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)
Condition: Metastatic Hormone Sensitive Prostate Cancer
MeSH terms: Prostatic Neoplasms; Hypersensitivity
Intervention: Enzalutamide; Placebo; Androgen deprivation therapy (ADT)
Intervention description: Oral; Oral; All participants were required to maintain ADT during study treatment, either using luteinizing hormone-releasing hormone (LHRH) agonist/antagonist or having a history of bilateral orchiectomy.
Intervention MeSH terms: Androgens
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 180.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Metastatic hormone sensitive prostate cancer; Androgen Deprivation Therapy (ADT); Xtandi; MDV3100; Enzalutamide

Summary:

      The purpose of this study was to evaluate the efficacy and safety of enzalutamide plus
      androgen deprivation therapy (ADT) versus placebo plus ADT in Chinese subjects with
      metastatic hormone sensitive prostate cancer (mHSPC). The study was conducted in two phases:
      Double-Blind treatment phase and open-label phase.
    

Eligibility criteria:

        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.)