A Randomized Study of Enzalutamide in Patients With Localized Prostate Cancer Undergoing Active Surveillance

This is a multicenter, randomized, open label exploratory study, conducted in the US and
Canada, evaluating the efficacy and safety of enzalutamide for extension of time to prostate
cancer progression (pathological or therapeutic) in patients with clinically localized,
histologically proven prostate cancer that is categorized as low risk or intermediate risk
and who are under AS.

Inclusion Criteria:

- Histologically proven adenocarcinoma of the prostate diagnosed (with ≥10 core biopsy)
within 6 months of screening. The biopsy that was used for this diagnosis must be
submitted for central pathology review.

- Prostate cancer categorized (as determined by central pathology review) as low risk is
defined as T1c-T2a, PSA<10, N0, M0 (or presumed N0, M0 if CT/bone scan not done due to
low risk of metastases), GS ≤ 6, ECOG status ≤2 and estimated life expectancy >5 years
OR intermediate risk is defined as T2b-T2c, PSA<20, N0, M0 (or presumed N0, M0 if
CT/bone scan not done), GS ≤7 (3+4 pattern only), ECOG status ≤ 2 and estimated life
expectancy > 5 years. Prostate cancer categorized (as determined by central pathology
review) to the very low risk category (T1c, GS ≤6, PSA <10 ng/mL, fewer than 3
prostate biopsy cores positive,

≤50% cancer in any core, PSA density <0.15 ng/mL/g) is not included.

- Ability to swallow study drugs and to comply with study requirements throughout the
study

- Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written
Informed Consent and privacy language as per national regulations must be obtained
from the subject or legally authorized representative prior to any study-related
procedures

- Throughout study, male subject and a female partner who is of childbearing potential
must use two acceptable methods of birth control (one of which must include a condom
barrier method of contraception) starting at screening and continuing throughout the
study period and for three months after the final study drug administration. Two
acceptable methods of birth control thus include the following:

1. Condom (barrier method of contraception) AND

2. One of the following is required:

i. Established use of oral, injected or implanted hormonal methods of contraception by
the female partner; ii. Placement of an intrauterine device or intrauterine system by
the female partner; iii. Additional barrier method: Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam / gel / film / cream / suppository by the
female partner; iv. Tubal ligation in the female partner.

- Must not donate sperm starting at screening throughout the study period and for 90
days after the final study drug administration.

Exclusion Criteria:

- Prior radiotherapy, surgery, chemotherapy, or hormonal therapy for prostate cancer

- Very low risk category (T1c, GS ≤6, PSA <10 ng/mL, fewer than 3 prostate biopsy cores
positive, ≤50% cancer in any core, PSA density <0.15 ng/mL/g)

- Prior transurethral resection of the prostate or prior transurethral microwave
thermotherapy of the prostate

- Use of oral glucocorticoids within 1 month of screening

- Use of 5 alpha reductase inhibitor within 1 month of screening or total use, within
the last two years prior to screening, of >3 months

- Presence of metastatic disease

- History of seizure or any condition that may predispose to seizures at any time in the
past. History of loss of consciousness or transient ischemic attack within 12 months
of screening

- Absolute neutrophil count < 1,500/μL, platelet count < 100,000/μL, or hemoglobin < 6.2
mmol/L (10 g/dL) at screening

- Total bilirubin >1.5 times the upper limit of normal (ULN) or alanine aminotransferase
(ALT) or aspartate aminotransferase (AST) ≥ 2.5 X ULN at screening

- Creatinine > 177 μmol/L (> 2 mg/dL) at screening

- Albumin < 30 g/L (3.0 g/dL) at screening

- Major surgery within 4 weeks prior to Randomization Visit

- Clinically significant cardiovascular disease including:

1. Myocardial infarction or uncontrolled angina within 6 months

2. Congestive heart failure New York Heart Association (NYHA) class 3 or 4

3. History of clinically significant ventricular arrhythmias

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

5. Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury
(mm Hg) at screening

6. Bradycardia as indicated by a heart rate of < 45 beats per minute on the
screening electrocardiogram (ECG) and on physical examination

7. Uncontrolled hypertension as indicated by at least 2 consecutive measurements of
a resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 105
mmHg at the Screening Visit

- Known hypersensitivity to enzalutamide or any of its components.

- Subject has received investigational therapy within 28 days or 5 half lives, whichever
is longer, prior to screening