Randomized Study to Evaluate MACE in Patients With Prostate Cancer Treated With Relugolix or Leuprolide Acetate

Study Overview
=================
Brief Summary
-----------------
This is a randomized study to evaluate the risk of major adverse cardiovascular events (MACE) for relugolix compared with leuprolide acetate. This study will collect clinical and cardiovascular risk factor data on patients ages 18 and older who are receiving relugolix or leuprolide acetate for their prostate cancer or as adjunct to radiation therapy with a treatment plan to be on androgen deprivation therapy (ADT) for at least one year.

Detailed Description
-----------------
Eligible patients will be randomized (1:1) to receive either relugolix or leuprolide acetate for prostate cancer or as an adjunct to primary or salvage radiation therapy. Patients who experience major adverse cardiovascular events (MACE) during the trial will be encouraged to stay on the study and continue to fill out questionnaires every 3 months. Each patient will also be asked to provide information regarding alternative contacts (eg, close relatives or friends, or primary care physician or cardiologist). In addition, patients will provide consent to obtain medical records (eg, hospitalizations, emergency room visits and clinic notes) for additional information, when appropriate. The primary endpoint in this study will be the time to first adjudicated MACE (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death). A surveillance approach will be used to collect clinical and cardiovascular risk data on patients receiving relugolix or leuprolide acetate for their prostate cancer. A rigorous, blinded adjudication of MACE by an independent clinical event adjudication committee (CEC) is included.

Official Title
-----------------
Relugolix Versus Leuprolide in Patients With Prostate Cancer: A Randomized, Open-Label Study to Assess Major Adverse Cardiovascular Events (REPLACE-CV)

