An Efficacy and Safety Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Chinese Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)

Inclusion Criteria:

Double Blind treatment Phase:

• Subject is diagnosed with histologically or cytologically confirmed adenocarcinomaof the prostate without neuroendocrine differentiation, signet cell or small cellhistology.

• Subject has metastatic prostate cancer documented by positive bone scan (for bonedisease) or measurable metastatic lesions on computed tomography (CT) or magneticresonance imaging (MRI) scan (for soft tissue). Subjects whose disease spread islimited to regional pelvic lymph nodes are not eligible.

• Once randomized at day 1, subject must maintain androgen deprivation therapy (ADT)with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist duringstudy treatment or have a history of bilateral orchiectomy (i.e., medical orsurgical castration).

• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.

• Subject has an estimated life expectancy of ≥ 12 months.

• Subject is able to swallow the study drug and comply with study requirements.

• A sexually active male subject with female partner(s) who is of childbearingpotential is eligible if:

• Agrees to use a male condom starting at screening and continue throughout thestudy treatment and for at least 3 months after the last dose of study drug. Ifthe male subject has not had a vasectomy or is not sterile at least 6 monthsprior to screening his female partner(s) is utilizing 1 form of highlyeffective birth control per locally accepted standards starting at screeningand continue throughout study treatment and for at least 3 months after themale subject receives his last dose of study drug.

• Subject must agree to abstinence or use a condom throughout the study period and forat least 3 months after the last dose of study drug if engaging in sexualintercourse with a pregnant or breastfeeding partner(s).

• Subject must agree not to donate sperm from first dose of study drug through 3months after the last dose of study drug.

• Subject agrees not to participate in another interventional study while ontreatment.

Open Label Phase:

• Before the sponsor's formal determination on study-wide unblinding, includes thesubject who has evidence of radiographic progression as confirmed during thedouble-blind treatment (only apply to the subject in the placebo arm).

• Subject has not met any of the discontinuation criteria in the main protocol.Subject in the placebo arm who achieved confirmed radiographic progression in thedouble-blinded period is eligible.

• Subject is willing to maintain ADT with LHRH agonist or antagonist or has had abilateral orchiectomy

• Subject is able to swallow enzalutamide capsules whole and to comply with studyrequirements throughout the study

• Subject and subject's female partner agree to follow contraception and spermdonation requirements in main protocol

• IRB-/IEC-approved written informed consent and privacy language as per nationalregulations must be obtained from the subject or legally authorized representativeprior to any study-related procedures (including withdrawal of prohibitedmedication, if applicable).

• Subject is considered an adult according to local regulation at the time of signinginformed consent.

• After the sponsor's formal determination on study-wide unblinding, includes thesubject who is randomized to receive treatment in the double-blind period (apply toall subjects).

Exclusion Criteria:

Double-Blind Treatment Phase:

• Subject has received any prior pharmacotherapy, radiation therapy or surgery formetastatic prostate cancer (the following exceptions are permitted):

• Up to 3 months of ADT with LHRH agonists or antagonists or orchiectomy with orwithout concurrent antiandrogens prior to day 1, with no radiographic evidenceof disease progression or rising prostate-specific antigen (PSA) levels priorto day 1;

• Subject may have 1 course of palliative radiation or surgical therapy to treatsymptoms resulting from metastatic disease if it was administered at least 4weeks prior to day 1;

• Up to 6 cycles of docetaxel therapy with final treatment administrationcompleted within 2 months of day 1 and no evidence of disease progressionduring or after the completion of docetaxel therapy;

• Up to 6 months of ADT with LHRH agonists or antagonists or orchiectomy with orwithout concurrent antiandrogens prior to day 1 if subject was treated withdocetaxel, with no radiographic evidence of disease progression or rising PSAlevels prior to day 1;

• Prior ADT given for < 39 months in duration and > 9 months before randomizationas neoadjuvant/adjuvant therapy.

• Subject had a major surgery within 4 weeks prior to day 1.

