Bipolar Androgen-based Therapy for Prostate Cancer (BAT)

This is an open-label, single site, single arm pilot study designed to determine the efficacy and safety of alternating androgen deprivation therapy (ADT) and parenteral testosterone in men with recurrent or newly metastatic prostate cancer. Eligible patients will initiate ADT with Luteinizing hormone-releasing hormone (LHRH) agonist (e.g. goserelin or leuprolide) if not surgically castrated for a total of 6 months. After this initial 6 month lead-in phase, patients will continue on ADT every three months but will also receive an intramuscular gluteal injection with either testosterone cypionate or testosterone enanthanate (T) at a dose of 400 mg every 4 weeks for a total of 3 injections (i.e.12 weeks of therapy).Both formulations of T have identical pharmacokinetics; exhibiting the same serum testosterone profile after intramuscular injection into healthy volunteers. Patients will then cycle back to ADT only for 12 weeks. This route and dose of T was selected based on data demonstrating that it produces an initial supraphysiologic serum level of testosterone (i.e. > 3-8 times normal level) with eugonadal levels achieved at the end of two weeks and return to low serum T levels by the fourth week post-injection. The investigators have termed this rapid cycling between supraphysiologic to low/castrate serum T Bipolar Androgen-based Therapy (BAT). One BAT cycle will be defined as 24 weeks (i.e. 12 weeks on T; 12 weeks off T). Patients will receive two cycles (i.e. 48 weeks) of BAT in total (see Study Scheme below). Upon completion of the 18 month study period patients will be assessed for response and will then have the option to continue on intermittent or continuous ADT at the discretion of their treating physician.

Patients will have prostate specific antigen (PSA) and imaging studies during the screening period. A second set of studies will be performed at the end of the 6-month LHRH agonist therapy lead-in period. Based on prior studies the investigators expect >80% of patients to have a PSA <4 ng/ml and without evidence of PSA progression after 6 months of ADT (Hussain et al. 2006; Crook et al. 2012). At the end of the lead-in phase only patients who either achieve a ≥50% reduction in PSA from their screening baseline (i.e. a major PSA response) or have a PSA < 4 ng/ml and are without signs of progression will be allowed to continue on the study. All others will be removed from study and replaced. Those replaced individuals will be considered to have not met the primary endpoint in our final analysis. PSA progression will be assessed at the end of the 18 month study period. Standard Prostate Cancer Working Group 2 (PCWG2) criteria for PSA progression will be used (Scher et al. 2008).

The primary endpoint for this trial will be the percent subjects with a PSA <4 ng/ml and without PSA progression at the end of the 18 month treatment period. Secondary endpoints will include: the rate of progression based on imaging and clinical assessments, percent of patient who have a complete PSA response (PSA < 0.2 ng/ml), metabolic changes, changes in quality of life as assessed through standard questionnaires, and safety.

CT and bone scans will be performed at the end of the second full cycle of BAT (i.e. at the end of the 18 month study period) and be used to assess for radiographic progression. Soft tissue metastasis will be evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (v1.1). Bone metastasis will be evaluated per the standard PCWG2 criteria. This requires the appearance of at least 2 new lesions with a confirmatory bone scan. For patients demonstrating radiographic progression the investigators will require a confirmatory scan after an additional 8 weeks so as not to misconstrue a tumor flare with true disease progression. A subject will be considered to have clinically progressed if he develops pain that, in the opinion of the investigator, is secondary to his cancer; he develops a pathologic fracture or other skeletal event. If there is uncertainty regarding whether a symptom is due to a patient's cancer, the subsequent workup will be at the investigator's discretion. Of the endpoints, only clinical progression will result in early study termination.

To evaluate the effect BAT has on the metabolic syndrome associated with ADT the investigators will monitor a number of parameters at baseline prior to initiation of ADT, after 6 month "Lead-in" phase of ADT and after the 2nd cycle of T. Studies will include measurements of bone density,estradiol, sex hormone binding globulins, fasting lipids, metabolic parameters (insulin, fasting glucose, hemoglobin A1c, leptin, TSH, T3, fibrinogen, C-reactive protein, serum C-telopeptide, blood pressure, Body Mass Index (BMI), body weight). Quality of life (QOL) will be recorded through a series of questionnaires. These surveys include the RAND-SF36 Quality of Life Survey, the Functional Assessment of Cancer Therapy - Prostate Cancer (FACT-P), the International Index of Erectile Function (IIEF), the International Prostate Symptom Score (IPSS) and a visual pain scale. Each of these instruments has been previously validated and is used extensively in clinical trials to assess the effects of treatment intervention on quality of life. QOL will be assessed at screening, after Lead-In Phase and at the end of each cycle of T or ADT.

Additional plasma and serum samples will be drawn and banked at -80°C at baseline prior to initiation of ADT, prior to initiating a cycle of T or ADT and upon completion of the study. These samples will be used for biologic and immunologic correlates. Examples of studies that may be performed include, but are not limited to: quantitative immunoglobulins, T-cell receptor excision circles (TREC) levels and circulating DNA studies.