This randomized phase III trial studies enzalutamide to see how well it works compared to enzalutamide, abiraterone, and prednisone in treating patients with castration-resistant metastatic prostate cancer. Androgens can cause the growth of prostate cancer cells. Drugs, such as enzalutamide, abiraterone acetate, and prednisone, may lessen the amount of androgens made by the body.

Patients are randomized to one of two treatment groups: enzalutamide or enzalutamide, abiraterone and prednisone. Treatment will continue until disease progression or unacceptable toxicity. Patients are followed for clinical outcomes for a maximum of 5 years post study treatment. The primary and secondary objectives are described below.

1. Primary Objective:

   To compare the overall survival of patients with progressive metastatic castration-resistant prostate cancer (CRPC) treated with either enzalutamide only or enzalutamide with abiraterone and prednisone

2. Secondary Objectives:

   • To assess the grade 3 or higher toxicity profile and compare safety by treatment arm.
   • To assess and compare post-treatment prostate-specific antigen (PSA) declines by treatment arm.
   • To compare radiographic progression free survival defined by Prostate Cancer Working Group 2 (PCWG2), and objective response rate, by treatment arm.
   • To test for radiographic progression free survival (rPFS) treatment interaction in predicting overall survival.
   • To assess pre- and post-treatment measures of tumor burden and bone activity using sodium fluoride (NaF) positron emission tomography (PET)/computed tomography (CT) and technetium (Tc) methylene diphosphonate (MDP) bone scintigraphy and correlate these measures with overall survival.
   • To develop and validate prognostic and predictive models of overall survival that include baseline clinical and molecular markers.

Eligibility Criteria:

1. Documentation of Disease - Progressive castration-resistant metastatic prostate cancer with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features

2. Patients must have measurable or non-measurable disease:

   1. Measurable Disease - For visceral or extra nodal lesions to be considered measurable, they must be ≥ 10 mm in one dimension, using spiral CT. For lymph nodes to be considered measurable (ie, target or evaluable lesions), they must be ≥ 20 mm in at least one dimension, using spiral CT.
   2. Non-Measurable Disease - All other lesions, including small lesions (longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT scan) and truly non-measurable lesions. Lesions that are considered non-measurable include bone lesions (only).
   3. Patients with node only disease (ie, no presence of visceral, extra nodal lesions or bone lesions) must have node(s) that measure ≥ 15 mm in short axis.

3. Progressive Disease - Patients must have progressive disease at study entry defined as one or more of the following three criteria that occurred while the patient was on androgen deprivation therapy. For patients enrolling on the basis of soft tissue or bone progression, the baseline scan must show progression relative to a comparison scan. If the comparison scan is not available, the baseline scan report must reference the previous scan to document progression.

   1. PSA progression defined by a minimum of two rising PSA levels with an interval of ≥ 1 week between each determination. Patients who received an anti-androgen must have progression documented by a minimum of two rising PSA levels with an interval of ≥ 1 week between each determination such that at least the second of these rises is ≥ 4 weeks since last flutamide, bicalutamide or nilutamide.

      The PSA value at the screening should be ≥ 2 µg/L (2 ng/mL) .

   2. Soft tissue disease progression defined by the protocol

   3. Bone disease progression defined by the Prostate Cancer Working Group 2 (PCWG2) with two or more new lesions on bone scan

4. Prior Treatment

   1. No treatment with prior taxane-based chemotherapy for metastatic disease

      • Patients who received prior taxane-based chemotherapy as neoadjuvant or adjuvant therapy for local disease, or who received taxane-based therapy in the PSA clinical (non-metastatic) state is allowable provided that the total duration of exposure was six cycles or less and chemotherapy was completed more than 6 months prior to registration
      • Taxane-based chemotherapy that was aborted due to allergic reactions or intolerance to chemotherapy and therefore received one cycle of prior therapy is allowable

   2. No prior enzalutamide, abiraterone or other novel antiandrogen or androgen synthesis inhibitor

   3. No treatment with any of the following for prostate cancer within 4 weeks prior to enrollment:

      • Hormonal therapy (e.g., androgen receptor [AR] antagonists, 5 alpha reductase inhibitors, estrogens) Note: Treatment with bicalutamide and nilutamide within 4 weeks prior to enrollment is not allowed. Treatment with flutamide within 4 weeks prior to enrollment is not allowed. Treatment with all other gonadotropin- releasing hormone (GnRH) analogues or antagonists is allowed.
      • Chemotherapy
      • Biologic therapy
      • Investigational therapy
      • Immunotherapy

   4. No use of herbal products that may decrease PSA levels within 4 weeks prior to enrollment

   5. No use of systemic steroids greater than the equivalent of 10 mg of prednisone/prednisolone per day within 4 weeks prior to enrollment

   6. No prior use of ketoconazole for greater than 7 days

   7. No prior radiation therapy or radionuclide therapy for the treatment of metastasis within four weeks prior to enrollment

   8. Patients receiving bisphosphonate therapy or denosumab must have been on a stable dose for at least 4 weeks prior to enrollment

   9. Patients must maintain ongoing androgen deprivation therapy with a GnRH analogue, antagonist, or bilateral orchiectomy (i.e., surgical or medical castration)

5. Patient History

   1. No known or suspected brain metastases (NOTE: patients with treated epidural disease are allowed)

   2. No planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery

   3. No structurally unstable bone lesions suggesting impending fracture

   4. No history of seizure or any condition that may increase the patient's seizure risk (e.g., prior cortical stroke, significant brain trauma). No history of transient ischemic attack (TIA) within 12 months of enrollment

   5. No clinically significant cardiovascular disease including:

      • Myocardial infarction (MI) within 6 months
      • Uncontrolled angina within 3 months
      • Congestive heart failure (CHF) with New York Heart Association (NYHA) class 3 or 4, or patients with NYHA class 3 or 4 in the past, unless a screening echocardiogram (echo) or multigated acquisition scan (MUGA) performed within three months demonstrates an ejection fraction (EF) > 45%
      • History of clinically significant ventricular arrhythmias (e.g., 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 (systolic blood pressure [BP] < 86 mmHg) or bradycardia (< 50 bpm) at screening
      • Uncontrolled hypertension (systolic BP > 170 mmHg or diastolic BP > 105 mmHg at screening)

   6. No gastrointestinal (GI) disorder that negatively affects absorption

   7. No major surgery within 4 weeks prior to enrollment

6. Age and performance status

   1. Age ≥ 18 years of age
   2. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
   3. Asymptomatic or mildly symptomatic from prostate cancer

7. Required Initial Laboratory Values

   1. Granulocytes ≥ 1,500/µL
   2. Platelet count ≥ 100,000/µL
   3. Hemoglobin ≥ 9 g/dL
   4. Creatinine ≤ 2 x upper limits of normal (ULN)
   5. Bilirubin ≤ 1.5 x ULN
   6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2 x ULN
   7. Albumin ≥ 3 g/dl
   8. Total testosterone ≤ 50 ng/dL (1.7 nmol/L)