Comeback From Long coursE Androgen Deprivation Therapy (ADT) With RElugolix and Darolutamide (CLEARED)

Inclusion Criteria:

* Participants must have histologically or cytologically confirmed prostate cancer.
* Hormone-sensitive prostate cancer (with detectable prostate-specific antigen \[PSA\] \> 0.02 ng/ml, testosterone ≥ lower limit of normal \[LLN\] per institutional assay) planned for two years of intensified androgen deprivation therapy per investigator discretion. This includes the following indications:

  * Treatment-naïve high risk lymph node-negative (N0) disease planned for primary radiation therapy
  * Treatment-naïve clinically pelvic lymph node positive (cN+) disease planned for primary radiation therapy
  * Pathologically pelvic lymph node positive (pN+) disease after prostatectomy planned for salvage radiation therapy
  * Regional nodal recurrence after prior local therapy (often in the context of radiation to lymph nodes)
  * Synchronous or metachronous low volume metastatic hormone sensitive prostate cancer (mHSPC) by Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) criteria planned for treatment interruption after 2 years (often in the context of radiation to sites of disease).
  * N.B: While CHAARTED criteria were established based on conventional imaging, patients who had PSMA PET imaging that would meet criteria for high volume disease (visceral metastases or ≥ 4 definitive bone metastases with at least one outside the axial skeleton) are excluded from this study.
* Prior hormonal therapy is permitted in the context of neoadjuvant/concurrent/adjuvant treatment with prior local therapy or biochemical recurrence by conventional imaging (for patients enrolling for recurrent rather than treatment-naïve disease), but patients must have had testosterone recovery to ≥ LLN at time of enrollment to this trial.
* Age ≥18 years. Children under 18 are excluded from this study as prostate cancer is a disease of adults.
* Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (Karnofsky ≥70%).
* Participants must meet the following organ and marrow function as defined below:

  * leukocytes ≥2500/mcL
  * absolute neutrophil count ≥1000/mcL
  * platelets ≥100,000/mcL
  * total bilirubin ≤ 1.5 institutional upper limit of normal (ULN) unless known or suspected Gilbert syndrome
  * aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5 × institutional ULN
  * glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 (based on Cockcroft-Gault formula, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) refit formula, OR creatinine clearance based on 24 hour urine collection)
* Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy (with no known or predicted drug-drug interactions with darolutamide and/or relugolix) with undetectable viral load within 6 months are eligible for this trial.
* For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable. If suppressive therapy is indicated, there must be no known or predicted drug-drug interactions with darolutamide and/or relugolix.
* Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if there are no known or predicted drug-drug interactions with darolutamide and/or relugolix and they have an undetectable HCV viral load.
* Participants 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. To be eligible for this trial, participants should be class 2B or better.
* Ability to swallow oral medications.
* The effects of darolutamide and/or relugolix on the developing human fetus are unknown. For this reason and because oral hormonal agents are known to be teratogenic, participants must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately. Participants treated or enrolled on this protocol must also not donate semen or sperm and agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of darolutamide and relugolix administration.
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Participants who received prior systemic therapy for the disease state (high risk localized, lymph node positive, or low volume mHSPC) for which they are enrolling on this trial. Prior hormonal therapy is permitted for patients with recurrent disease after prior therapy.
* Participants who previously experienced any rise in PSA with castrate level testosterone (\< 50 ng/dl).
* Participants who are receiving any other investigational agents for this condition.
* Participants with brain metastases, leptomeningeal disease, or metastases involving other visceral organs since these patients would be considered to have "high volume" metastatic disease by CHAARTED criteria.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to relugolix or darolutamide.
* Participants with predicted significant drug-drug interaction with darolutamide and/or relugolix are ineligible or must be monitored carefully as detailed below:

  * Participants receiving combined P-glycoprotein (P-gp) and strong CYP3A inducers (e.g. apalutamide, carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort) or combined P-gp and moderate CYP3A4 inducers (e.g. efavirenz, rifabutin) are ineligible.
  * Participants receiving combined P-gp and strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, posaconazole, clarithromycin, cobicistat, cyclosporine, tacrolimus, nelfinavir, ritonavir, lopinavir, saquinivir, tipranavir) are ineligible to enroll.
  * Participants receiving Breast cancer resistance protein (BCRP) substrates (e.g. glyburide, cimetidine, nitrofurantoin, dipyridamole, sulfasalazine, and rosuvastatin) are not excluded but participants should be monitored more frequently for adverse reactions to the BCRP substrate drug, and dose reduction of the BCRP substrate drug should be considered.
  * Participants receiving P-gp inhibitors are not excluded but participants must be able to dose the P-gp inhibitor at least 6 hours after relugolix dose during the conduct of the study. Participants unable to dose the P-gp inhibitor at least 6 hours after relugolix dose, or requiring twice daily or more frequent dosing of a P-gp inhibitor are ineligible.
  * Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
* Participants with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
* Participants with psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant and nursing women are excluded from this study because they do not develop prostate cancer.
* Concurrent active malignancy. Patients with non-melanomatous skin cancer, superficial bladder cancer, cancer not needing active systemic therapy for at least 2 years and would not affect imaging assessments for prostate cancer, cancer for which the treating investigator deems the subject to be in remission, or any prior malignancy that was treated with curative intent (no evidence of disease for at least 3 years) are also permitted to enroll.