• Subject received treatment with 5-α reductase inhibitors (finasteride, dutasteride)within 4 weeks prior to day 1.

• Subject received treatment with estrogens, cyprotoerone acetate or androgens within 4 weeks prior to day 1.

• Subject received treatment with systemic glucocorticoids greater than the equivalentof 10 mg per day of prednisone within 4 weeks prior to day 1, intended for thetreatment of prostate cancer.

• Subject received treatment with herbal medications that have known hormonalantiprostate cancer activity and/or are known to decrease PSA levels within 4 weeksprior to day 1.

• Subject received prior aminoglutethimide, ketoconazole, abiraterone acetate orenzalutamide for the treatment of prostate cancer or participation in a clinicalstudy of an investigational agent that inhibits the androgen receptor or androgensynthesis (e.g., TAK-700, ARN-509, ODM-201).

• Subject received investigational agent within 4 weeks prior to day 1.

• Subject has known or suspected brain metastasis or active leptomeningeal disease.

• Subject has a history of another invasive cancer within 3 years of screening, withthe exception of fully treated cancers with a remote probability of recurrence.

• Subject has absolute neutrophil count < 1500/μL, platelet count < 100000/μL orhemoglobin < 10 g/dL (6.2 mmol/L) at screening. NOTE: May not have received anygrowth factors within 7 days or blood transfusions within 28 days prior to thehematology values obtained at screening.

• Subject has total bilirubin ≥ 1.5 x the upper limit of normal (except subjects withdocumented Gilbert's disease), or alanine aminotransferase or aspartateaminotransferase ≥ 2.5 x the upper limit of normal at screening.

• Subject has creatinine > 2 mg/dL (177 μmol/L) at screening.

• Subject has albumin < 3.0 g/dL (30 g/L) at screening.

• Subject has a history of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke or significant brain trauma, brain arteriovenousmalformation).

• Subject has history of loss of consciousness or transient ischemic attack within 12months prior to day 1.

• Subject has clinically significant cardiovascular disease, including the following:

• Myocardial infarction within 6 months prior to screening;

• Unstable angina within 3 months prior to screening;

• New York Heart Association class III or IV congestive heart failure or ahistory of New York Heart Association class III or IV congestive heart failureunless a screening echocardiogram or multigated acquisition scan performedwithin 3 months before the randomization date demonstrates a left ventricularejection fraction ≥ 45%;

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

• History of Mobitz II second-degree or third-degree heart block without apermanent 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 thescreening electrocardiogram;

• Uncontrolled hypertension as indicated by a minimum of 2 consecutive bloodpressure measurements showing systolic blood pressure > 170 mm Hg or diastolicblood pressure > 105 mm Hg at screening.

• Subject has gastrointestinal disorder affecting absorption.

• Subject has any concurrent disease, infection or comorbid condition that interfereswith the ability of the subject to participate in the study, which places thesubject at undue risk or complicates the interpretation of data.

• Subject received bisphosphonates or denosumab within 2 weeks prior to day 1 unlessadministered at stable dose or to treat diagnosed osteoporosis.

• Subject has shown a hypersensitivity reaction to the active pharmaceuticalingredient or any of the study capsule components.

Open-Label Phase:

• Subject has taken commercially available enzalutamide

• After unblinding, subject has started any new investigational agent oranti-neoplastic therapy intended to treat prostate cancer

• Subject has any clinically significant disorder or condition including excessivealcohol or drug abuse, or secondary malignancy, which may interfere with studyparticipation in the opinion of the investigator or medical monitor

• Subject has current or previously treated brain metastasis or active leptomeningealdisease

• Subject has a history of seizure or any condition that may increase the risk ofseizure

• Subject's disease has progressed radiographically during the double-blind period ofthe study and treatment with study drug was stopped prior to study-wide unblinding. (Note: Subject who progressed radiographically while in the double-blind period ofthe study and continued treatment per protocol is allowed to participate in theopen-label phase.)