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 adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell or small cell histology.
• Subject has metastatic prostate cancer documented by positive bone scan (for bone disease) or measurable metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI) scan (for soft tissue). Subjects whose disease spread is limited 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 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 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 childbearing potential is eligible if:

• Agrees to use a male condom starting at screening and continue throughout the study treatment and for at least 3 months after the last dose of study drug. If the male subject has not had a vasectomy or is not sterile at least 6 months prior to screening his female partner(s) is utilizing 1 form of highly effective birth control per locally accepted standards starting at screening and continue throughout study treatment and for at least 3 months after the male subject receives his last dose of study drug.
• Subject must agree to abstinence or use a condom throughout the study period and for at least 3 months after the last dose of study drug if engaging in sexual intercourse with a pregnant or breastfeeding partner(s).
• Subject must agree not to donate sperm from first dose of study drug through 3 months after the last dose of study drug.
• Subject agrees not to participate in another interventional study while on treatment.

Open Label Phase:

• Before the sponsor's formal determination on study-wide unblinding, includes the subject who has evidence of radiographic progression as confirmed during the double-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 the double-blinded period is eligible.
• Subject is willing to maintain ADT with LHRH agonist or antagonist or has had a bilateral orchiectomy
• Subject is able to swallow enzalutamide capsules whole and to comply with study requirements throughout the study
• Subject and subject's female partner agree to follow contraception and sperm donation requirements in main protocol
• IRB-/IEC-approved written informed consent and privacy language as per national regulations must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
• Subject is considered an adult according to local regulation at the time of signing informed consent.
• After the sponsor's formal determination on study-wide unblinding, includes the subject who is randomized to receive treatment in the double-blind period (apply to all subjects).

Exclusion criteria

Double-Blind Treatment Phase:

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

• Up to 3 months of ADT with LHRH agonists or antagonists or orchiectomy with or without concurrent antiandrogens prior to day 1, with no radiographic evidence of disease progression or rising prostate-specific antigen (PSA) levels prior to day 1;
• Subject may have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to day 1;
• Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of day 1 and no evidence of disease progression during or after the completion of docetaxel therapy;
• Up to 6 months of ADT with LHRH agonists or antagonists or orchiectomy with or without concurrent antiandrogens prior to day 1 if subject was treated with docetaxel, with no radiographic evidence of disease progression or rising PSA levels prior to day 1;
• Prior ADT given for < 39 months in duration and > 9 months before randomization as 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 equivalent of 10 mg per day of prednisone within 4 weeks prior to day 1, intended for the treatment of prostate cancer.
• Subject received treatment with herbal medications that have known hormonal antiprostate cancer activity and/or are known to decrease PSA levels within 4 weeks prior to day 1.
• Subject received prior aminoglutethimide, ketoconazole, abiraterone acetate or enzalutamide for the treatment of prostate cancer or participation in a clinical study of an investigational agent that inhibits the androgen receptor or androgen synthesis (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, with the exception of fully treated cancers with a remote probability of recurrence.
• Subject has absolute neutrophil count < 1500/μL, platelet count < 100000/μL or hemoglobin < 10 g/dL (6.2 mmol/L) at screening. NOTE: May not have received any growth factors within 7 days or blood transfusions within 28 days prior to the hematology values obtained at screening.
• Subject has total bilirubin ≥ 1.5 x the upper limit of normal (except subjects with documented Gilbert's disease), or alanine aminotransferase or aspartate aminotransferase ≥ 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 arteriovenous malformation).
• Subject has history of loss of consciousness or transient ischemic attack within 12 months 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 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 (e.g., 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;
• 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.
• Subject has gastrointestinal disorder affecting absorption.
• Subject has any concurrent disease, infection or comorbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data.
• Subject received bisphosphonates or denosumab within 2 weeks prior to day 1 unless administered at stable dose or to treat diagnosed osteoporosis.
• Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient 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 or anti-neoplastic therapy intended to treat prostate cancer
• Subject has any clinically significant disorder or condition including excessive alcohol or drug abuse, or secondary malignancy, which may interfere with study participation in the opinion of the investigator or medical monitor
• Subject has current or previously treated brain metastasis or active leptomeningeal disease
• Subject has a history of seizure or any condition that may increase the risk of seizure
• Subject's disease has progressed radiographically during the double-blind period of the study and treatment with study drug was stopped prior to study-wide unblinding. (Note: Subject who progressed radiographically while in the double-blind period of the study and continued treatment per protocol is allowed to participate in the open-label phase.)