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

Inclusion Criteria: 1. Histologically confirmed diagnosis of adenocarcinoma of the prostate within 180 days prior to registration at very high risk of recurrence as determined by 2 or more of the following combinations: * cT3a/b * PSA ≥20 * Gleason score 8-10 * ≥33% core involvement OR any patient with pelvic lymph node involvement ≥1cm as determined by pelvic CT or MRI imaging will meet eligibility criteria for enrollment. 2. Standard staging exams for patients with high-risk prostate cancer including bone scan or NaF Positron Emission Tomography (PET) /CT scan, and pelvic and prostate MRI. 3. No distant metastases (M0) on bone scan or NaF PET/CT within 90 days prior to registration. Equivocal bone scan findings are allowed if the physician determines that distant metastases are unlikely based on clinical judgment. 4. Zubrod Performance Status 0-2 within 60 days prior to enrollment. 5. Age ≥18 6. Complete blood count (CBC) with differential obtained within 30 days prior to registration on study, with adequate bone marrow function defined as follows: 1. Absolute neutrophil count (ANC) ≥1,800 cells/mm3 2. Platelets ≥100,000 cells/mm3 3. Hemoglobin ≥8.0 g/dl (The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable) 4. Serum creatinine \<2.0 mg/dl and creatinine clearance \>40 mL/min within 30 days prior to registration 5. Bilirubin \<1.5 x ULN and Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) \<2 × ULN within 21 days prior to registration 7. Patients, even if surgically sterilized (i.e., status post vasectomy), who: 1. Agree to practice effective barrier contraception during the entire study treatment period and for 4 months (120 days) after the last dose of study drug, or 2. Agree to completely abstain from intercourse 8. Patient must be able to provide study-specific informed consent prior to study entry. Exclusion Criteria: 1. Definite evidence of metastatic disease 2. Prior radical prostatectomy or bilateral orchiectomy for any reason 3. Prior invasive malignancy (except non-melanoma skin cancer) unless disease-free or not requiring systemic therapy for a minimum of 3 years. 4. Prior systemic chemotherapy for prostate cancer (Note that prior chemotherapy for a different cancer is allowed). 5. Prior radiotherapy, including brachytherapy, to the region of the prostate that would result in overlap of radiation therapy fields. 6. Previous hormonal therapy such as LHRH agonists (e.g. goserelin, leuprolide), anti-androgens (e.g. flutamide, bicalutamide), estrogens (e.g. DES), or surgical castration (orchiectomy) 7. Known hypersensitivity to enzalutamide or related compounds 8. History of adrenal insufficiency 9. Patients who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. 10. Prior allergic reaction to the drugs involved in this protocol. 11. Cushing's syndrome 12. Severe chronic renal disease (serum creatinine \>2.0 mg/dl and confirmed by creatinine clearance \<40 mL/minute) 13. Chronic liver disease (bilirubin \>1.5x ULN, ALT or AST \>2x ULN) 14. Active/Uncontrolled Viral Hepatitis 15. Chronic treatment with glucocorticoids within one year. 16. History of seizure including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). Also, current or prior treatment with antiepileptic medications for the treatment of seizures or history of loss of consciousness or transient ischemic attack within 12 months prior to randomization. 17. Clinically significant cardiovascular disease including: 1. Myocardial infarction within 6 months prior to screening 2. Uncontrolled angina within 3 months prior to screening 3. Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multigated acquisition (MUGA) scan performed within 3 months results in a left ventricular ejection fraction that is ≥45%; 4. History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes); 5. History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place; 6. Uncontrolled hypertension as indicated by a resting systolic blood pressure \>170 mm Hg or diastolic blood pressure \>105 mm Hg at screening. Patients with initially elevated systolic blood pressure \>170 mm Hg or diastolic blood pressure \>105 mm Hg are eligible if they undergo medical management and are re-screened.