Metformin Yields No Benefit in Low-Risk Prostate Cancer on Active Surveillance

Use of metformin did not reduce progression in male patients with low-risk prostate cancer on active surveillance, though the observed adverse effects (AEs) in patients with obesity may warrant further investigation, according to results from the randomized, double-blind phase 3 MAST trial (NCT01864096) published in the Journal of Clinical Oncology.

Among the 408 eligible patients who were enrolled in the trial and randomly assigned to either the metformin arm (n = 205) or the placebo arm (n = 203), 144 experienced either therapeutic or pathologic progression, with 70 cases of progression in the metformin arm and 74 in the placebo arm. In the metformin arm and placebo arm, the progression-free survival (PFS) probability was 94% (95% CI, 90%-97%) and 96% (95% CI, 93%-99%), respectively, at 12 months, 62% (95% CI, 54%-70%) and 69% (95% CI, 62%-76%) at 24 months, and 58% (95% CI, 51%-67%) and 60% (95% CI, 53%-68%) at 36 months. Per the Kaplan-Meier survival curves, there was no significant difference in time to progression between the treatment arms (P = .59). Notably, the HR for progression in the metformin group was 1.09 (95% CI, 0.79-1.52).

Overall, pathologic progression was observed in 136 patients, with 66 instances in the metformin arm and 70 in the placebo arm. In the metformin arm and placebo arm, the PFS probability was 94% (95% CI, 91%-98%) and 96% (95% CI, 94%-99%), respectively, at 12 months, 64% (95% CI, 57% to 72%) and 70% (95% CI, 63% to 77%) at 24 months, and 58% (95% CI, 51% to 67%) and 61% (95% CI, 54% to 69%) at 36 months. No statistically significant difference was observed (P = .66; HR, 0.77; 95% CI, 0.77-1.51).

A planned a priori analysis was stratified by body mass index (BMI). Patients with a BMI of 30 or greater who were assigned to the metformin group had a higher risk of pathologic progression per Kaplan-Meier survival curves.The HR for progression in the metformin group was 2.36 (95% CI, 1.21-4.59; P = .0092), highlighting the significantly increased risk associated with metformin use in this subgroup, whereas in patients with a BMI less than 30, the HR was 0.82 (95% CI, 0.55-1.23; P = .33). In the Cox proportional hazards model including the treatment group, BMI category, and interaction term, the interaction between BMI and treatment arm was significant (P = .0092).

Overall, the HR for progression in the metformin group was 1.09 (95% CI, 0.78-1.53; P = .60). In the BMI less than 30 and BMI of 30 or higher subgroups, the HRs were 0.86 (95% CI, 0.58-1.29; P = .48) and 2.19 (95% CI, 1.13-4.26; P = .021), respectively.

Further, therapeutic progression was observed in 45 patients, with 27 cases in the metformin arm and 18 in the placebo arm. In the metformin and placebo arms, the PFS probability was 97% (95% CI, 94% to 99%) and 98% (95% CI, 97% to 100%), respectively, at 12 months, 83% (95% CI, 77% to 89%) and 91% (95% CI, 87% to 95%) at 24 months, and 81% (95% CI, 75% to 88%) and 90% (95% CI, 86% to 95%) at 36 months. The difference between the 2 arms was not significant (HR, 1.73; 95% CI, 0.95-3.14; P = .068). The per-protocol sensitivity analysis revealed that the HR for the metformin group was 1.76 (95% CI, 0.97-3.20; P = .063).

“In conclusion, these findings demonstrate no benefit in adding metformin as a means of delaying progression among patients with low-risk [prostate cancer] on [active surveillance]. Furthermore, a potentially harmful effect was noted among obese men,” wrote lead study author Neil E Fleshner, MD, MPH, FRCSC, of the Division of Urologic Oncology at Princess Margaret Cancer Center of University Health Network in Toronto, Ontario, Canada.

A total of 408 patients were included in the analysis and randomly assigned, in a 1:1 ratio, to either receive metformin at 850 mg once daily, escalating to 850 mg twice daily over 1 month, or receive placebo. Eligible patients were between 18 and 80 years old with a biopsy-confirmed, low-risk, localized prostate cancer, and decided to undertake expectant management as their primary treatment. Those who received prior prostate cancer treatment, had any prior use of metformin, sulfonylureas, thiazolidinediones, or insulin, and a diagnosis of type 1 or 2 diabetes were excluded from participation.

The median age of patients was 62.0 years (IQR, 57.5-67.0), and 93.5% of patients were White. Most patients had clinical stage T1c disease (93.7%). The mean baseline BMI was 28.0 kg/m² (SD, 4.0), and 73.4% were considered nonobese and defined as having a BMI less than 30.

The primary end point of the trial was time to progression, defined as the earliest occurrence of therapeutic or pathologic progression.

The B0 rate at 18 months was 27.3% in the metformin group and 28.1% in the placebo group (P = .880); at 36 months, it was 41.0% vs 31.1%, respectively (P = .181).

Regarding safety, the most reported adverse effects (AEs) were gastrointestinal, which occurred more frequently in the metformin group. Diarrhea occurred in 19% of the metformin group vs 8% of the placebo group, and nausea, dyspepsia, or abdominal pain occurred in 9% of the metformin group vs 1% of the placebo group. These AEs were typically mild or moderate in severity, and no significant differences were observed in serious AEs between the 2 groups.

Reference

Fleshner NE, Bernardino RM, Izawa J, et al. Metformin active surveillance trial in low-risk prostate cancer. J Clin Oncol. 2025;43(34):3662-3671. doi:10.1200/JCO-25-01070