Metformin Fails to Delay Progression in Low-Risk Prostate Cancer Active Surveillance
核心洞察
The phase 3 MAST trial found that metformin did not reduce progression in 408 men with low-risk prostate cancer on active surveillance compared to placebo over 36 months.
Progression-free survival rates were similar between metformin and placebo groups at 36 months (58% vs 60%), with no significant difference in time to progression.
Obese patients receiving metformin showed significantly increased risk of pathologic progression compared to placebo, warranting further investigation.
A large randomized trial has found that metformin provides no benefit in delaying disease progression among men with low-risk prostate cancer undergoing active surveillance, with concerning signals of potential harm in obese patients. The findings from the phase 3 MAST trial, published in the Journal of Clinical Oncology, challenge the hypothesis that this widely used diabetes medication could serve as a chemopreventive agent in prostate cancer management.
Trial Design and Patient Population
The multicenter, double-blind MAST trial (NCT01864096) enrolled 408 eligible patients between November 2013 and November 2023, randomly assigning them in a 1:1 ratio to receive either metformin 850 mg twice daily or placebo for up to 36 months. Participants were men aged 18 to 80 years with biopsy-confirmed, low-risk, localized prostate cancer who had chosen expectant management as their primary treatment approach.
The study population had a median age of 62.0 years, with 93.5% being White patients. Most participants (93.7%) had clinical stage T1c disease, and the mean baseline body mass index was 28.0 kg/m², with 73.4% classified as non-obese (BMI less than 30).
Primary Efficacy Results
After a median follow-up of 36 months, 144 patients experienced either therapeutic or pathologic progression, with 70 cases in the metformin arm and 74 in the placebo arm. The progression-free survival probability showed no significant difference between treatment groups across all time points measured.
At 12 months, progression-free survival was 94% (95% CI, 90%-97%) in the metformin group versus 96% (95% CI, 93%-99%) in the placebo group. By 24 months, these rates were 62% (95% CI, 54%-70%) and 69% (95% CI, 62%-76%), respectively. At 36 months, the rates converged to 58% (95% CI, 51%-67%) for metformin and 60% (95% CI, 53%-68%) for placebo.
The hazard ratio for progression in the metformin group was 1.09 (95% CI, 0.79-1.52), with no statistically significant difference observed between treatment arms (P = .59).
Concerning Findings in Obese Patients
A pre-planned subgroup analysis stratified by body mass index revealed a troubling signal among obese patients. Those with a BMI of 30 or greater who received metformin had a significantly higher risk of pathologic progression compared to placebo, with a hazard ratio of 2.36 (95% CI, 1.21-4.59; P = .0092).
In contrast, patients with a BMI less than 30 showed no significant difference between treatment arms (HR = 0.82; 95% CI, 0.55-1.23; P = .33). The interaction between BMI and treatment arm was statistically significant (P = .0092), suggesting that obesity modifies metformin's effect on prostate cancer progression.
Safety Profile
Metformin was generally well-tolerated, though gastrointestinal adverse events occurred more frequently in the treatment group. Diarrhea was reported in 19% of metformin patients versus 8% of placebo patients, while nausea, dyspepsia, or abdominal pain occurred in 9% of the metformin group compared to 1% of the placebo group. These adverse events were typically mild to moderate in severity, and no significant differences were observed in serious adverse events between groups.
Secondary Endpoints
The trial also evaluated negative biopsy rates as a secondary endpoint. At 18 months, the B0 rate was 27.3% in the metformin group and 28.1% in the placebo group (P = .880). By 36 months, these rates were 41.0% versus 31.1%, respectively, though this difference was not statistically significant (P = .181).
Therapeutic progression was observed in 45 patients overall, with 27 cases in the metformin arm and 18 in the placebo arm. While the hazard ratio suggested a potential increase in therapeutic progression with metformin (HR = 1.73; 95% CI, 0.95-3.14), this difference did not reach statistical significance (P = .068).
Clinical Implications
"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 (搜索).
The investigators concluded that "metformin did not reduce progression in men with low-risk [prostate cancer on active surveillance]. The observed adverse effect in obese patients merits further investigation."
These results suggest that metformin should not be recommended as an adjunctive therapy for men with low-risk prostate cancer on active surveillance, particularly given the potential for harm in obese patients who represent a significant portion of this patient population.