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 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.