Trial of Radiotherapy With Leuprolide and Enzalutamide in High Risk Prostate Cancer

PRIMARY OBJECTIVES: I. To determine the feasibility and safety of the combination of enzalutamide and leuprolide acetate (leuprolide) in patients undergoing definitive radiation therapy for high-risk prostate cancer or with pelvic nodal involvement. II. To determine the prostate-specific antigen (PSA) complete response rate with the combination of enzalutamide and leuprolide (PSA-complete response (CR) as determined by PSA nadir =\< 0.3) in patients undergoing radiation therapy for high-risk prostate cancer or pelvic nodal involvement. SECONDARY OBJECTIVES: I. To determine time to biochemical failure as determined by the American Society for Radiation Oncology (ASTRO) Phoenix definition of nadir + 2 ng/mL, local progression, regional progression, and distant metastases. II. To determine time to clinical progression free survival III. To assess changes in PSA nadir and PSA and testosterone levels. IV. To assess changes in hemoglobin A1c (HbA1c), fasting glucose, fasting insulin and fasting lipid and cholesterol levels. V. To document changes in quality of life outcomes. EXPLORATORY OBJECTIVES: I. To identify potential mutations and changes gene copy number associated with enzalutamide resistance in patients with high risk prostate cancer. II. To identify gene expression patterns, splice variants, and gene signatures associated with enzalutamide treatment and enzalutamide resistance in patients with high risk prostate cancer. III. To identify changes in the immune response with enzalutamide treatment. OUTLINE: Patients receive enzalutamide orally (PO) once daily (QD) and leuprolide acetate intramuscularly (IM) every 1, 3, 4, or 6 months for 24 months. Patients also undergo standard of care intensity-modulated radiation therapy (IMRT) 5 days per week for 5 weeks beginning at week 8, followed by optional brachytherapy. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 6 weeks, 3-4 months, 6, 12, 18, 24, and 36 months.