KEY TAKEAWAYS
- The study aimed to assess the effect of metformin on OS and metabolic outcomes in mHSPC with ADT.
- Metformin did not improve survival in all metastatic patients but enhanced outcomes and metabolic parameters in high-volume cases.
Metformin is a commonly used and well-tolerated anti-diabetic medication. Previous research indicates that metformin may possess anti-cancer properties across various malignancies, including prostate cancer. This study hypothesized that metformin could mitigate the metabolic adverse effects associated with androgen deprivation therapy (ADT) and potentially enhance overall survival through these effects.
Silke Gillessen and the team aimed to assess the impact of combining metformin with ADT on overall survival and metabolic parameters in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
They performed an inclusive analysis of non-diabetic patients with metastatic hormone-sensitive prostate cancer who were randomly allocated 1:1 to receive either standard of care (SOC) or SOC plus metformin within the STAMPEDE trial. SOC included ADT with or without radiotherapy, docetaxel, or an androgen receptor pathway inhibitor (ARPI).
The primary outcome was overall survival (OS), with a target hazard ratio (HR) of 0.8, providing 92% power and a 2.5% one-sided significance level. Seven pre-specified subgroup analyses were conducted but were not pre-powered.
About 1,874 patients with metastatic hormone-sensitive prostate cancer were randomized from September 2016 to March 2023. The arms were well balanced: median age 69 years (IQR 63-73); median PSA 84 ng/ml (IQR 24-352); 1,758 patients (94%) had de novo disease, and 116 (6%) had relapsed disease. Planned SOC included 82% receiving docetaxel and 3% receiving an ARPI. After a median follow-up of 60 months, the HR for OS between the arms was 0.91 (P=0.148; 95% CI 0.80-1.03).
The median OS was 63 months (95% CI 58-69) in the SOC arm and 69 months (95% CI 63-73) in the SOC plus metformin arm. In patients with high versus low volume disease (CHAARTED definition), the HR was 0.79 (P=0.006; 95% CI 0.66-0.93) and 1.0 (P=0.992; 95% CI 0.79-1.26), respectively, with an interaction P-value of 0.086.
For progression-free survival (PFS), the overall HR was 0.92 (P=0.164; 95% CI 0.81-1.04), with HRs of 0.76 (P=0.001; 95% CI 0.64-0.89) and 1.10 (P=0.401; 95% CI 0.88-1.37) in the high and low volume subgroups, respectively, with an interaction P-value of 0.006.
Metabolic parameters that improved significantly with metformin included reduced weight gain, fasting glucose, HbA1c, and total and LDL cholesterol. Fewer patients developed metabolic syndrome. Adverse events (AE) of grade 3 or higher were reported in 52% of the SOC arm and 57% of the SOC plus metformin arm, with gastrointestinal AEs increasing with metformin.
The study concluded that metformin does not improve survival in unselected metastatic patients but may enhance cancer outcomes and survival in patients with high-volume disease. Additionally, metabolic parameters were significantly improved overall.
The trial was sponsored by the Medical Research Council.
Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/18
Clinical Trial: https://clinicaltrials.gov/study/NCT00268476
Gillessen S, Murphy L.R, James N.D, et al. (2024). “LBA70 – Adding metformin to androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC): Overall survival (OS) results from the multi-arm, multi-stage randomised platform trial STAMPEDE.” Presented at ESMO 2024 (Abstract LBA70).
