A Randomized Phase II Study Comparing Bipolar Androgen Therapy vs. Enzalutamide in Asymptomatic Men With Castration Resistant Metastatic Prostate Cancer
Overview
- Phase
- Phase 2
- Intervention
- Testosterone cypionate
- Conditions
- Castration Resistant Metastatic Prostate Cancer
- Sponsor
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Enrollment
- 222
- Locations
- 17
- Primary Endpoint
- Progression Free Survival as Measured by Number of Months Until Clinical or Radiographic Progression
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
Asymptomatic men with progressive metastatic Castration-resistant prostate cancer (CRPC) post- treatment with abiraterone acetate (pre-chemotherapy for metastatic disease) will be treated on a randomized, multi-Institutional open label study to determine if treatment with intramuscular T given on a dose/schedule designed to result in rapid cycling from the polar extremes of supraphysiologic to near castrate levels [i.e. Bipolar Androgen Therapy (BAT)] will improve primary and secondary objectives vs. enzalutamide as standard therapy.
Detailed Description
Eligible patients will have metastatic CRPC with no disease related symptoms and progression on Androgen deprivation therapy and will have progressed post-treatment with abiraterone. Patients will continue on Androgen deprivation therapy with Luteinising Hormone Releasing Hormone agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) or Luteinising Hormone Releasing Hormone antagonist (Degarelix) if not surgically castrated throughout the duration of the study to inhibit endogenous testosterone production. Patients will be randomized 1:1 and stratified based on duration of prior abiraterone acetate therapy (6 months or less or greater than 6 months). Patients randomized to BAT (Arm A) will receive intramuscular injections with either testosterone cypionate or testosterone enanthate at a dose of 400 mg every 28 days. This dose was selected based on data demonstrating that it produces an initial supraphysiologic serum level of T (i.e. \> 1500 ng/dL or 3-10 times normal level) with eugonadal levels achieved at the end of two weeks and near castrate levels after 28 days. Patients randomized to enzalutamide (Arm B) will receive daily oral dose of 160 mg. Each cycle is defined as 28 days. Patients will have Prostate-specific antigen level and symptoms assessment checked every cycle. Every 3 cycles patients will have repeat bone/CT scans to evaluate treatment response status. On CT scan, radiographic progression will be defined by RECIST criteria (i.e. \>20% increase in the sum of target lesions). On bone scan, radiographic progression will be defined by PCWG2 criteria as ≥ 2 new bone lesions. However, for the first reassessment scan only, patients should remain on study and have a confirmatory scan performed 12 weeks (3 cycles) later. If this confirmatory scan shows 2 or more additional new lesions, this defines progression. The date of progression is the date of the first reassessment bone scan. If the confirmatory scan does not show any additional new lesions, patient remains on study. If progression is observed on subsequent bone scans, a confirmatory scan is not required; the date of this bone scan is the date of progression. Patients with Prostate-specific antigen progression but with disease response or stable disease on imaging studies will remain on study until radiographic or other clinical progression criteria are met. Patients with radiographic disease progression will not receive continued BAT (arm A) or enzalutamide (arm B) and will be eligible for crossover to the opposite therapy. Patients on the BAT arm A can cross over to receive enzalutamide at time of progression or can choose to go off study and be treated with other standard of care treatments. Patients on the enzalutamide arm B will be allowed to cross-over to receive BAT or can choose to go off study and be treated with other standard of care treatments. Patients with clinical progression due to prostate cancer must meet study exclusion criteria to be permitted to cross-over to the opposite treatment. Patients with clinical progression due to pain from prostate cancer are not permitted to cross-over.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Eastern Cooperative Oncology Group Performance status ≤2
- •Age ≥18 years
- •Histologically-confirmed adenocarcinoma of the prostate
- •Treated with continuous androgen ablative therapy (either surgical castration or luteinizing hormone-releasing hormone agonist/antagonist)
- •Documented castrate level of serum testosterone (\<50 ng/dl)
- •Metastatic disease radiographically documented by CT/MRI or bone scan.