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Relugolix
* Drug: Leuprolide Acetate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has voluntarily signed and dated the informed consent form prior to baseline visit; Is a male and 18 years of age or older on the day of signing and dating the informed consent form; Patient has sufficient cognitive function in the investigator's opinion to complete the questionnaires and other activities related to the study; Has a histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate; Is, in the opinion of the investigator, a candidate for at least 12 months of continuous ADT for the management of prostate cancer with one of the following clinical disease state presentations: Evidence of biochemical (prostate-specific antigen [PSA], confirmed with two measurements at least one week apart) or clinical relapse following local primary intervention with curative intent (such as surgery, radiation therapy, cryotherapy, or high-frequency ultrasound and not a candidate for salvage treatment by surgery); Metastatic hormone-sensitive disease (metastases in regional lymph node[s] are considered N1 and will, therefore, be stratified as non-metastatic); Advanced localized disease unlikely to be cured by local primary intervention with curative intent; Patients receiving primary or salvage radiation therapy with adjuvant ADT; Patients with high-risk cardiovascular disease defined as prior history of MACE (myocardial infarction, stroke, coronary revascularization [including percutaneous procedures] or revascularization affecting cerebral blood flow [including carotid procedures]) > 1 month before enrollment in the study; OR Patients with ≥ 3 of the following cardiovascular risk factors: Age (≥ 55 years of age); Hypertension defined as self-reported high blood pressure, or use of a blood pressure-lowering medication; Diabetes defined as self-reported diabetes or use of hypoglycemic medication for the purposes of lowering blood glucose and/or HbA1c; Dyslipidemia defined as self-reported high cholesterol or use of a lipid-lowering medication; Current cigarette use, defined as smoking within the year prior to the screening visit; Family history of cardiovascular disease, defined as a myocardial infarction or stroke or coronary revascularization or revascularization affecting cerebral blood flow (ie, carotid procedures) or sudden death in a first-degree relative < 60 years old; Testosterone concentration before starting relugolix or leuprolide acetate of ≥ 150 ng/dL (1.50 ng/mL or 5.2 nmol/L) within 6 months prior to screening; Patients, in the opinion of the investigator, must be equally eligible for either treatment in the study. If either the patient or the physician has a strong preference that one of the treatments be prescribed over the other, the patient must not be enrolled; Patients must not be participating or intending to participate in an interventional therapeutic study (observational trial is acceptable with approval of Medical Monitor). Exclusion Criteria: Any significant cardiovascular conditions per the investigator within 1 month before study entry including but not limited to: myocardial infarction, stroke, New York Heart Association class III or IV heart failure, thromboembolic events, major cardiovascular or cerebrovascular procedures or any other condition that in the investigator's opinion puts the patient at unacceptable risk to enter the study; Any major cardiovascular or cerebrovascular procedures planned within the 1 month after enrollment; Patients with QT interval corrected for heart rate (QTc) determined using Fridericia's formula (QTcF; QTcF = QT/[R-R interval {RR}^0.33]) > 470 msec within 6 months of screening; Uncontrolled hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg) at the time of screening; Previously received gonadotropin-releasing hormone (GnRH) receptor agonist (eg, leuprolide, goserelin, histrelin, triptorelin), GnRH receptor antagonist, or other forms of ADT (estrogen or any other antiandrogen, eq, enzalutamide, abiraterone, apalutamide, bicalutamide, darolutamide) for > 18 months total duration. Use of ADT was or an anti-androgen ≤ 12 months prior to randomization is also excluded. Once enrolled in the study, patients may be treated with ADT and anti-androgen (abiraterone, enzalutamide, apalutamide, darolutamide) and first-generation anti-androgens (eq bicalutamide) may be given to patients upon randomization to leuprolide acetate; Metastases to brain per prior clinical evaluation; Prescriber plans to switch from relugolix to leuprolide acetate or another GnRH agonist or antagonist or from leuprolide acetate to relugolix or another GnRH agonist or antagonist during the study; Treatment with any investigational product within 28 days or 5 half-lives (whichever is longer). Exception: treatment for prostate cancer with any investigational products where the mechanism of action is testosterone lowering. In this circumstance, there must be a minimum 12-month treatment free interval; Active malignancy beyond prostate cancer with the exception of the following: Adequately treated basal cell carcinoma or squamous cell carcinoma of the skin; Adequately treated Stage I cancer from which the patient is currently disease-free for ≥ 2 years; Any other cancer from which the patient has been disease-free for ≥ 5 years; Other malignancy upon agreement with the medical monitor.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relugolix<br>Oral relugolix 120 mg once daily with a loading dose of 360 mg on Day 1 | Drug: Relugolix<br>* Relugolix tablet<br>* Other names: T-1331285;|
| Active Comparator: Leuprolide Acetate<br>Subcutaneous or intramuscular leuprolide acetate 22.5 mg 3-M depot or 45 mg 6-M injection or Leuprolide acetate injectable emulsion (42 mg injectable emulsion is not allowed) | Drug: Leuprolide Acetate<br>* Leuprolide acetate injection<br>* Other names: Leuprolide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Major Adverse Cardiovascular Event (MACE) | Time to first adjudicated MACE defined as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death | From date of enrollment until date of first confirmed MACE, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time Course of Events Related to MACE | Time to first adjudicated MACE or death due to all cause, time to first adjudicated nonfatal or fatal myocardial infarction, time to first adjudicated nonfatal or fatal stroke, time to adjudicated cardiovascular death, time to recurrent adjudicated MACE, and time to start of ADT in combination with enzalutamide/abiraterone/apalutamide/darolutamide for disease progression | From date of enrollment until date of first confirmed MACE, assessed up to 5 years | 
| Incidence of Safety Outcomes | Incidence of selective safety data including all treatment-emergent serious adverse events, nonserious adverse events leading to discontinuation of relugolix or leuprolide acetate, and clinical laboratory tests as obtained per standard of care | Screening; Day 1; 3, 6, 9, and 12 months; and every 3 months thereafter | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ORGOVYX, relugolix, prostate cancer, leuprolide acetate