TOPLINE:
A phase 3 trial found that metformin did not delay disease progression in men with low-risk prostate cancer on active surveillance. However, it did significantly increase the risk for pathologic progression among those with obesity.
METHODOLOGY:
- Active surveillance is a standard approach for managing men with low‑risk prostate cancer to help delay or avoid treatment, but a significant number of patients eventually experience disease progression. Preclinical and epidemiologic data have suggested that metformin, a common antidiabetic drug, could reduce the spread of cancer and potentially improve patient outcomes.
- To assess whether metformin can delay disease progression in prostate cancer, researchers conducted a randomized, multicenter, double-blind, placebo-controlled phase 3 trial involving 408 participants (median age, 62 years) with low-risk localized prostate cancer managed with active surveillance.
- Participants were randomly assigned to receive either metformin (n = 205) or placebo (n = 203) and followed up for a median of 36 months. Metformin was started at 850 mg once daily and titrated to 850 mg twice daily over 1 month.
- The primary endpoint was time to progression, defined as the earliest occurrence of therapeutic progression (initiation of primary therapy) or pathologic progression (involvement of more than one third of biopsy cores, ≥ 50% cancer involvement in any core, or a Gleason score ≥ 4).
- The mean baseline BMI was 28, with 26.6% of patients classified as having obesity (BMI ≥ 30).
TAKEAWAY:
- Overall, 144 patients experienced disease progression (either therapeutic or pathologic): 70 in the metformin arm and 74 in the placebo group, with no significant difference observed in progression-free survival (PFS; hazard ratio [HR], 1.09; 95% CI, 0.79-1.52; P = .59).
- Pathologic progression occurred in 136 patients: 66 in the metformin arm and 70 in the placebo group. The probability of PFS at 36 months was 58% with metformin vs 61% with placebo, with no significant difference between groups (HR, 0.77; P = .66). Therapeutic progression occurred in 45 patients: 27 in the metformin arm and 18 in the placebo arm, again with no significant difference between groups (HR, 1.73; P = .068).
- In a subgroup analysis, metformin was associated with an increased risk for pathologic progression among patients with obesity (HR, 2.36; P = .0092) but not among men without obesity.
- At 36 months, rates of a negative biopsy were not significantly different between the metformin (41.0%) and placebo (31.1%) groups (P = .181). Gastrointestinal adverse events, however, were more frequent with metformin, including diarrhea (19% vs 8%) and nausea, dyspepsia, or abdominal pain (9% vs 1%).
IN PRACTICE:
“These findings demonstrate no benefit in adding metformin as a means of delaying progression among patients with low-risk PCa [prostate cancer] on AS [active surveillance],” the authors wrote, adding, however, that “a potential harmful effect was noted among obese man.”
SOURCE:
The study, led by Neil E. Fleshner, MD, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada, was published online in Journal of Clinical Oncology.
LIMITATIONS:
The trial had a long accrual period during which diagnostic practices (notably multiparametric MRI) evolved, which may have influenced risk stratification and monitoring. The study population predominantly consisted of White participants, limiting generalizability to more diverse populations. Additionally, recruitment challenges were exacerbated by the COVID pandemic, potentially affecting the trial’s conduct.
DISCLOSURES:
The study received support from the Canadian Cancer Research Institute, the Prostate Cancer Foundation, and the Princess Margaret Foundation-Hold’em for Life Challenge/Love Chair in Cancer. Several authors reported receiving honoraria or research funding from and having other ties with various sources. Full disclosures are noted in the original article.