- •Must have had disease progression while on abiraterone acetate alone or abiraterone acetate in combination with other investigational agents based on:
- •Prostate-specific antigen progression defined as an increase in Prostate-specific antigen, as determined by 2 separate measurements taken at least 1 week apart
- •Radiographic disease progression, based on RECIST 1.1 in patients with measurable soft tissue lesions, or PCWG2 for patients with bone disease
- •Screening Prostate-specific antigen must be ≥ 1.0 ng/mL.
Exclusion Criteria
- •Pain due to metastatic prostate cancer requiring treatment intervention.
- •Eastern Cooperative Oncology Group Performance status ≥3
- •Prior treatment with enzalutamide is prohibited
- •Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant prostate cancer is prohibited.
- •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).
- •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)
- •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
- •Active uncontrolled infection, including known history of HIV/AIDS or hepatitis B or C.
- •Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule.
- •Patients receiving anticoagulation therapy with Coumadin are not eligible for study. \[Patients on non-coumadin anticoagulants (Lovenox, Xarelto, etc.) are eligible for study. Patients on Coumadin who can be transitioned to lovenox prior to starting study treatments will be eligible\].
Arms & Interventions
Arm A: Testosterone cypionate or testosterone enanthate
Patients on BAT will receive testosterone cypionate or testosterone enanthate administered as an intramuscular injection. A dose of 400 mg of either agent will be injected intramuscularly (IM) every 28 days.
Intervention: Testosterone cypionate
Arm A: Testosterone cypionate or testosterone enanthate
Patients on BAT will receive testosterone cypionate or testosterone enanthate administered as an intramuscular injection. A dose of 400 mg of either agent will be injected intramuscularly (IM) every 28 days.
Intervention: Testosterone Enanthate
Arm B: Enzalutamide
Patients randomized to enzalutamide will be prescribed enzalutamide 40 mg tablets and instructed to take 4 tablets per day orally for 28 days/cycle.
Intervention: Enzalutamide
Outcomes
Primary Outcomes
Progression Free Survival as Measured by Number of Months Until Clinical or Radiographic Progression
Time Frame: up to 2 years
Time to clinical progression will be defined as months from randomization to any of the following (whichever occurs earlier): * Cancer pain requiring initiation of chronic administration of opiate analgesia (oral opiate use for ≥3 weeks; parenteral opiate use for ≥7 days. Patients with cancer pain requiring opiate analgesia for relief should also be assessed by the investigator for the need for initiating systemic chemotherapy or palliative radiation. * Development of a skeletal-related event (SRE): pathologic fracture, spinal cord compression, or need for surgical intervention or radiation therapy to the bone. * Development of clinically significant symptoms due to loco-regional tumor progression (e.g. urinary obstruction) requiring surgical intervention or radiation therapy.
Secondary Outcomes
- Quality of Life as Assessed by the Positive Affect Score of the Positive and Negative Affect Schedule (PANAS)(up to 1 year)
- Change in Quality of Life as Assessed by the International Index of Erectile Function (IIEF) Questionnaire(up to 1 year)
- Time to Prostate-Specific Antigen Progression(Up to 2 years)
- Quality of Life as Assessed by the Negative Affect Score of the Positive and Negative Affect Schedule (PANAS)(up to 1 year)
- Quality of Life as Assessed by Short Form 36(up to 1 year)
- Quality of Life as Assessed by FACIT Fatigue Scale(up to 1 year)
- Pain Severity as Assessed by the Brief Pain Inventory(1 year)
- Pain Interference as Assessed by the Brief Pain Inventory(1 year)
- Overall Survival(up to 3 years)
- Progression Free Survival on Crossover Treatment(up to 2 years)
- Radiographic Progression(up to 2 years)
- Prostate-Specific Antigen Response Rate(Up to 2 years)
- Objective Response Rate as Determined by RECIST(Up to 2 years)