Enzalutamide/Leuprolide +/- Abiraterone/Pred in Prostate

In this research study, the investigators are comparing the effectiveness of enzalutamide
with or without abiraterone acetate for men with high-risk, localized prostate cancer.

Abiraterone acetate with prednisone and enzalutamide are currently FDA-approved for use in
the treatment of patients with metastatic castration-resistant prostate cancer, however they
are investigational for the treatment of localized prostate cancer. Abiraterone acetate works
by decreasing the production of male sex hormones, which cause prostate cancer growth.
Enzalutamide works by blocking the effects of male sex hormones, which cause prostate cancer
growth.

The FDA (the U.S. Food and Drug Administration) has not approved the combination of
enzalutamide and abiraterone acetate as neoadjuvant therapy for high risk prostate cancer
undergoing prostatectomy but each drug has been approved for the treatment of more advanced
prostate cancer.

Participants will be randomized to one of two study arms. Randomization means that the
participant is put into a group by chance. It is like flipping a coin. Neither participant
nor the research doctor will choose what group participants are randomized to.

The names of the study medications involved in this study are:

- Enzalutamide

- Abiraterone Acetate

- Prednisone

- Leuprolide Acetate

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.