A Study of Enzalutamide Versus Bicalutamide in Castrate Men With Metastatic Prostate Cancer

An open-label period was added to the main protocol. Following unblinding at the end of the
double-blind period and demonstration of a statistically significant advantage of
enzalutamide over bicalutamide as assessed by the primary endpoint, all ongoing enzalutamide
treated participants and ongoing or previous bicalutamide treated participants that met entry
criteria were offered open-label enzalutamide at the discretion of the participant and study
investigators.

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the prostate without neuroendocrine
differentiation or small cell features

- Ongoing androgen deprivation therapy with a Luteinizing Hormone Receptor Hormone
(LHRH) agonist or antagonist at a stable dose and schedule within 4 weeks of
randomization or bilateral orchiectomy (i.e., surgical or medical castration)

- Metastatic disease documented by one of the following:

- At least two bone lesions on bone scan, or

- Soft tissue disease documented by computed tomography (CT)/ magnetic resonance
imaging (MRI), or

- Unequivocal pelvic adenopathy short axis > 2.0 cm in diameter by CT/MRI

- Progressive disease at study entry defined as one or more of the following three
criteria occurring in the setting of castrate levels of testosterone:

- Prostate Specific Antigen (PSA) progression defined by a minimum of three rising
PSA levels with an interval of ≥ 1 week between each determination. The PSA value
should be ≥ 2 µg/L (2 ng/mL);

- Soft tissue disease progression defined by Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1;

- Bone disease progression defined by two or more new lesions on bone scan

- Asymptomatic or mildly symptomatic from prostate cancer (i.e. the score on the Brief
Pain Inventory-Short Form (BPI-SF) Question #3 must be < 4); no use of opiate
analgesics for prostate cancer-related pain currently or anytime within 4 weeks prior
to randomization

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, including
subjects with decreased performance status not attributed to progressive and
symptomatic prostate cancer

- Estimated life expectancy of ≥ 12 months

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

- A male subject and his female spouse/partner who is of childbearing potential must use
two acceptable methods of birth control (one of which must include a condom as a
barrier method of contraception) starting at Screening and continuing throughout the
study period, and for 3 months after final study drug administration. Two acceptable
forms of birth control include:

1. Condom (barrier method of contraception), AND

2. In addition to a condom, one of the following acceptable forms of contraception
is required:

- Established use of oral, injected or implanted hormonal methods of
contraception.

- Placement of an intrauterine device (IUD) or intrauterine system (IUS).

- Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault
caps) with spermicidal foam/gel/film/cream/suppository.

- Tubal ligation for at least 6 months prior to Screening

- Vasectomy or other surgical castration at least 6 months prior to Screening

Exclusion Criteria:

- Prior cytotoxic chemotherapy for prostate cancer

- Severe concurrent disease, infection, or comorbidity that would make the subject
inappropriate for enrollment

- Known or suspected brain and/or skull metastasis or active epidural disease

- History of another malignancy within the previous 5 years other than curatively
treated non-melanomatous skin cancer

- Current or prior treatment with estrogens and/or drugs with anti-androgenic properties
such as spironolactone > 50 mg/day, or progestational agents for the treatment of
prostate cancer within 6 months prior to randomization

- Current or prior use of ketoconazole for the treatment of prostate cancer

- Use of antiandrogens within 6 weeks prior to randomization

- Documented prior disease progression while receiving antiandrogens. Disease
progression defined as PSA progression, radiographic progression and/or clinical
deterioration.

- Current or prior treatment with 5-α reductase inhibitors or anabolic steroids within 6
months prior to randomization

- Prior use of systemic glucocorticoids (the equivalent of 10 mg of prednisone) within 3
months prior to randomization or expectation of their use during the study

- Radiation therapy to bone lesions or prostatic bed within 4 weeks prior to
randomization

- Major surgery within 2 months prior to randomization

- History of seizure including febrile seizure or any condition that may predispose to
seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss
of consciousness requiring hospitalization). Also, current or prior treatment with
anti-epileptic medications for the treatment of seizures or history of loss of
consciousness or transient ischemic attack within 12 months prior to randomization

- Clinically significant cardiovascular disease including myocardial infarction within
past six months or uncontrolled angina within past three months