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Title A Randomized Phase II Study Comparing Bipolar Androgen Therapy vs. Enzalutamide in Asymptomatic Men with Castration Resistant Metastatic Prostate Cancer

IRB JHU1815

CC 15-1068

Hospital Main Campus

Phase Phase 2

Disease Prostate

Description

Primary Objectives

• To determine if treatment with supraphysiologic testosterone (T) will improve radiographic progression free survival compared to enzalutamide in asymptomatic men with evidence of progressive metastatic CRPC post-treatment with abiraterone. Radiographic progression-free survival is based on parameters suggested by PCWG2 and modified RECIST (Appendix 1) as the time from randomization to the occurrence of one of the following:
  • A patient is considered to have progressed by bone scan if: The first bone scan with ≥2 new lesions compared to baseline is observed ≥12 weeks from randomization (a total of ≥2 new lesions compared to baseline). A subsequent verification scan will not be required for this study.
  • Progression of soft tissue lesions measured by CT or MRI as defined by RECIST criteria version 1.1.
  • Death from any cause

Secondary Objectives

• Further investigate the safety of cyclical parenteral testosterone in asymptomatic men with recurrent castrate resistant prostate cancer. Safety will be evaluated by the incidence, severity, duration, causality, seriousness, and type(s) of adverse events as assessed by the revised National Cancer Institute Common Toxicity Criteria (NCI CTC), version 4.0 published 28 May 2009 (Appendix 2).
• PSA response rate [Proportion of patients achieving a PSA decline ≥ 50% according to Prostate Cancer Working Group (PCWG2) criteria]
• Objective response rate in patients with measurable disease on CT scan using RECIST criteria
• Time to PSA progression to each arm of therapy based on PCWG2 criteria
• PSA response rate to enzalutamide post-BAT
• PSA response rate to BAT post-enzalutamide
• Comparison of effect of each treatment arm on quality of life as assessed by patient completion of validated instruments (Appendix 8)

Inclusion Criteria

1. Performance status ≤2
2. Age ≥18 years
3. Histologically-confirmed adenocarcinoma of the prostate
4. Treated with continuous androgen ablative therapy (either surgical castration or LHRH agonist/antagonist)
5. Documented castrate level of serum testosterone (<50 ng/dl)
6. Metastatic disease radiographically documented by CT/MRI or bone scan.
7. Must have had disease progression while on abiraterone acetate alone or abiraterone acetate in combination with other investigational agents based on:
   • PSA progression defined as an increase in PSA, as determined by 2 separate measurements taken at least 1 week apart AND/OR
   • Radiographic disease progression, based on RECIST 1.1 in patients with measurable soft tissue lesions or PCWG2 for patients with bone disease
8. Screening PSA must be ≥ 1.0 ng/mL
9. Prior treatment with additional second line hormone therapies is permitted.
10. No prior treatment with enzalutamide, ARN-509, ODM-201, galeterone or other investigational AR targeted treatment is allowed.
11. Prior docetaxel for hormone-sensitive prostate cancer is permitted if ≤ 6 doses were given in conjunction with first-line androgen deprivation therapy and >12 months since last dose of docetaxel.
12. Prior treatment with Provenge vaccine and 223Radium (Xofigo) is allowed if >4 weeks from last dose.
13. Patients must be withdrawn from abiraterone for ≥ 2 weeks.
14. Patients must be weaned off prednisone and be off therapy for ≥ 1 week prior to starting therapy.
15. Acceptable liver function:
    • Bilirubin < 2.5 times institutional upper limit of normal (ULN)
    • AST (SGOT) and ALT (SGPT) < 2.5 times ULN
16. Acceptable renal function:
    • Serum creatinine < 2.5 times ULN
17. Acceptable hematologic status:
    • Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 x109/L)
    • Platelet count ≥ 100,000 platelet/mm3 (100 x109/L)
    • Hemoglobin ≥ 9 g/dL
18. At least 4 weeks since prior radiation
19. Ability to understand and willingness to sign a written informed consent document.
20. Patients on either treatment arm will be considered for crossover if they demonstrate evidence of radiographic disease progression from the initial treatment.

Exclusion Criteria

1. Pain due to metastatic prostate cancer requiring treatment intervention.
2. Prior treatment with enzalutamide is prohibited
3. Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant prostate cancer is prohibited.
4. Requires urinary catheterization for voiding due to obstruction secondary to prostatic enlargement well documented to be due to prostate cancer or benign prostatic hyperplasia (BPH).
5. Evidence of disease in sites or extent that, in the opinion of the investigator, would put the patient at risk from therapy with testosterone (e.g. femoral metastases with concern over fracture risk, severe and extensive spinal metastases with concern over spinal cord compression, extensive liver metastases)
6. Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study
7. Active uncontrolled infection, including known history of HIV/AIDS or hepatitis B or C.
8. Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule.
9. Prior history of a thromboembolic event within the last 12 months and not currently on systemic anticoagulation.
10. Prior history of an unprovoked thromboembolic event at any time and not currently on systemic anticoagulation.