Castration Compared to Castration Plus Metformin as First Line Treatment for Patients With Advanced Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Placebo; Metformin
Intervention description: All eligible subjects will be randomized in a 1:l manner to receive a bottle containing sufficient 500mg tablets of placebo after castration, blinded to the patient and the study team.; All eligible subjects will be randomized in a 1:l manner to receive a bottle containing sufficient 500mg tablets of metformin after castration, blinded to the patient and the study team.
Intervention MeSH terms: Metformin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 41.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Prostate Cancer; Metformin; Castration therapy

Summary:

      Prostate cancer is the most common non-cutaneous cancer in men. Patients with recurrent or
      metastatic prostate cancer are treated with androgen-deprivation therapy, often termed
      castration therapy. While the short and medium term benefits of castration are clear in
      relation to therapeutic efficacy in patients with prostate cancer, it is now appreciated that
      the resulting hypogonadism associated with castration is responsible for adverse consequences
      or metabolic syndrome that include increase in body mass index (BMI) and fat mass,
      hyperinsulinemia and insulin resistance, hyperlipidemia, reduced lean body mass (LBM) and
      muscle strength, osteoporosis, sexual dysfunction, poor quality of life and higher
      cardiovascular mortality. Lower testosterone levels in men independently predict the
      development of metabolic syndrome. Low testosterone levels in men are associated with insulin
      resistance and diabetes. Metformin is commonly prescribed for the treatment of type II
      diabetes because it lowers both glucose and insulin levels. Studies show preliminary evidence
      that metformin might have both antineoplastic and chemopreventative activity. Castration
      therapy decreases insulin sensitivity, adversely alters lipid profiles and results in weight
      gain, and it may be associated with a greater incidence of diabetes and cardiovascular
      disease. Little is known about the optimal strategy to mitigate the adverse metabolic effects
      of castration in men with prostate cancer. The rationale for using metformin in castrated men
      with advanced prostate cancer stems from the observation that castration therapy is
      associated with the metabolic syndrome, hyperinsulinemia and insulin resistance. Furthermore,
      reports that hyperinsulinemia stimulates insulin receptor expression on prostate cancer
      leading to tumor growth and development of castrate resistant prostate cancer suggest
      metformin through its activation of the AMPK-LKBI pathway reduces liver gluconeogenesis
      secondarily decreasing insulin levels may circumvent tumor growth and resistance to
      castration therapy. More importantly, evidence that metformin inhibits the mTOR pathway
      implicates an added therapeutic benefit as an anti-cancer agent.
    

Eligibility criteria:

        Inclusion Criteria:

        (Eligible subjects must meet one of the inclusion criteria 1-3 and all of items 4-6)

          1. Men with metastatic prostate cancer that require castration therapy with either using
             an LHRH analogue or surgical castration are eligible. Complete androgen blockade using
             anti-androgen therapy prior to castration or up to 4 weeks following castration
             therapy is permitted to prevent disease flare. Thereafter anti-androgen therapy may
             continue or be discontinued based on treating physicians preference.

             OR

          2. Any men with prostate cancer who are candidates for castration therapy despite no
             evidence of definite metastatic disease including patient with biochemical failure or
             'rising PSA' are also permitted to enter study provided castration therapy is planned
             for a minimum of a year. Patients with biochemical failure prior to enrolment should
             have also have already received appropriate salvage therapy. Men with prostate cancer
             who have already started castration therapy are also permitted to enter study provided
             castration therapy was initiated within one month of study entry.

             OR

          3. Men with prostate cancer previously treated with castration therapy for management of
             localized prostate cancer in the adjuvant setting or in combination with radiation
             therapy are permitted to enter study provided they currently have known metastatic
             disease and have non-castrate testosterone levels (Testosterone > 50 ng/dL).

          4. An ECOG performance status of 0-2.

          5. Patients will need to have documentation of metastatic disease in bone and/or soft
             tissue, and a baseline PSA of ≥ 5 ng/ml. If patients have already had castration
             therapy, their baseline PSA value will be reflective of the value prior to castration.
             Patients with biochemical failures, with rising PSA (baseline PSA does not need to be
             ≥ 5 nglml to be eligible), without metastatic disease are also eligible if castration
             therapy is indicated for minimum of 7 months and for these patients any PSA value is
             permitted.

          6. Patients must have provided informed consent, be willing to have blood specimens
             taken, and exhibit no severe other medical or psychiatric problems.

        Exclusion Criteria:

          1. Patients with severe medical or psychiatric diseases are INELIGIBLE. (Patients with
             stable chronic diseases such as high cholesterol or hypertension ARE eligible.)
             Examples of problems that would make patients INELIGIBLE include severe heart failure,
             or hypoxia due to severe lung disease.

          2. Patients with clinical or biochemical evidence of renal failure or liver failure are
             INELIGIBLE. Creatinine and bilirubin needs to be less than or equal to 1.3~up per
             limit of normal (ULN), and ASTIALT less than or equal to 2.5 x ULN unless liver
             metastasis is present then up to 5 X ULN permitted).

          3. Patients already receiving metformin or anti-diabetic medications are INELIGIBLE.

          4. If any patient develops symptomatic diabetes requiring drug therapy, he must receive
             such a therapy, which may include metformin. This must be documented, and the patient
             will not continue on the study.

          5. Patients with important infections requiring antibiotics are INELIGIBLE, but patients
             who acquire minor infections while on the study may remain on the study.

          6. Alcohol abuse problems make patients INELIGIBLE. Patients need to be consuming less
             than or equal to 14 units of alcohol weekly.

          7. Patients with history or evidence of lactic acidosis or metabolic acidosis will be
             excluded.