A Randomized Phase 3 Trial of Metformin in Patients Initiating Androgen Deprivation Therapy as Prevention and Intervention of Metabolic Syndrome: The PRIME Study.

Abstract

We investigated whether metformin decreases metabolic syndrome (MS) risk in patients with prostate cancer (PCa) receiving androgen deprivation therapy (ADT). In this phase 3, multicenter, double-blind, randomized controlled trial, normoglycemic patients with PCa planned for at least 9 months of ADT were randomized 2:1 to receive metformin 850 mg or placebo twice daily orally for 18 months. The primary objective was to compare proportions of MS at 18 months between the study arms. Between July 2018 and November 2023, 166 patients were randomized. The trial closed prematurely on November 24, 2023, because of drug supply cessation and the planned enrollment numbers (n = 300) were not met. A total of 90 (metformin) and 45 patients (placebo) were analyzed in the final analysis. The median follow-up was 24 months (IQR: 19.5-36 months). Proportions of MS between metformin and placebo arms were 38/90 (42%) vs 26/45 (58%) at baseline (<i>P</i> = .09) and 40/73 (55%) vs 23/34 (68%) at 18 months (<i>P</i> = .2). Significant reductions in mean (SD) body weight occurred with metformin at 9 (-0.9 [4] vs +1.8 [3.8] kg; <i>P</i> < .001) and 12 months (-0.33 [3.9] vs +1.8 [3.9] kg; <i>P</i> = .004). Mean (SD) hemoglobin A1c was lowered with metformin at 9% (-0.02% [0.23%] vs +0.08% [0.26%]; <i>P</i> = .02) and 12 months (+0.03% [0.27%] vs +0.08% [0.27%]; <i>P</i> = .03). Significantly smaller increments in mean (SD) waist circumferences were noted with metformin at 9 (+0.8 [4.3] vs +2.9 [5.7] cm; <i>P</i> = .03), 12 (+1.9 [5.1] vs +3.3 [6] cm; <i>P</i> = .15), and 18 months (+1.8 [3.8] vs +3.8 [6.1] cm; <i>P</i> = .03). Metformin did not reduce the risk of MS in patients with PCa on ADT. However, significant improvements in body weight, waist circumference, and hemoglobin A1c suggest a potential role for metformin in reducing ADT-related complications.