Phase 3 Trial: Metformin in Men Receiving ADT for Prostate Cancer

Metformin may help blunt some of the harmful hormonal and metabolic changes caused by androgen deprivation therapy (ADT) in men with prostate cancer, according to a correlative analysis from the PRIME phase III randomized trial. ADT is a standard treatment for locally advanced and metastatic prostate cancer, but it is also associated with metabolic syndrome, insulin resistance, weight gain, and other endocrine changes that can affect long-term health. The new analysis suggests that adding metformin may partially offset some of these biomarker shifts, especially the rise in leptin, a hormone linked to adiposity, insulin resistance, and potentially aggressive prostate cancer biology.

PRIME was a multicenter, double-blind, placebo-controlled clinical trial in which 166 normoglycemic men with prostate cancer receiving ADT were randomized to metformin or placebo. For this correlative study, serum samples were available from 47 men in the metformin arm and 32 in the placebo arm. Biomarkers were measured at baseline, 9 months, and 12 months, including IGF-1, IGFBPs, leptin, adiponectin, GDF15, insulin, C-peptide, GIP, GLP-1, and IL-6. The goal was to determine whether metformin could mitigate the laboratory changes associated with ADT and the development of metabolic syndrome and type 2 diabetes.

The most consistent effect was on leptin. In the placebo group, leptin increased markedly over time, while the rise was significantly smaller in the metformin group. That matters because leptin is not just a marker of fat mass; it is also involved in inflammatory signaling and has been associated with worse prostate cancer outcomes in observational studies. Metformin was also associated with more favorable changes in IGFBP1, IL-6, C-peptide, and GLP-1, suggesting broader effects on insulin signaling and inflammation. At the same time, ADT alone was associated with significant increases in GDF15 and IGFBP3, reinforcing the idea that androgen suppression drives substantial endocrine remodeling.

These results do not show that metformin improves survival or directly enhances cancer control, but they do support a biologically plausible role for metformin as a supportive therapy during ADT. The main clinical value may be in reducing the metabolic burden of treatment, particularly in men at risk for diabetes or metabolic syndrome. The leptin signal is especially interesting because it raises the possibility that metabolic modulation could also have implications for prostate cancer progression, though that remains unproven.

The broader literature on metformin in prostate cancer has been mixed, with some studies suggesting benefits on weight, glucose control, or metabolic markers, and others showing limited or no clear clinical effect. Even so, this trial adds important mechanistic evidence by showing that metformin can alter biomarker changes induced by ADT.

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