Randomized Study to Evaluate MACE in Patients With Prostate Cancer Treated With Relugolix or Leuprolide Acetate (REPLACE-CV)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Relugolix; Drug: Leuprolide Acetate

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.

• Study Type: Interventional
• Enrollment (Estimated): 2250
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Clinical Trials at Myovant; Phone Number: 650-278-8743; Email: ClinicalTrials@Myovant.com

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Urology Associates of Mobile
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Arizona Urology Specialists, PLLC
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Arkansas Urology
  • California
    • Downey, California, United States, 90241
      • Genesis Research, LLC Satellite
    • Fountain Valley, California, United States, 92708
      • Orange Coast Memorial Medical Center
    • Los Alamitos, California, United States, 90270
      • Genesis Research , LLC
    • Los Angeles, California, United States, 90048
      • Tower Urology
    • Monterey, California, United States, 93940
      • Pacific Cancer Care
    • Murrieta, California, United States, 92562
      • Tri Valley Urology Medical Group
    • Murrieta, California, United States, 92563
      • Tri Valley Urology Medical Group Satellite
    • San Bernardino, California, United States, 92404
      • San Bernadino Urological Associates Medical Group
    • San Diego, California, United States, 92123
      • Genesis Research, LLC
    • Sherman Oaks, California, United States, 91411
      • Genesis Research, LLC Satellite
    • Temecula, California, United States, 92592
      • Tri Valley Urology Medical Group Satellite
    • Torrance, California, United States, 90503
      • Genesis Research, LLC Satellite
    • Torrance, California, United States, 90505
      • Genesis Research, LLC Satellite
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • MedStar Washington Hospital Center
    • Washington, District of Columbia, United States, 20036
      • Urologic Surgeons of Washington
  • Florida
    • Daytona Beach, Florida, United States, 32114
      • Advanced Urology Institute
    • Jacksonville, Florida, United States, 32216
      • East Coast Institute for Research, LLC
    • Jacksonville, Florida, United States, 32204
      • East Coast Institute for Research, LLC Satellite
    • Jacksonville, Florida, United States, 32256
      • East Coast Institute for Research, LLC Satellite
    • Lake City, Florida, United States, 32024
      • Lake City Cancer Center, LLC
    • Miami, Florida, United States, 33145
      • SG Research LLC
    • Tampa, Florida, United States, 33609
      • Florida Urology Partners, LLP
    • Tampa, Florida, United States, 33578
      • Florida Urology Partners, LLP Satellite
    • Tampa, Florida, United States, 33615
      • Florida Urology Partners, LLP Satellite
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University
    • Augusta, Georgia, United States, 30912
      • Georgia Cancer Center Satellite
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Luke's Regional Medical Center
    • Boise, Idaho, United States, 83712
      • St. Luke's Regional Medical Center Satellite
    • Fruitland, Idaho, United States, 83619
      • St. Luke's Cancer Institute - Fruitland Satellite
    • Meridian, Idaho, United States, 83642
      • St. Luke's Cancer Institute - Meridian Satellite
    • Meridian, Idaho, United States, 83642
      • St. Luke's Meridian Medical Center Satellite
    • Nampa, Idaho, United States, 83687
      • St. Luke's Cancer Institute - Nampa Satellite
    • Nampa, Idaho, United States, 83687
      • St. Luke's Nampa Medical Center Satellite
    • Twin Falls, Idaho, United States, 83301
      • St. Luke's Cancer Institute Satellite
    • Twin Falls, Idaho, United States, 83301
      • St. Luke's Magic Valley Medical Center Satellite
  • Illinois
    • Bloomington, Illinois, United States, 61704
      • Illinois CancerCare - Bloomington Satellite
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60625
      • Swedish Hospital Satellite
    • Chicago Ridge, Illinois, United States, 60415
      • Associated Urological Specialists
    • Evanston, Illinois, United States, 60201
      • NorthShore University Health System - Evanston Hospital
    • Galesburg, Illinois, United States, 61401
      • Illinois CancerCare - Galesburg Satellite
    • Glenview, Illinois, United States, 60026
      • NorthShore University Health System - Glenbrook Hospital Ambulatory Care Center Satellite
    • Highland Park, Illinois, United States, 60035
      • NorthShore University Health System - Highland Park Hospital Ambulatory Care Center Satellite
    • Lake Barrington, Illinois, United States, 60010
      • Comprehensive Urologic Care
    • New Lenox, Illinois, United States, 60451
      • Advanced Urology Associates
    • Ottawa, Illinois, United States, 61350
      • Illinois CancerCare - Ottawa Satellite
    • Pekin, Illinois, United States, 61554
      • Illinois CancerCare - Pekin Satellite
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare, P.C.
    • Peru, Illinois, United States, 61354
      • Illinois CancerCare - Peru Satellite
    • Washington, Illinois, United States, 61571
      • Illinois CancerCare - Washington Satellite
  • Indiana
    • Carmel, Indiana, United States, 46032
      • Urology of Indiana, LLC Satellite
    • Greenwood, Indiana, United States, 46143
      • Urology of Indiana, LLC
    • Lafayette, Indiana, United States, 47904
      • IU Health Arnett Cancer Center
    • Muncie, Indiana, United States, 47303
      • IU Health Ball Memorial Hospital Satellite
