Enzalutamide in Patients With High-risk Prostate Cancer

This is a pilot phase II study evaluating the clinical activity and safety of Enzalutamide
(formerly known as MDV3100) a novel androgen receptor (AR) inhibitor in men with high-risk
prostate cancer who have undergone local definitive therapy with radical prostatectomy.

Primary Objectives:

-To evaluate the clinical efficacy of enzalutamide in patients with high-risk prostate cancer
with regards to: Time to disease progression defined by biochemical recurrence (BCR)

Secondary Objectives:

-To further evaluate the safety of enzalutamide in patients with high-risk prostate cancer

Patients will receive daily oral therapy with enzalutamide at 160mg (4 capsules) orally once
daily (QD). Patients will continue on study until progressive disease, drug intolerability,
consent withdrawal or completion of study at 24 months.

Inclusion Criteria:

- Understand and voluntarily sign an informed consent form.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

- Histologically confirmed adenocarcinoma of the prostate.

- Patients must have undergone a Radical Prostatectomy (any surgical technique is
permitted) within 3 months from study entry and have high-risk disease define by any
of the following:

- Pathological stage T3a, T3b, T4 (any grade or iPSA)

- Gleason' sum ≥ 8 (any stage or iPSA)

- Initial Pre-operative PSA ≥ 20ng/mL (any GS or pT stage)

- Any stage/PSA/Gleason patients with a 35% or greater chance of biochemical
failure at 5 years based on Kattan's nomogram
http://nomograms.mskcc.org/Prostate/PostRadicalProstatectomy.

- Patients with Lymph node (LN) positive disease, regardless of iPSA, pT stage or
GS provided their post-operative PSA 6-8 weeks after surgery is ≤ 0.4ng/mL.
(Lymph node dissection is desired but not mandated)

- Able to swallow the study drug and comply with study requirements.

- Patients must have normal organ and marrow function as defined below:

- Testosterone ≥ 50 ng/dL per laboratory reference range

- Baseline Post-RP PSA ≤ 0.4

- Hemoglobin ≥ 10.0 g/dL independent of transfusion

- Absolute neutrophil count ≥1,500/mcL

- Platelet count ≥100,000/ìL

- Serum albumin ≥ 3.5 g/dL

- Serum potassium ≥ 3.5 mmol/L

- Liver function: serum bilirubin < 1.5 x ULN (except for patients with documented
Gilbert's disease) and AST or ALT < 2.5 x ULN

Exclusion Criteria:

- Severe concurrent disease, infection, or co-morbidity that, in the judgment of the
investigator, would make the patient inappropriate for enrollment

- Prior radiotherapy to the prostate or pelvis (related to prostate cancer). Concurrent
adjuvant radiation therapy is permitted once patient has been enrolled on trial.

- Prior use of Abiraterone acetate or cytotoxic chemotherapy for prostate cancer

- Prior androgen deprivation with Luteinizing hormone-releasing hormone (LHRH) is
permitted provided that testosterone levels prior to study entry have recovered to
normal limits per reference laboratory.

- No prior anti-androgen therapy (bicalutamide, flutamide or Nilutamide) is permitted

- Prior use of 5-alpha reductase inhibitors is permitted provided such medications were
stopped 7-14 days prior to enrollment

- 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 greater
than the equivalent of 10 mg of prednisone per day within 2 weeks of enrollment

- Active unresolved infection

- Known history of central nervous system (CNS) metastases

- Patients must have no known history of HIV

- Evidence of metastatic disease as evidenced by a CT or MRI of abdomen and pelvis
and/or whole body bone scan (WBS). To be done prior to treatment start and up to 4
months prior to radical prostatectomy date.

- History of seizure or any condition that may predispose to seizure (e.g., prior
cortical stroke, significant brain trauma). Also, history of loss of consciousness or
transient ischemic attack within 12 months of enrollment.

- Clinically significant cardiovascular disease including:

- Myocardial infarction within 6 months prior to Screening;

- Uncontrolled angina within 3 months prior to Screening;

- Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or
patients with history of congestive heart failure NYHA class 3 or 4 in the past,
unless a screening echocardiogram (ECHO) or multi-gated acquisition scan (MUGA)
performed within 3 months results in a left ventricular ejection fraction that is
≥ 45%

- History of clinically significant ventricular arrhythmias (e.g., ventricular
tachycardia, ventricular fibrillation, torsades de pointes)

- History of Mobitz II second degree or third degree heart block without a
permanent pacemaker in place

- Hypotension as indicated by systolic blood pressure < 86 mmHg at the Screening
visit

- Bradycardia as indicated by a heart rate of < 50 beats per minute on the
Screening ECG

- Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or
diastolic blood pressure > 105 mmHg at the Screening visit

- Gastrointestinal disorder affecting absorption (e.g., Gastrectomy, active peptic ulcer
disease within last 3 months)

- Any condition or reason that, in the opinion of the Investigator, interferes with the
ability of the patient to participate in the trial, which places the patient at undue
risk, or complicates the interpretation of safety data.

- The effects of enzalutamide on the developing human fetus at the recommended
therapeutic doses are unknown. Thus, men must agree to use adequate contraception
(barrier method of birth control or abstinence) prior to study entry, for the duration
of study participation, and for 6 months after the usage of enzalutamide. Should the
patient's partner become pregnant or suspect she is pregnant while the patient is
participating in this study, the patient should inform his treating physician
immediately.