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

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.

Following unblinding at the end of the double-blind period and demonstration of a statistically significant advantage of enzalutamide over placebo when added to ADT as assessed by the primary endpoint of rPFS, subjects were eligible to transition to an open-label portion of the study.

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