Metformin to treat prostate cancer (PCa) and prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Results of a randomized double-blind placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced PCa.
Publication: Journal of Clinical Oncology
Abstract
e16502
Background: ADT results in metabolic syndrome, characterized by hyperinsulinemia, insulin resistance and obesity. The hyperinsulinemia may result in ADT resistance; therefore preventing metabolic syndrome could have a therapeutic impact on PCa. In diabetes, metformin (MET) decreases glucose & insulin by inhibiting hepatic gluconeogenesis. There is preclinical evidence for additional antineoplastic activity due to mTOR inhibition secondary to AMPK activation. Methods: Men with biochemical relapse or advanced PCa due to receive ADT were randomized 1:1 in a double blind manner to MET (500mg TID) or placebo (P). Subjects required normal oral glucose tolerance test at baseline, with fasting serum insulin/glucose, PSA, MET, weight and waist circumference (WC) monitored at baseline, week 12 and 28. The primary endpoint of study was the metabolic consequences of MET vs P. Secondary endpoints were PSA response and PBMC analysis of downstream target of mTOR, phospho-S6 kinase. Results: 36 men were randomized to MET or P, mean age 68.4; biochemical failure (n = 15) & metastatic disease (n = 21). Mean weight, WC and insulin at baseline in MET cohort was 187 lbs, 41.14 cm and 10.03 mIU/L respectively, and 177.65 lbs, 40.52 cm and 8.02 mIU/L in P cohort. An increase in mean weight, WC and insulin levels was seen in both cohorts. At wk 12 and 28, no statistical difference in weight, WC and insulin was observe in either cohort. 4 men randomized to MET had undetectable serum drug levels despite drug-diary suggesting compliance; excluding them did not result in significant metabolic change. Assessing efficacy, 50% in MET and 53.3% in P cohort achieved undetectable PSA at wk 28; difference not statistically significant. PBMC analysis demonstrated variable down-regulation of phospho-S6 kinase in the metformin cohort. Conclusions: This study detected no impact of MET addition to ADT on the risk of metabolic syndrome and no additional anti-tumor effects. Control of hyperinsulinemia related to diabetes by MET does not necessarily imply MET has a similar action on hyperinsulinemia due to ADT. Clinical trial information: NCT02620423.
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© 2017 by American Society of Clinical Oncology.
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Published in print: May 20, 2017
Published online: May 30, 2017
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Metformin to treat prostate cancer (PCa) and prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Results of a randomized double-blind placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced PCa.. JCO 35, e16502-e16502(2017).
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Journal of Clinical Oncology 2017 35:15_suppl, e16502-e16502
Journal of Clinical Oncology 2017 35:15_suppl, e16502-e16502
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