A Study of Enzalutamide Versus Bicalutamide in Castrate Men With Metastatic Prostate Cancer

A Randomized, Double-Blind, Phase II, Efficacy and Safety Study of MDV3100 Versus Bicalutamide in Castrate Men With Metastatic Prostate Cancer

The purpose of this study was to determine the efficacy and safety of oral enzalutamide compared to bicalutamide in castrate men with metastatic prostate cancer who have progressed while on Luteinizing Hormone Receptor Hormone (LHRH) agonist/antagonist or after receiving a bilateral orchiectomy.

An open-label period was added to the main protocol. Following unblinding at the end of the double-blind period and demonstration of a statistically significant advantage of enzalutamide over bicalutamide as assessed by the primary endpoint, all ongoing enzalutamide treated participants and ongoing or previous bicalutamide treated participants that met entry criteria were offered open-label enzalutamide at the discretion of the participant and study investigators.

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features

• Ongoing androgen deprivation therapy with a Luteinizing Hormone Receptor Hormone (LHRH) agonist or antagonist at a stable dose and schedule within 4 weeks of randomization or bilateral orchiectomy (i.e., surgical or medical castration)

• Metastatic disease documented by one of the following:

  • At least two bone lesions on bone scan, or
  • Soft tissue disease documented by computed tomography (CT)/ magnetic resonance imaging (MRI), or
  • Unequivocal pelvic adenopathy short axis > 2.0 cm in diameter by CT/MRI

• Progressive disease at study entry defined as one or more of the following three criteria occurring in the setting of castrate levels of testosterone:

  • Prostate Specific Antigen (PSA) progression defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value should be ≥ 2 µg/L (2 ng/mL);
  • Soft tissue disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1;
  • Bone disease progression defined by two or more new lesions on bone scan

• Asymptomatic or mildly symptomatic from prostate cancer (i.e. the score on the Brief Pain Inventory-Short Form (BPI-SF) Question #3 must be < 4); no use of opiate analgesics for prostate cancer-related pain currently or anytime within 4 weeks prior to randomization

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, including subjects with decreased performance status not attributed to progressive and symptomatic prostate cancer

• Estimated life expectancy of ≥ 12 months

• Able to swallow the study drug and comply with study requirements

• A male subject and his female spouse/partner who is of childbearing potential must use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at Screening and continuing throughout the study period, and for 3 months after final study drug administration. Two acceptable forms of birth control include:

  1. Condom (barrier method of contraception), AND

  2. In addition to a condom, one of the following acceptable forms of contraception is required:

     • Established use of oral, injected or implanted hormonal methods of contraception.
     • Placement of an intrauterine device (IUD) or intrauterine system (IUS).
     • Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
     • Tubal ligation for at least 6 months prior to Screening
     • Vasectomy or other surgical castration at least 6 months prior to Screening

Exclusion Criteria:

• Prior cytotoxic chemotherapy for prostate cancer
• Severe concurrent disease, infection, or comorbidity that would make the subject inappropriate for enrollment
• Known or suspected brain and/or skull metastasis or active epidural disease
• History of another malignancy within the previous 5 years other than curatively treated non-melanomatous skin cancer
• Current or prior treatment with estrogens and/or drugs with anti-androgenic properties such as spironolactone > 50 mg/day, or progestational agents for the treatment of prostate cancer within 6 months prior to randomization
• Current or prior use of ketoconazole for the treatment of prostate cancer
• Use of antiandrogens within 6 weeks prior to randomization
• Documented prior disease progression while receiving antiandrogens. Disease progression defined as PSA progression, radiographic progression and/or clinical deterioration.
• Current or prior treatment with 5-α reductase inhibitors or anabolic steroids within 6 months prior to randomization
• Prior use of systemic glucocorticoids (the equivalent of 10 mg of prednisone) within 3 months prior to randomization or expectation of their use during the study
• Radiation therapy to bone lesions or prostatic bed within 4 weeks prior to randomization
• Major surgery within 2 months prior to randomization
• History of seizure including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). Also, current or prior treatment with anti-epileptic medications for the treatment of seizures or history of loss of consciousness or transient ischemic attack within 12 months prior to randomization
• Clinically significant cardiovascular disease including myocardial infarction within past six months or uncontrolled angina within past three months