Title Phase III Trial fo Enzalutamide versus Enzalutamide, Abiraterone and Prednisone for castration resistant metastatic prostate cancer

IRB A031201

CC 14-332

Hospital Beachwood, Fairview, Florida Weston, Hillcrest, Independence, Main Campus, Mansfield, North Coast Cancer, South Pointe, Strongsville, Wooster

Phase Phase 3

Disease Prostate

Drug Enzalutamide



  1. To compare the overall survival of patients with progressive metastatic CRPC treated with either a) enzalutamide only or b) enzalutamide with abiraterone and prednisone
  1. To assess the grade 3 or higher toxicity profile and compare safety by treatment arm
  2. To assess and compare post-treatment PSA declines by treatment arm
  3. To compare radiographic progression free survival defined by Prostate Cancer Working Group 2 (PCWG2), and objective response rate, by treatment arm
  4. To test for fPFS treatment interaction in predicting overall survival.
  5. To assess pre- and post- treatment measures of tumor burden and bone activity using NaF PET/CT and Tc MDP bone scintigraphy and correlate these measures with overall survival
  6. To develop and validate prognostic and predictive models of overall survival that include baseline clinical and molecular markers
Inclusion Criteria

Inclusion Criteria

  1. 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
    • Measurable Disease

      For visceral or extra-nodal lesions to considered measurable, they must be ≥ 10 mm in one dimension, using spiral CT.

      For lymph nodes to be considered measurable (i.e., target or evaluable lesions), they must be ≥ 20 mm in at least one dimension, using spiral CT.

    • 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 (i.e. no presence of visceral, extra nodal lesions or bone lesions) must have node(s) that measure ≥ 15 mm in short axis.
  4. 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.
    • 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 ≥ week between each determination such that at least the second of these rises is ≥ 4 weeks since last flutamide or ≥ 6 weeks since last bicalutamide or nilutamide. The PSA value at the screening should be ≥ 2 μg/L (2ng/mL)
    • Soft tissue disease progression defined by Section 13.2.3.
    • Bone disease progression defined by PCWG2 with two or more new lesions on bone scan.
  5. No treatment with prior taxane-based chemotherapy for metastatic disease
    1. 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.
    2. Taxane-based chemotherapy that was aborted due to allergic reactions or intolerance to chemotherapy and therefore received 1 cycle of prior therapy is allowable.
  6. No prior enzalutamide, abiraterone, or other novel antiandrogen or androgen synthesis inhibitor
  7. No treatment with any of the following for prostate cancer within 4 weeks prior to enrollment:
    • Hormonal therapy (e.g., AR antagonists, 5 alpha reductase inhibitors, estrogens).

      Note: Treatment with bicalutamide and nilutamide within 6 weeks prior to enrollment is not allowed. Treatment with flutamide within 4 weeks prior to enrollment is not allowed. Treatment with all other GnRH analogues or antagonists is allowed.

    • Chemotherapy
    • Biologic therapy
    • Investigational therapy
    • Immunotherapy
  8. No use of herbal products that may decrease PSA levels within 4 weeks prior to enrollment
  9. No use of systemic steroids > 10 mg of prednisone/prednisolone per day within 4 weeks prior to enrollment
  10. No prior use of ketoconazole for greater than 7 days
  11. No prior radiation therapy or radionuclide therapy for the treatment of metastasis within four weeks prior to enrollment
  12. Patients receiving bisphosphonate therapy or denosumab must have been on a stable dose for at least 4 weeks prior to enrollment
  13. Patients must maintain ongoing androgen deprivation therapy with a GnRH analogue, antagonist, or bilateral orchiectomy (i.e. surgical or medical castration)
  14. No known or suspected brain metastases (NOTE: patients with treated epidural disease are allowed)
  15. No planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery
  16. No structurally unstable bone lesions suggesting impending fracture
  17. 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 TIA within 12 months of enrollment.
  18. No clinically significant cardiovascular disease including:
    • MI within 6 months
    • Uncontrolled angina within 3 months
    • CHF with NYHA class 3 or 4, or patients with NYHA class 3 or 4 in the past, unless a screening echo or MUGA performed within three months demonstrates and 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 BP < 86 mmHg) or bradycardia (< 50 bpm) at screening
    • Uncontrolled hypertension (systolic BP > 170 mmHg or diastolic BP > 105 mmHg at screening
  19. No GI disorder that negatively affects absorption
  20. No major surgery within 4 weeks prior to enrollment
  21. Age ≥ 18 years of age
  22. ECOG performance status of 0-1
  23. Asymptomatic or mildly symptomatic from prostate cancer

    A score of 0-1 on BPI-SF Question #3 (worst pain in last 24 hours) will be considered asymptomatic, and a score of 2-3 will be considered mildly symptomatic (see Appendix II)

  24. Required Initial Laboratory Values:
    • Granulocytes ≥ 1,500/μL
    • Platelet count ≥ 100,000/μL
    • Hemoglobin ≥ 9 g/dL
    • Creatinine ≤ 2 x upper limits of normal (ULN)
    • Bilirubin ≤ 1.5 x ULN
    • AST or ALT ≤ 2 x ULN
    • Albumin ≥ 3 g/dL
    • Serum Testosterone ≤ 50 ng/dL (1.7 nmol/L)
Exclusion Criteria

Exclusion Criteria

Exclusion Criteria Not Available