ARN-509 and Leuprolide in Intermediate and High-risk Prostate Cancer

Primary Objective: To evaluate the differential effect of neo-adjuvant leuprolide and ARN-509
on dihydrotestosterone (DHT) concentration in benign prostate tissue based on HSD3B1
genotype.

Secondary Objective(s): To evaluate the differential effect of neoadjuvant leuprolide and
ARN-509 on other androgen (testosterone (T), dehydroepiandrosterone (DHEA), androstenediol,
5α-androstanedione (5α-dione), androstenedione (AD), androsterone and 5α-androstanediol)
concentrations in benign and malignant prostate tissue based on HSD3B1 genotype.

To compare the level of DHT, T, DHEA, androstenediol, 5α-dione, AD, androsterone and
5α-androstanediol between normal and malignant prostate tissue after neoadjuvant treatment
with leuprolide and ARN-509

To determine the safety of the combination of Leuprolide and ARN-509 administered prior to
radical prostatectomy

To evaluate prostatic specific antigen (PSA), FKBP5, TMPRSS2, EZH2, H3K27 and UBE2C tissue
expression (via immunohistochemistry (IHC) and quantitative polymerase chain reaction (qPCR))
in benign and malignant prostate tissue after treatment with Leuprolide and ARN-509 and
ARN-509.

Inclusion Criteria:

- Adenocarcinoma of the prostate with histological or cytological confirmation without
neuroendocrine differentiation or small cell histology and with G 4+3 or higher, and
PSA ≥ 10, and ≥T2b, for whom radical prostatectomy has been recommended and who choose
to undergo radical prostatectomy.

- A minimum tissue requirement of ≥3 core biopsies with tumor involvement and at least
50% tumor involvement in one of the core biopsies is required.

- Have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Hemoglobin of ≥ 10 g/dL, independent of transfusion and/or growth factors within 3
months prior to randomization

- Platelet count of ≥ 100k/mL independent of transfusion and/or growth factors within 3
months prior to randomization

- Serum albumin ≥3.0 g/dL

- Serum creatinine < 2.0 times the upper limit of normal (ULN) {or a calculated
creatinine clearance ≥ 60 mL/min}

- Serum potassium ≥3.5 mmol/L

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN

- Total serum bilirubin levels < 1.5 x ULN (Note: In subjects with Gilbert's syndrome,
if total bilirubin is >1.5 × ULN, measure direct and indirect bilirubin and if direct
bilirubin is ≤1.5 × ULN, subject may be eligible)

- Be capable of swallowing study agents whole as a tablet

- Be willing/able to adhere to the prohibitions and restrictions specified in this
protocol

- Have signed an informed consent document indicating that the subject understands the
purpose of and procedures required for the study and are willing to participate in the
study.

- Medications known to lower the seizure threshold must be discontinued or substituted
at least 4 weeks prior to study entry.

- Agrees to use a condom (even men with vasectomies) and another effective method of
birth control if he is having sex with a woman of childbearing potential or agrees to
use a condom if he is having sex with a woman who is pregnant while on study drug and
for 3 months following the last dose of study drug. Must also agree not to donate
sperm during the study and for 3 months following the last dose of study drug.

Exclusion Criteria:

- The use of any prior hormones including luteinizing hormone-releasing hormone (LHRH)
agonists , LHRH antagonists, antiandrogens such as bicalutamide, flutamide and
nilutamide, and/or the use of 5-alpha reductase inhibitors, prostate cancer (PC) Spes
(or PC-x product), Megestrol Acetate, or estrogen containing nutriceuticals within 6
months of study treatment initiation.

- Prior radiation therapy, immunotherapy, chemotherapy or other investigational therapy
given for prostate cancer.

- "Currently active" second malignancy other than non-melanoma skin cancers or
non-muscle invasive transitional cell carcinoma of bladder. Patients are not
considered to have a "currently active" malignancy if they have completed therapy and
are now considered (by their physician) to be at less than 30% risk for relapse.

- History of seizure or condition that may pre-dispose to seizure (including but not
limited to prior stroke, transient ischemic attack, loss of consciousness within 1
year prior to randomization, brain arteriovenous malformation; or intracranial masses
such as schwannomas and meningiomas that are causing edema or mass effect)

- Current systemic steroid therapy (inhaled or topical steroids are also not allowed)

- Have received treatment with any form of therapy with CYP17 inhibitory activity such
as ketoconazole, aminoglutethimide, or an antiandrogen such as bicalutamide within 6
months of study treatment initiation.

- Use of herbal products that may have hormonal anti-prostate cancer activity and/or are
known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids within 6
months of enrollment

- Active infection (eg, human immunodeficiency virus [HIV] or viral hepatitis)

- Have uncontrolled hypertension;subjects with a history of hypertension are permitted
in the study provided their blood pressure is controlled by anti-hypertensive therapy.

- Have a known history of pituitary or adrenal dysfunction

- Have clinically significant heart disease as evidenced by severe or unstable angina,
myocardial infarction, symptomatic congestive heart failure, arterial or venous
thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including
transient ischemic attacks), or clinically significant ventricular arrhythmias within
6 months prior to randomization

- Have a history of gastric bypass surgery or severe malabsorption that may interfere
with the absorption of the study agents

- Be taking or require the use of prohibited medications as listed

- Have any condition that, in the opinion of the investigator, would compromise the
well-being of the subject or the study or prevent the subject from meeting or
performing study requirements