A Study of Enzalutamide Re-treatment in Metastatic Castration-resistant Prostate Cancer After Docetaxel and/or Cabazitaxel Treatment

Participants received treatment with open-label enzalutamide, until radiographic or clinical
progression (such as pathological fracture, cord compression, worsened pain requiring
radiation therapy, or opioid analgesic dose increase or initiation), or unacceptable
toxicity. Participants were to be allowed to continue enzalutamide until the next treatment
was initiated. If another non-cytotoxic, non-investigational, antineoplastic agent was
initiated after protocol-defined progression had been determined, enzalutamide was to be
continued as long as the participant was tolerating enzalutamide and continued androgen
deprivation therapy. Participants were to have a safety follow-up visit approximately 30 days
following the last dose of study drug or prior to the initiation of a subsequent anti-cancer
drug or investigational agent, whichever occurred first. Disease progression and survival
were to be followed every 12 weeks for a maximum of 3 years from first dose. The study should
have ended when the last participant has been followed for 1 year from the date of first
dose, but the study was terminated and results up to the last date of evaluation (15 March
2017) are reflected in this disclosure.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the prostate without
signet ring cell features.

- Presence of metastatic disease (M1) as assessed by computed tomography/ magnetic
resonance imaging (CT/MRI) and/or whole-body radionuclide bone scan.

- Subject has been previously treated with enzalutamide for at least 8 months, and
stopped enzalutamide due to progressive disease (not due to adverse events), followed
by at least 4 cycles of docetaxel and/or cabazitaxel chemotherapy, with or without
other intervening anti-cancer therapies (including but not limited to
aminoglutethimide, ketoconozole, abiraterone acetate, Rad-223, or sipuleucel-T), prior
to receiving chemotherapy. Note: for patients who receive sequential taxanes, there
must not have been progressive disease upon ending the first taxane, or use of any
anti-cancer agents between the two taxanes.

- Ongoing androgen deprivation therapy with an gonadotropin releasing hormone (GnRH)
analogue or prior bilateral orchiectomy (medical or surgical castration). For patients
who have not had bilateral orchiectomy, there must be a plan to maintain effective
GnRH-analogue for the duration of the trial.

- Testosterone ≤ 1.73 nmol/L (≤ 50 ng/dL) at screening.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at screening.

- Estimated life expectancy of ≥ 6 months at screening.

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

- Throughout study, male subject and a female partner who is of childbearing potential
must use 2 acceptable methods of birth control (1 of which must include a condom
barrier method of contraception) starting at screening and continuing throughout the
study period and for 3 months after final study drug administration. Two acceptable
methods of birth control thus include the following:

- Condom (barrier method of contraception) AND

- One of the following is required:

- Established use of oral, injected, or implanted hormonal method of contraception
by the female partner performed at least 6 months before screening;

- Placement of an intrauterine device or intrauterine system by the female partner;

- Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) with
spermicidal foam/gel/film/cream/suppository by the female partner;

- Tubal ligation in the female partner.

- Vasectomy or other procedure resulting in infertility (e.g., bilateral
orchiectomy), performed at least 6 months before screening

- Must not donate sperm from screening through 3 months after final study drug
administration.

Exclusion Criteria:

- Known or suspected neuroendocrine/small cell feature.

- Use of any antineoplastic treatment post-chemotherapy, including but not limited to
aminoglutethimide, ketoconozole, abiraterone acetate, Rad-223, sipuleucel-T, or
enzalutamide. Continuing steroids is permitted.

- Palliative radiation therapy within 2 weeks of Day 1, or within 4 weeks of Day 1 if a
radionuclide was utilized.

- Use of an investigational agent within 4 weeks of Day 1 visit.

- Major surgery within 4 weeks prior to Day 1 visit.

- History of seizure or any condition that may predispose to seizures (e.g., prior
cortical stroke or significant brain trauma) at any time in the past. History of loss
of consciousness or transient ischemic attack within 12 months of screening.

- History of clinically significant cardiovascular disease including:

- Myocardial infarction or uncontrolled angina within 3 months;

- History of congestive heart failure New York Heart Association (NYHA) class 3 or
4 in the past, unless a screening echocardiogram or multi-gated acquisition scan
performed within three 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.

- Clinically significant cardiovascular disease at screening including:

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

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

- 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.

- Subject has a known or suspected hypersensitivity to enzalutamide or any components of
the formulation used.

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

- Known or suspected brain metastasis or leptomeningeal disease.

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

- Absolute neutrophil count < 1,500/μL, platelet count < 75,000/μL, or hemoglobin < 5.6
mmol/L (9 g/dL) at screening.

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

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

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

- Treatment with abiraterone acetate prior to enzalutamide for metastatic castration -
resistant prostate cancer (mCRPC) in the prechemotherapy setting. (Note: Patients who
have received concomitant enzalutamide and abiraterone acetate therapies are not
excluded).