Comparing the effects of relugolix and leuprolide on heart health in prostate cancer patients

Inclusion Criteria:

* Pathologically proven diagnosis of adenocarcinoma of the prostate within 270 days prior to registration.
* Unfavorable intermediate risk prostate cancer, defined as having ALL the following bulleted criteria:

  * Has at least one intermediate risk factor (IRF):

    * Prostate-specific antigen (PSA) 10-20 ng/mL
    * Clinical stage tumor (T)2b-c (digital rectal exam \[DRE\] and/or imaging) by American Joint Committee on Cancer (AJCC) 8th edition
    * Gleason Score 7 (Gleason 3+4 or 4+3 \[International Society of Urological Pathology \[ISUP\] grade group 2-3\])
  * Has one or more of the following "unfavorable" intermediate-risk designators:

    * \> 1 IRF
    * Gleason 4+3=7 (ISUP grade group 3)
    * ≥ 50% of biopsy cores positive

      * Biopsies may include "sextant" sampling of right/left regions of the prostate, often labeled base, mid-gland and apex. All such "sextant" biopsy cores should be counted. Men may also undergo "targeted" sampling of prostate lesions (guided by MRI, ultrasound or other approaches). A targeted lesion that is biopsied more than once and demonstrates cancer (regardless of number of targeted cores involved) should count as a single additional positive core sampled and positive. In cases of uncertainty, count the biopsy sampling as sextant core(s).
    * Absence of high-risk features
* Appropriate stage based on the following diagnostic workup:

  * History/physical examination within 120 days prior to registration
  * Negative bone imaging (M0) with Tc-99m bone scan or fluciclovine (18F) sodium fluoride (NaF) positron emission tomography (PET) within 120 days prior to registration
  * Clinically negative lymph nodes (N0) as established by conventional imaging (pelvic +/- abdominal CT or MRI), within 120 days prior to registration (lymph nodes equivocal or questionable by imaging are eligible if the nodes are ≤ 1.0 cm in short axis and/or if biopsy is negative)
  * Prostate specific membrane antigen (PSMA) or fluciclovine PET negative for nodal or distant metastatic disease is an acceptable substitute for the above bone and pelvic imaging
* Age ≥ 18
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 120 days prior to registration.
* Non-castrate testosterone level (\> 50 ng/dL) within 120 days prior to registration.
* Absolute neutrophil ≥ 1,000 cells/mm\^3 (within 120 days prior to registration)
* Hemoglobin ≥ 10 g/dL (within 120 days prior to registration)
* Platelet count ≥ 100,000 cells/mm\^3 (within 120 days prior to registration)
* Creatinine clearance (CrCl) ≥ 30 mL/min estimated by Cockcroft-Gault Equation (within 120 days prior to registration)

  * For African American patients, CrCl ≥ 30 mL/min is estimated by the alternative formula that takes race into account
* Total bilirubin: 1.5 ≤ institutional upper limit of normal (ULN) (within 120 days prior to registration)
* Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT)(serum glutamic-pyruvic transaminase \[SGPT\]) ≤ 2.5 × institutional ULN (within 120 days prior to registration)
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Note: HIV testing is not required for eligibility for this protocol.
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B).

* For patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

  * Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy.
* The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.

Exclusion Criteria:

* Previous radical surgery (prostatectomy) or any form of curative-intent ablation whether focal or whole-gland (e.g., cryosurgery, High-intensity focused ultrasound (HIFU), laser thermal ablation, etc.) for prostate cancer.
* Definitive clinical or radiologic evidence of metastatic disease (M1).
* Prior invasive malignancy (except non-melanomatous skin cancer) or hematologic malignancy unless disease free for a minimum of 3 years.
* Prior radiotherapy to the prostate/pelvis region that would result in overlap of radiation therapy fields.
* Previous bilateral orchiectomy.
* Previous hormonal therapy, such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., leuprolide, goserelin, buserelin, triptorelin) or LHRH antagonist (e.g. degarelix), anti-androgens (e.g., flutamide, bicalutamide, cyproterone acetate). ADT started prior to study registration is not allowed.
* Prior use of 5-alpha-reductase inhibitors is allowed; however, it must be stopped ≥ 30 days prior to the pre-registration PSA measure for determining enrollment eligibility.
* Prior testosterone replacement therapy is allowed; however, any replacement therapy must be stopped for at least 1 year prior to registration.
* Severe, active co-morbidity defined as follows:

  * Current/uncontrolled angina or arrhythmias
  * New York Heart Association Functional Classification II-IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.)
  * History of any condition that in the opinion of the investigator, would preclude participation in this study
* Patients with significant obstructive urinary symptoms that are suspected to be secondary to prostate cancer and/or benign prostatic hypertrophy.
* Disabilities that prevent performing moderate intensity exercise test with exercise (treadmill) stress test and muscle function tests (walking/gait assessments and grip strength).
* Patients unable to tolerate MRI (e.g. claustrophobia), has contraindications to MRI (e.g. metals and implants incompatible with MRI), body habitus preventing MRI scanning, or allergy to gadolinium-based contrast.
* Significant uncontrolled gastrointestinal (e.g. Crohn's disease, ulcerative colitis) or metabolic disease (e.g. diabetes, hyperlipidemia).
* Active inflammatory or immune-related disease treated with steroids or immunosuppressive agents.
* Inability to swallow oral pills.
* High risk features, which includes any of the following:

  * Gleason 8-10 \[ISUP grade group 4-5\]
  * PSA\>20
  * cT3-4 by digital exam OR gross extra-prostatic extension on imaging \[indeterminate MRI evidence will not count and the patient will be eligible\]