Highlight
– The Metformin Active Surveillance Trial (MAST), a multicenter, randomized, double‑blind, placebo‑controlled phase III trial, found no reduction in time to progression for men with low‑risk prostate cancer assigned to metformin versus placebo over 36 months (HR 1.09; 95% CI 0.79–1.52; P = .59).
– Negative biopsy rates at 36 months were numerically higher with metformin (41.0% vs 31.1%) but did not reach statistical significance (P = .181).
– A pre‑specified subgroup analysis unexpectedly suggested an increased risk of pathologic progression among obese participants (BMI ≥ 30) randomized to metformin (HR 2.36; 95% CI 1.21–4.59; P = .0092), a finding that requires replication and mechanistic study.
Background
Active surveillance (AS) is an established management strategy for men with low‑risk, localized prostate cancer (PCa), aiming to avoid overtreatment while preserving the option for curative therapy if disease progresses. Despite low baseline risk, a substantial minority of men on AS demonstrate clinical or pathologic progression over time and require definitive treatment. There is interest in identifying well‑tolerated agents that could delay progression and reduce the need for intervention.
Metformin, a widely used insulin‑sensitizing drug for type 2 diabetes, has attracted attention because of preclinical anticancer effects (AMPK activation, inhibition of mTOR signaling, modulation of tumor metabolism) and observational epidemiology that suggested improved cancer outcomes in some cohorts of metformin users. These signals prompted randomized testing of metformin in several cancer prevention or adjuvant settings, including prostate cancer. The Metformin Active Surveillance Trial (MAST) was designed to test whether metformin could slow progression in men with low‑risk PCa managed expectantly.
Study design
MAST was a multicenter, randomized, double‑blind, placebo‑controlled phase III trial. Eligible men with low‑risk, localized prostate cancer on active surveillance were randomized 1:1 to metformin 850 mg twice daily or matching placebo and followed for up to 36 months. The primary endpoint was time to progression, defined as therapeutic and/or pathologic progression. Progression‑free survival (PFS) was analyzed using Kaplan‑Meier methods and Cox proportional hazards models. The trial accrued 408 participants (205 metformin, 203 placebo) and had a median follow‑up of 36 months.
Key findings
Primary outcome: progression‑free survival
At a median follow‑up of 36 months, 144 participants experienced progression events (70 in the metformin arm, 74 in the placebo arm). There was no statistically significant difference in PFS between the two arms (hazard ratio [HR] 1.09; 95% confidence interval [CI] 0.79–1.52; P = .59), indicating that metformin at 850 mg twice daily did not reduce the risk of progression for men on AS during the trial period.
Secondary endpoints: biopsy outcomes
The proportion of negative surveillance biopsies at 36 months was 41.0% in the metformin arm versus 31.1% in the placebo arm (P = .181). Although numerically higher negative biopsy rates with metformin could suggest less histologic progression, the difference did not reach statistical significance and must be interpreted cautiously in the context of the neutral primary end point.
Prespecified subgroup analyses
Of particular note, a prespecified subgroup analysis by body mass index (BMI) identified a statistically significant association between metformin assignment and increased pathologic progression among obese participants (BMI ≥ 30): HR 2.36 (95% CI 1.21–4.59; P = .0092). This adverse signal was unexpected given hypotheses that metabolic modulation could be beneficial in obesity‑related tumor biology and suggests potential heterogeneity of metformin’s effects by metabolic phenotype.
Safety and tolerability
The summary available from the trial report did not detail safety or adverse event profiles comprehensively. Metformin is generally well tolerated, with gastrointestinal side effects being the most common. Because safety data specific to this trial were not provided in the summary, clinicians should consult the full publication for treatment‑emergent adverse events, discontinuations, and any imbalances between arms.
Expert commentary and interpretation
MAST provides high‑quality randomized evidence that challenges optimism about repurposing metformin as an agent to delay progression among men with low‑risk prostate cancer on active surveillance. The neutral primary outcome (PFS) argues against routine off‑label use of metformin for this indication.
The discordance between the non‑significant numerical increase in negative biopsies and the neutral PFS highlights several methodological and biological considerations. First, surveillance biopsy sampling error and variability in adherence to surveillance schedules can influence biopsy‑based endpoints. Second, composite progression endpoints that include therapeutic actions (e.g., initiation of treatment) are susceptible to non‑biologic influences such as physician or patient preference. Third, a relatively limited follow‑up of 36 months may be insufficient to capture long‑term effects on clinically meaningful outcomes.
The signal of increased pathologic progression among obese participants is potentially the most consequential and hypothesis‑generating aspect of the trial. Biologically, obesity is associated with altered insulin/IGF signaling, chronic inflammation, and changes in adipokine milieu, all of which can affect tumor biology. Metformin’s mechanisms — including lowering systemic insulin and direct intracellular metabolic effects — might interact with the obesity‑driven tumor microenvironment in complex ways. It is conceivable that in certain metabolic contexts metformin could exert paradoxical effects on tumor adaptation or selection. Alternatively, the finding could reflect chance, baseline imbalance, or differential adherence; therefore, replication in other datasets or pooled analyses is essential before changing practice.
Methodological limitations to consider include the trial’s follow‑up duration, the absence of detailed safety data in the provided summary, and potential heterogeneity in surveillance protocols across centers. The trial’s strengths are its randomized, double‑blind, placebo‑controlled design and multicenter conduct, which increase internal validity and generalizability to men similar to those enrolled.
Clinical implications
For clinicians managing men with low‑risk prostate cancer on active surveillance, MAST indicates that metformin should not be prescribed with the expectation of delaying progression based on the current evidence. Shared decision‑making should emphasize that the study did not demonstrate benefit and that there may be an increased risk of pathologic progression among obese patients assigned to metformin — a finding that argues against empiric use in this subgroup until further data are available.
For researchers, the trial highlights the importance of stratifying by metabolic phenotype in future chemoprevention or repurposing studies and of incorporating mechanistic correlative studies (metabolic profiling, insulin/IGF axis biomarkers, adipokine panels, and tissue‑level analyses) to clarify heterogeneity of effects. Longer follow‑up and meta‑analytic pooling of randomized data will help determine whether signals observed at 36 months persist, attenuate, or evolve into clinically meaningful differences in definitive treatment rates or metastasis‑free survival.
Conclusion
The Metformin Active Surveillance Trial (MAST) provides robust evidence that metformin does not reduce progression in men with low‑risk prostate cancer managed with active surveillance over a median of 36 months. The unexpected association between metformin and increased pathologic progression in obese participants is an important, hypothesis‑generating finding that requires confirmation and mechanistic exploration. At present, metformin should not be used as a progression‑delaying therapy in this setting outside of clinical trials.
Funding and clinicaltrials.gov
Funding and detailed trial registration information were not supplied in the summary excerpt provided. Readers should consult the full publication for funding sources, conflict‑of‑interest disclosures, and ClinicalTrials.gov registration and identifier.
References
Fleshner NE, Bernardino RM, Izawa J, et al. Metformin Active Surveillance Trial in Low‑Risk Prostate Cancer. J Clin Oncol. 2025 Oct 30: JCO2501070. doi: 10.1200/JCO-25-01070. Epub ahead of print. PMID: 41166665.
Thumbnail Prompt
A contemplative middle-aged man sitting in a modern urology clinic, looking at a computer screen displaying prostate biopsy images and a schematic prostate; on the desk, two pill bottles are visible, one labeled ‘Metformin’ and one ‘Placebo’; a BMI scale graphic overlays the corner, and the lighting is clinical but warm, conveying both medical seriousness and human concern.