostate Cancer AJCC v8

Intervention / Treatment
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* Radiation: Radiation therapy
* Drug: Leuprolide
* Drug: Relugolix


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (radiation therapy alone)<br>Patients undergo definitive radiation therapy alone (IMRT, SBRT, proton therapy, brachytherapy) in the absence of disease progression or unacceptable toxicity. | Radiation: Radiation therapy<br>* Undergo radiation therapy<br>* Other names: Stereotactic body radiotherapy;|
| Experimental: Arm II (radiation therapy plus leuprolide)<br>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<br>* Undergo radiation therapy<br>* Other names: Stereotactic body radiotherapy;Drug: Leuprolide<br>* Given IM or SC<br>* Other names: Lupron;|
| Experimental: Arm III (radiation therapy plus relugolix)<br>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<br>* Undergo radiation therapy<br>* Other names: Stereotactic body radiotherapy;Drug: Relugolix<br>* Given PO<br>* Other names: TAK-385;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Coronary plaque volume in major coronary arteries (i.e. left anterior descending, left circumflex, right major coronary arteries) | Using cardiac computed tomography angiography (CCTA), coronary plaque volume will be determined by measuring extent of coronary vessel luminal stenosis on an ordinal scale 0-100% as defined by the Society of Cardiac Computed Tomography. Change in luminal stenosis from baseline to month 12 will be tested using paired tests (Wilcoxon signed rank test or McNemar test). The incidence of moderate-to-severe atherosclerosis (defined as >50% luminal stenosis of a major coronary vessel) at month 12 will be compared between the three treatment groups using Fisher's exact test. Finally, the percent change of maximal stenosis from baseline to month 12 between the three treatment arms will be compared using Kruskal-Wallist test followed by pairwise Wilcoxon signed rank test (P-value adjusted for multiple testing using Holm-Bonferroni method). Multivariable adjustment will be utilized that control for anti-platelet/coagulation and statin use using general logistic regression. | From baseline to 12 months post-treatment initiation | 
| Incidence of high-risk coronary plaque features at month 12 after treatment initiation | Using CCTA, high-risk plaque features, categorized as positive remodeling, low attenuation plaque, and spotty calcium, will be measured at month 0 and month 12 for each treatment arm. Differences in incidence of high-risk plaque features amongst the three treatment arms will be compared using Fisher's exact test. Multivariable adjustment will be utilized that control for anti-platelet/coagulation and statin use using general logistic regression. | 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. Incidence curves will be estimated by the Kaplan-Meier method and compared between the three treatment arms using a two-sided log-rank test followed by pairwise comparisons with Bonferonni correction. | From baseline to at least 2 years post-treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute and late patient-reported morbidity | Adverse events will be assess using patient-reported outcomes (PRO) questionnaires including EPIC-26, IPSS, and SHIM scoring. Assessment will be collected before and at the end of radiotherapy treatment and in follow-up. For each symptom and each domain (i.e. frequency, severity, and interference), counts and frequencies will be provided for the worst score experienced by the patient by treatment arm. The proportion of patients with scores >=1 and >=3 will be compared between groups using a chi-square test (or Fisher's exact test if cell frequencies are <5). | Baseline and month 0, 3, 6, 12, 18, 24 | 
| Testosterone kinetics | Change in total and free testosterone levels 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. Testosterone levels over time will be assessed using mixed effects regression modeling. | Baseline and month 0, 3, 6, 12 |