Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance
Condition: Castration Resistant Metastatic Prostate Cancer
MeSH terms: Prostatic Neoplasms
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Testosterone cypionate; Enzalutamide; Testosterone Enanthate
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Depo-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. Depo-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate.; Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water. Enzalutamide is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.; Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative.
Other intervention name(s): Depo-Testosterone Injection; Xtandi; Delatestryl
Intervention MeSH terms: Methyltestosterone; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Testosterone; Enzalutamide; Abiraterone; Androgen Ablative Therapies; Bipolar Androgen Therapy