Castration Compared to Castration Plus Metformin as First Line Treatment for Patients With Advanced Prostate Cancer
Status:
Completed
Trial end date:
2016-09-01
Target enrollment:
Participant gender:
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.
Phase:
Phase 2
Details
Lead Sponsor:
Devalingam Mahalingam The University of Texas Health Science Center at San Antonio