  • Iowa
    • Council Bluffs, Iowa, United States, 51501
      • Adult and Pediatric Urology P.C. Satellite
    • Creston, Iowa, United States, 50801
      • Greater Regional Medical Center
  • Kansas
    • Wichita, Kansas, United States, 67226
      • Wichita Urology Group
    • Wichita, Kansas, United States, 67205
      • Wichita Urology Group Satellite
    • Wichita, Kansas, United States, 67206
      • Wichita Urology Group Satellite
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • Comprehensive Urology
    • Troy, Michigan, United States, 48084
      • Michigan Institute of Urology
  • Missouri
    • Osage Beach, Missouri, United States, 65065
      • Lake Regional Health System
    • Saint Louis, Missouri, United States, 63141
      • Specialty Clinical Research of St. Louis
    • Saint Louis, Missouri, United States, 63141
      • Urology of St. Louis Satellite
  • Montana
    • Billings, Montana, United States, 59102
      • St. Vincent - Frontier Cancer Center
    • Billings, Montana, United States, 59101
      • St. Vincent Healthcare Satellite
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Adult and Pediatric Urology P.C.
  • New Jersey
    • Pennington, New Jersey, United States, 08534
      • Capital Health Medical Center - Hopewell
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Comprehensive Cancer Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • Syracuse, New York, United States, 13210
      • Associated Medical Professionals of NY, PLLC
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Oncology Specialists of Charlotte
    • Raleigh, North Carolina, United States, 27612
      • Associated Urologists of North Carolina
  • North Dakota
    • Grand Forks, North Dakota, United States, 58201
      • Altru Cancer Center
    • Grand Forks, North Dakota, United States, 58201
      • Altru Health System Satellite
    • Grand Forks, North Dakota, United States, 58201
      • Altru Professional Center Satellite
  • Ohio
    • Avon, Ohio, United States, 44011
      • University Hospitals Seidman Cancer Center at UH Avon Health Center Satellite
    • Cincinnati, Ohio, United States, 45212
      • TriState Urologic Services PSC Inc.
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Gahanna, Ohio, United States, 43230
      • Central Ohio Urology Group
    • Gahanna, Ohio, United States, 43230
      • Central Ohio Urology Group Satellite
    • Mentor, Ohio, United States, 44060
      • University Hospitals Seidman Cancer Center at UH Mentor Health Center Satellite
    • Middleburg Heights, Ohio, United States, 44130
      • Helios CR, LLC
    • Orange Village, Ohio, United States, 44122
      • UH Minoff Health Center at Chagrin Highlands
  • Pennsylvania
    • Bala-Cynwyd, Pennsylvania, United States, 19004
      • MidLantic Urology
    • Lancaster, Pennsylvania, United States, 17604
      • Keystone Urology Specialists
    • Sayre, Pennsylvania, United States, 18840
      • Guthrie Medical Group, PC
    • Sayre, Pennsylvania, United States, 18840
      • Robert Packer Hospital Satellite
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center
    • North Charleston, South Carolina, United States, 29406
      • Lowcountry Urology Clinics
  • Tennessee
    • Nashville, Tennessee, United States, 37209
      • Urology Associates, P.C.
  • Texas
    • Harlingen, Texas, United States, 78550
      • Valley Cancer Associates
    • Houston, Texas, United States, 77027
      • Houston Metro Urology CRC, LLC
    • San Antonio, Texas, United States, 78240
      • The Urology Place
    • San Antonio, Texas, United States, 78229
      • Urology San Antonio Clinical Trials
  • Utah
    • Logan, Utah, United States, 84341
      • Logan Regional Hospital Satellite
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center Satellite
    • Ogden, Utah, United States, 84403
      • McKay-Dee Hospital Satellite
    • Provo, Utah, United States, 84604
      • Utah Valley Hospital
    • Saint George, Utah, United States, 84790
      • St. George Regional Hospital Satellite
  • Virginia
    • Alexandria, Virginia, United States, 22311
      • Potomac Urology Center, PC
    • Richmond, Virginia, United States, 23235
      • Virginia Urology
    • Virginia Beach, Virginia, United States, 23462
      • Urology of Virginia
    • Woodbridge, Virginia, United States, 22191
      • Potomac Urology Satellite
  • Washington
    • Spokane, Washington, United States, 99202
      • Spokane Urology

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Relugolix; Oral relugolix 120 mg once daily with a loading dose of 360 mg on Day 1	Drug: Relugolix; Relugolix tablet; Other Names: TAK-385; MVT-601; RVT-601; T-1331285; ORGOVYX
Active Comparator: Leuprolide Acetate; 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; Leuprolide acetate injection; 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

Collaborators and Investigators

• Sponsor: Myovant Sciences GmbH

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2023
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): February 28, 2027

Study Registration Dates

• First Submitted: October 25, 2022
• First Submitted That Met QC Criteria: October 31, 2022
• First Posted (Actual): November 4, 2022

Study Record Updates

• Last Update Posted (Estimated): January 29, 2024
• Last Update Submitted That Met QC Criteria: January 26, 2024
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: prostate cancer; relugolix; ORGOVYX; leuprolide acetate
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Androgen Antagonists; Leuprolide; Relugolix
• Other Study ID Numbers: MVT-601-056

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