Metformin for Rising PSA Remote Trial

Men with an isolated PSA recurrence after local therapy are an ideal population for the evaluation of novel therapies given the minimal disease burden, generally indolent natural history, and patients' preference to avoid the adverse effects of androgen deprivation therapy. Metformin has shown anti-prostate cancer activity in preclinical models and cohort studies. Metformin, a biguanide oral antihyperglycemic agent, abrogates hyperinsulinemia in individuals with and without diabetes and has shown promising anti-prostate cancer activity in preclinical models, epidemiologic studies, and retrospective cohorts. Several epidemiologic/retrospective studies have shown that metformin has a positive impact on overall survival among men with prostate cancer.

These nonclinical and clinical studies have led to calls for prospective studies of metformin in patients with prostate cancer. This is a pilot telemedicine study of metformin in patients with a rising PSA ("biochemical recurrence") after definitive local therapy for prostate cancer.

The current study is supported by the following rationale:

• A large proportion of clinical trials close prematurely due to poor accrual.
• Geographic inaccessibility is a barrier to clinical trial participation.
• Metformin is a safe and inexpensive medication that has demonstrated anti-prostate cancer activity in nonclinical and epidemiologic studies. Importantly, metformin has been shown to be safe in non-diabetic patients (e.g., patients with polycystic ovary disease) and does not cause hypoglycemia.
• Use of novel technologies may facilitate clinical trial accrual and minimize the burden of participation for patients. Ultimately, these approaches may also decrease the cost of drug development and increase the pace of progress.

In the absence of prohibitive toxicities or disease progression (defined in 4.4), patients may continue treatment for the 6-month study period. This study will include a baseline visit for study enrollment at Mount Sinai. The remainder of the visits will be telemedicine visits conducted using secure video conferencing.

Inclusion criteria

• Histologically confirmed adenocarcinoma of the prostate. (*in situations where pathology reports documenting prostate cancer are no longer available such as when the initial biopsy or prostatectomy was performed in the remote past, a documented history of prior prostate cancer and prostate cancer treatment in prior medical records will be sufficient)
• Biochemical disease progression after radical prostatectomy and/or radiation therapy (external-beam radiation therapy and/or brachytherapy), and no radiographic evidence of metastases.

• Men with history of radical prostatectomy are required to have baseline PSA > 0.5 ng/mL (Prior treatment with neoadjuvant, adjuvant, or salvage radiation therapy is allowed, again, with screening PSA greater than or equal to 0.5 ng/mL required for eligibility).
• Men treated with primary radiation therapy are required to have baseline PSA ≥ 1.0 ng/mL above their post radiation nadir for men who were treated with primary radiation therapy (external beam and/or brachytherapy). Men who had primary radiation therapy followed by salvage prostatectomy are eligible if screening PSA is greater than or equal to 0.5 ng/mL.
• Men with previous neoadjuvant adjuvant hormone therapy are eligible if testosterone level at screening is non-castrate (≥ 50 ng/dl). Men previously treated with intermittent hormonal therapy are also eligible if level of testosterone at screening is non-castrate (≥ 50 ng/dl).
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).
• Subjects must have normal organ as defined below:

• AST(SGOT)/ALT(SGPT) less than or equal to 1.8 X institutional upper limit of normal
• Serum bilirubin ≤ ULN (except for subjects with Gilbert's Disease who are eligible despite elevated serum bilirubin level)
• Creatinine ≤ 1.5 mg/dL and/or creatinine clearance > 60 ml/min
• English speaking

Exclusion criteria

• Concurrent use of other investigational agents or other prostate cancer therapies (e.g., androgen deprivation therapy)
• Currently taking metformin, sulfonylureas, thiazolidinedione, insulin, or other antidiabetic drugs for any reason.
• Known hypersensitivity or intolerance to metformin
• Condition associated with increased risk of metformin-associated lactic acidosis:

• New York Heart Association Class III or IV Heart Failure
• Intake of 3 or more alcoholic beverages per day
• Known history of lactic acidosis