Metformin Offers No Survival Boost in Metastatic Prostate Cancer

An antidiabetic mainstay did not provide an additional survival benefit to patients with metastatic hormone-sensitive prostate cancer, according to results from a phase III trial.

In STAMPEDE, overall survival was not statistically better among non-diabetic patients given metformin instead of standard of care alone (67.4 months vs 61.8 months, HR 0.91, 95% CI 0.80-1.03), reported Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona, and colleagues.

Results were similar between groups regarding secondary outcomes including prostate cancer-specific survival, progression-free survival (PFS), metastatic PFS, and failure-free survival, according to the report, initially presented at last year’s European Society for Medical Oncology Congress and now published in Lancet Oncology.

“Addition of metformin, a widely used, safe, and cheap metabolic regulatory drug to standard of care is not recommended for patients with metastatic hormone-sensitive prostate cancer in general,” wrote Gillessen and colleagues. “Further work is needed to better understand the potential anticancer effect observed in patients with high-volume disease and to identify patients who might benefit most from the addition of metformin to treatment.”

This analysis from the STAMPEDE trial — a multi-arm, multi-stage randomized phase III platform trial evaluating multiple treatments in patients with high-risk or metastatic prostate cancer — had investigators seeking non-diabetic patients with metastatic disease with adequate renal function and WHO performance status 0-2.

All patients were planned to receive long-term androgen deprivation therapy (ADT) but could also receive additional standard of care treatments according to clinician choice, including radiotherapy to the prostate, docetaxel, or, from 2021 onward, an androgen receptor pathway inhibitor (ARPI).

Of note, the trial was conducted from September 2016 to March 2023, covering a period preceding the current era of ADT plus ARPI therapy for standard of care in the hormone-sensitive setting.

While metformin use was not associated with survival or oncologic benefits overall, it was associated with metabolic protection from ADT. Gillessen and colleagues found that at 104 weeks, patients receiving metformin had significantly less weight gain, lower fasting glucose concentrations, lower total cholesterol, lower LDL cholesterol, lower HbA1c, and lower waist measurements than those receiving standard of care alone.

These improved metabolic outcomes alone “are meaningful,” stressed Neeraj Agarwal, MD, and two colleagues of University of Utah Health in Salt Lake City, in a commentary accompanying the study.

They noted that as the median overall survival of patients with metastatic hormone-sensitive prostate cancer increases, their long-term mortality risk gradually shifts to non-prostate cancer causes.

“Despite the absence of survival benefits in the STAMPEDE trial, given its metabolic benefits, metformin addition could still emerge as a reasonable adjunctive strategy to mitigate ADT-induced metabolic derangements and improve overall cardiometabolic health,” wrote Agarwal and colleagues.

“However, the question remains whether all patients undergoing ADT or only those high-risk individuals with pre-existing metabolic dysfunction should receive metformin in addition to ADT,” the editorialists cautioned.

STAMPEDE otherwise follows a line of randomized trials (e.g., MAST, TAXOMET, IMPROVE) that have failed to prove cancer progression or survival benefits to metformin across disease stages.

Gillessen’s group had 1,874 patients with metastatic disease randomized to receive standard of care with or without metformin.

The median patient age was 69 years, and median prostate-specific antigen was 84 ng/mL; 94% of the cohort was newly diagnosed with metastatic disease, the remaining 6% diagnosed with metachronous relapsing disease. Most (82%) received ADT plus docetaxel, while 3% received abiraterone, enzalutamide (Xtandi), or apalutamide.

Median time to most recent case report from follow-up was 60 months, whereas median time to date last known to be alive was 69 months.

Study authors reported no evidence of an effect of metformin on prostate cancer-specific survival in the overall population, nor any strong suggestion of heterogeneity of effect for any of the prespecified subgroups.

Only with PFS and metastatic PFS were there indications of a potential anticancer benefit among metformin users with high-volume disease instead of low-volume disease (P=0.012 and P=0.013 for interaction, respectively).

As for safety, the proportion of patients experiencing grade 1-5 adverse events (AEs) was similar between the two study groups, with the exception of gastrointestinal AEs. Grade ≥3 gastrointestinal AEs were reported in 7% of patients in the standard of care group and 9% in the standard of care plus metformin group, while no other body systems showed a difference in grade 3 AEs.

STAMPEDE authors acknowledged the trial’s open-label design as a limitation. They also cautioned that they could not be certain how well patients adhered to their assigned metformin, and that there was a paucity of patients who received ADT plus an ARPI.