A Phase 3, Randomized, Efficacy and Safety Study of Enzalutamide Plus
Leuprolide, Enzalutamide Monotherapy, and Placebo Plus Leuprolide in Men
With High-Risk Nonmetastatic Prostate Cancer Progressing After Definitive
Therapy.

1. Age 18 years or older and willing and able to provide informed consent.
2. Histologically or cytologically confirmed adenocarcinoma of the
prostate at initial biopsy, without neuroendocrine differentiation, signetcell,
or small cell features.
3. Prostate cancer initially treated by radical prostatectomy or
radiotherapy (including brachytherapy) or both, with curative intent.
Prostate cryoablation is not considerd definitive therapy for this study, but
its prior to use is not exlusionary
4. PSA doubling time <= 9 months as calculated by the sponsor.
5. Screening PSA by the central laboratory >= 1 ng/mL for patients who had
radical prostatectomy (with or without radiotherapy) as primary treatment for
prostate cancer and at least 2 ng/mL above the nadir for patients who had
radiotherapy only as primary treatment for prostate cancer.
6. Serum testosterone >= 150 ng/dL (5.2 nmol/L) at screening.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1 at screening.
8. Estimated life expectancy of >= 12 months.
9. Able to swallow the study drug and comply with study requirements.
10. Throughout study, the patient and his female partner who is of
childbearing potential must use 2 acceptable methods of birth control (1
of which must include a condom as a barrier method of contraception)
from screening through 3 months after the last dose of study drug or per
local guidelines where these require additional description of
contraceptive methods. Two acceptable methods of birth control thus
include the following:
* Condom (barrier method is required)
AND
* One of the following is required:
- Established and ongoing use of oral, injected, or implanted hormonal
method of contraception by the female partner
- Placement of an intrauterine device or intrauterine system by the
female partner
- Additional barrier method including contraceptive sponge and
occlusive cap (diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/suppository by the female partner
- Tubal ligation in the female partner performed at least 6 months
before screening
- Vasectomy or other procedure resulting in infertility (eg, bilateral
orchiectomy), performed at least 6 months before screening
11. Throughout the study, the patient must use a condom if having sex
with a pregnant woman.
12. Must agree not to donate sperm from first dose of study drug
through 3 months after the last dose of study drug.

1. Prior or present evidence of distant metastatic disease as assessed by
computed tomography (CT) or magnetic resonance imaging (MRI) or chest x-ray for
soft tissue disease and whole-body radionuclide bone scan for bone disease.
Patients with soft tissue pelvic disease may be eligible if the short axis of
the largest lymph node is < 20 mm for lymph nodes below aortic bifurcation. If
the screening bone scan shows a lesion suggestive of metastatic disease, the
patient will be eligible only if a second imaging modality (plain film, CT, or
MRI) does not show bone metastasis. If the imaging results are equivocal or
consistent with metastasis by central radiology review, the patient is not
eligible for enrollment unless otherwise approved by the sponsor.
Positron-emission tomography (PET) is not an evaluable imaging modality for
this study.
2. Prior hormonal therapy. Neoadjuvant/adjuvant therapy to treat prostate
cancer <= 36 months in duration and >= 9 months before randomization, or a single
dose or a short course (<= 6 months) of
hormonal therapy given for rising PSA >= 9 months before randomization is
allowed.
3. Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone
acetate, or enzalutamide for prostate cancer.
4. Prior systemic biologic therapy, including immunotherapy, for prostate
cancer.
5. Major surgery within 4 weeks before randomization date.
6. Treatment with 5-α reductase inhibitors (finasteride, dutasteride) within 4
weeks of randomization.
7. For patients who had a prior prostatectomy, a suitable candidate for salvage
radiotherapy as determined by the investigator in consideration of appropriate
guidelines (eg, American Society for Radiation Oncology / American Urological
Association [ASTRO/AUA]; European Association of
Urology [EAU]).
8. Participation in a clinical study of an investigational agent that inhibits
the androgen receptor or androgen synthesis (eg, TAK-700, ARN-509, ODM-201);
patients who received placebo are allowed.
9. Use of any other investigational agent within 4 weeks before randomization
date.
10. Known or suspected brain metastasis or active leptomeningeal disease.
11. History of another invasive cancer within 3 years before screening, with
the exception of fully treated cancers with a remote probability of recurrence.
The medical monitor and investigator must agree that the possibility of
recurrence is remote.
12. Absolute neutrophil count < 1500/µL, platelet count < 100,000/µL,
or hemoglobin < 10 g/dL (6.2 mmol/L) at screening. NOTE: May not
have received any growth factors or blood transfusions within 7 days
before the hematology values obtained at screening.
13. Total bilirubin (TBili) >= 1.5-times the upper limit of normal (except
patients
with documented Gilbert's disease), or alanine aminotransferase (ALT)
or aspartate aminotransferase (AST) >= 2.5-times the upper limit of
normal at screening.
14. Creatinine > 2 mg/dL (177 µmol/L) at screening.
15. Albumin < 3.0 g/dL (30 g/L) at screening.
16. History of seizure or any condition that may predispose to seizure
(eg, prior cortical stroke or significant brain trauma). History of loss of
consciousness (unless of cardiac origin) or transient ischemic attack
within 12 months before randomization
17. Clinically significant cardiovascular disease including the following:
- Myocardial infarction within 6 months before screening
- Unstable angina within 3 months before screening
- New York Heart Association class III or IV congestive heart failure or a
history of New York Heart Association class III or IV congestive heart
failure unless a screening echocardiogram or multigated acquisition scan
performed within 3 months before the randomization date demonstrates
a left ventricular ejection fraction >= 45%
- History of clinically significant ventricular arrhythmias (eg, sustained
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 mm Hg at
screening
- Bradycardia as indicated by a heart rate of <= 45 beats per minute on
the screening electrocardiogram (ECG)
- Uncontrolled hypertension as indicated by a minimum of 2 consecutive
blood pressure measurements showing systolic blood pressure > 170
mm Hg or diastolic blood pressure > 105 mm Hg at screening
18. Gastrointestinal disorder affecting absorption.
19. Hypersensitivity reaction to enzalutamide or any of the capsule
components, including Labrasol, butylated hydroxyanisole, and butylated
hydroxytoluene.
20. Contraindication to the use of leuprolide, such as a previous
hypersensitivity reaction to an LHRH analogue or any of the excipients in
the leuprolide injection.
21. Ongoing drug or alcohol abuse as per investigator judgment.
22. Any concurrent disease, infection, or comorbid condition that interferes
with the ability of the patient to participate in the study, which
places the patient at undue risk, or complicates the interpretation of
data, in the opinion of the investigator or medical monitor.