Relugolix and Enzalutamide in Combination With Radiation Therapy for the Treatment of Very High Risk Prostate Cancer, OPTIMAL Trial

PRIMARY OBJECTIVE: I. To determine the efficacy of radiation therapy (RT) with androgen deprivation therapy (ADT) (relugolix) and an androgen receptor signaling inhibitor (enzalutamide), for a total duration of 18 months, in patients with National Comprehensive Cancer Network (NCCN) very high-risk prostate cancer, as determined by a 2-year biopsy positivity rate. SECONDARY OBJECTIVES: I. To determine the 4-year disease free survival (DFS) (biochemical failure of prostate specific antigen \[PSA\] nadir +2ng/mL, local or regional recurrence, distant metastasis, or death from any cause). II. To evaluate testosterone recovery. EXPLORATORY OBJECTIVES: I. To evaluate impact on patient-reported health-related quality of life utilizing (1) Expanded Prostate Cancer Index Composite, EPIC-26 and (2) European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLC-C30). II. To investigate a relationship between magnetic resonance imaging (MRI)-positron emission tomography (PET) radiomic response (baseline and after neoadjuvant therapy) correlated with pathologic and disease control endpoints. OUTLINE: Patients receive relugolix orally (PO) once daily (QD) and enzalutamide PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 18 months in the absence of disease progression or unacceptable toxicity. After 4 months of treatment with relugolix and enzalutamide, patients begin image-guided radiation therapy (IGRT) per standard of care. Patients also undergo fluorine F 18 piflufolastat PET/MRI and CT on the trial, undergo collection of blood samples throughout the trial, and undergo biopsy during follow up. After completion of study treatment, patients are followed up every 3-6 months for up to 30 months (48 months after study registration).