A Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)
Condition: Metastatic Hormone Sensitive Prostate Cancer
MeSH terms: Prostatic Neoplasms; Hypersensitivity
Intervention: Enzalutamide; Placebo
Intervention description: Oral; Oral
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1150.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Androgen Deprivation Therapy (ADT); Metastatic hormone sensitive prostate cancer; Xtandi; Enzalutamide

Summary:

      The purpose of this study was to evaluate the efficacy of enzalutamide plus androgen
      deprivation therapy (ADT) as measured by radiographic progression-free survival (rPFS) based
      on central review. The study also evaluated the safety of enzalutamide plus ADT in mHSPC.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject is considered an adult according to local regulation at the time of signing
             informed consent.

          -  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 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 ADT with an 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.

        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 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

        Exclusion Criteria:

          -  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 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 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 or
             hemoglobin < 10 g/dL (6.2 mmol/L).

          -  Subject has total bilirubin (TBL) ≥ 1.5 x the upper limit of normal (ULN) (except
             subjects with documented Gilbert's disease), or alanine aminotransferase (ALT) or
             aspartate 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 12
             months prior to day 1.

          -  Subject has clinically significant cardiovascular disease.

          -  Subject received bisphosphonates or denosumab within 2 weeks prior to day 1 unless
             administered 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 of
             the study and treatment with study drug was stopped prior to study-wide unblinding.
             (Note: Subjects who progressed radiographically while in the double-blind portion of
             the study and continued treatment per protocol are allowed to participate in the open
             label extension.)

          -  After study-wide 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

          -  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