Enzalutamide/Leuprolide +/- Abiraterone/Pred in Prostate

Inclusion Criteria:

* Male greater than or equal 18 years of age.
* Histologically confirmed adenocarcinoma of the prostate without histological variants (including overt neuroendocrine differentiation, small cell neuroendocrine carcinoma features, sarcomatoid features, pure ductal adenocarcinoma, squamous or transitional cell carcinoma).
* Must have tissue available from the pre-treatment diagnostic biopsy (tissue blocks if possible; if not possible, 10 unstained slides from each positive core sample for a total of 30 slides).
* Must have three core biopsies involved with cancer (a minimum of 6 core biopsies must be obtained). Prostate biopsy must be within three months from screening.
* Participants must have the following features:

  * Intermediate-risk disease defined as Gleason 4+3=7 disease OR
  * High-risk disease defined as Gleason 8-10 OR PSA \> 20 ng/dL OR T3 disease (by prostate MRI)
* No evidence of metastatic or nodal disease as determined by radionuclide bone scans CT/MRI.
* Participants must be candidates for RP and considered surgically resectable by urologic evaluation.
* ECOG performance status 0 to 1 (Appendix A).
* Participants must have normal organ and marrow function as defined below:

  * WBC ≥ 3,000/mcL
  * ANC ≥ 1,500/mcL
  * Platelets ≥ 100,000/mcL
  * Serum potassium ≥ 3.5 mmol/L
  * AST, ALT, and total bilirubin ≤ 1.5 x Institutional ULN
  * Calculated creatinine clearance ≥ 60 mL/min
  * PTT ≤ 60, INR ≤ 1.5 x Institutional ULN unless on warfarin therapy (investigator would need to determine if safe for participant to stop warfarin prior to biopsy and warfarin therapy)
  * Controlled blood pressure defined as a systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg on no more than three anti-hypertensive agents. Drug formulations containing two or more anti-hypertensive agents will be counted based on the number of active agents in each formulation.

Exclusion Criteria:

* Prior hormone therapy for prostate cancer including orchiectomy, antiandrogens (including first-generation antiandrogens, enzalutamide, ARN-509 and others), CYP17 inhibitors (including abiraterone, TAK-700, galeterone, ketoconazole, and others), estrogens, LHRH agonist/antagonists. Prior therapy with 5α-reductace inhibitors is allowed. LHRH therapy allowed if begun within 4 weeks of day 1.
* Prior chemotherapy, radiation therapy, or immunotherapy for prostate cancer.
* Prior systemic treatment with an azole drug within four weeks of screening visit.
* Hypogonadism or severe androgen deficiency as defined by screening serum testosterone \< 200 ng/dL.
* Clinically significant cardiovascular disease including:
* Acute coronary syndrome within 6 months of screening visit;

  * Hypotension defined as a systolic blood pressure \< 86 mmHg;
  * Bradycardia defined as a heart rate of \< 50 beats per minute, unless pharmaceutically induced and thus reversible (i.e. beta blockers);
  * Uncontrolled angina (requiring escalating doses of nitrates) within 3 months of screening visit;
  * Congestive heart failure NYHA Class III or IV or subjects with a history of congestive heart failure NYHA Class III or IV, unless screening ECHO results in left ventricular ejection fraction that ≥ 45%;
  * History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes);
  * Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on screening EKG \> 470 msec;
  * History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;
* History of seizure or any condition or concurrent medication that may predispose to seizure.
* Thromboembolism within 6 months of screening visit.
* Severe hepatic impairment (Child-Pugh Class C).
* Active or symptomatic viral hepatitis or chronic liver disease.
* History of pituitary or adrenal dysfunction.
* GI disorders which may interfere with the absorption of the study drug.
* Pre-existing condition that warrants long-term corticosteroid use.
* Concomitant use of medications that may alter pharmacokinetics of abiraterone or enzalutamide.
* Individuals with a history of a different malignancy are ineligible except for the following circumstances: 1) individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, or 2) individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: non-muscle invasive bladder cancer, basal cell or squamous cell carcinoma of the skin.
* Major surgery or radiation therapy within 30 days of screening.