A Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)

Inclusion Criteria:

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

• 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 metastatic lesions on computed tomography (CT) or magnetic resonanceimaging (MRI) scan (for soft tissue). Subjects whose disease spread is limited toregional pelvic lymph nodes are not eligible.

• Once randomized at day 1, subject must maintain ADT with an LHRH agonist orantagonist during study treatment or have a history of bilateral orchiectomy (i.e.,medical or surgical castration).

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

Inclusion Criteria for Open-Label Extension:

• Subject received randomized double-blind treatment in ARCHES

• Subject has not met any of the discontinuation criteria in the main ARCHES protocol

• 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

Exclusion Criteria:

• 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 PSA levels prior to 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 AR or androgen synthesis (e.g.,TAK-700, ARN-509, ODM-201).

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

• Subject has absolute neutrophil count < 1500/μL, platelet count < 100000/μL orhemoglobin < 10 g/dL (6.2 mmol/L).

• Subject has total bilirubin (TBL) ≥ 1.5 x the upper limit of normal (ULN) (exceptsubjects with documented Gilbert's disease), or alanine aminotransferase (ALT) oraspartate aminotransferase (AST) ≥ 2.5 x the ULN .

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

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

• Subject has a history of seizure or any condition that may predispose to seizure.

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

• Subject has clinically significant cardiovascular disease.

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

Exclusion Criteria for Open-Label Extension:

• Subject has taken commercially available enzalutamide (Xtandi).

• 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: Subjects who progressed radiographically while in the double-blind portion ofthe study and continued treatment per protocol are allowed to participate in theopen label extension.)

• After study-wide 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

• 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