ESMO 2024: Adding Metformin to ADT for Patients with mHSPC: Overall Survival Results from the Multi-Arm, Multi-Stage Randomized Platform Trial STAMPEDE

(UroToday.com) The 2024 ESMO annual meeting included a session on prostate cancer, featuring a presentation by Dr. Silke Gillessen discussing results from STAMPEDE assessing the addition of metformin to ADT for patients with mHSPC. ADT is standard of care in advanced prostate cancer, but it has metabolic adverse effects. Metformin is a widely used, well tolerated anti-diabetic agent. Several studies suggest metformin has anti-cancer activity in different malignancies, including prostate cancer. Dr. Gillessen and colleagues hypothesized that metformin also reduces the development of ADT-induced metabolic adverse effects, possibly improving overall survival via these mechanisms.

Non-diabetic patients with mHSPC were randomly allocated 1:1 to standard of care or standard of care + metformin within STAMPEDE. Standard of care included ADT ± radiotherapy ± docetaxel ± androgen receptor pathway inhibitor. The primary outcome was overall survival. The trial design is as follows:

image-0.jpg

The planned sample size was 1,8000 patients with mHSPC, assuming a median overall survival of 54 months, with 2.5% 1-sided significance, this would give 92% power to detect a treatment difference hazard ratio of 0.80; 7 subgroup analyses were pre-specified but not pre-powered. The final analysis was triggered by 473 events in the control arm, with a data freeze on July 3, 2024.

There were 1,874 patients with mHSPC randomized from September 2016 through March 2023. The arms were well balanced, with a median age of 69 years (IQR 63-73), median PSA of 84 ng/ml (IQR 24-352), and de novo metastatic disease in 1,758 (94%) patients versus relapsed in 116 (6%). Planned standard of care included 82% of patients receiving docetaxel and 3% receiving androgen receptor pathway inhibitor:

image-1.jpg

After a median follow-up of 60 months, the HR for overall survival between arms was 0.91 (95% CI 0.80-1.03; p = 0.148). The median overall survival was 63.1 (95% CI 57.6-68.7) and 69.1 (95% CI 62.7-73.2) months in the standard of care and standard of care + metformin arms, respectively:

image-2.jpg

In patients with high versus low volume disease (CHAARTED definition), HR was 0.79 (95% CI 0.66-0.93; p = 0.006) and 1.00 (95% CI 0.79-1.26; p = 0.992), respectively, with an interaction p-value of 0.086:

image-3.jpg

Overall survival by subgroup analysis is as follows:

image-4.jpg

For progression-free survival, the overall HR was 0.92 (95% CI 0.81-1.04; p = 0.164) with HRs of 0.76 (95% CI 0.64-0.89; p = 0.001) and 1.10 (95% CI 0.88-1.37; p = 0.401) in the high and low volume subgroups, respectively (interaction p-value = 0.006):

image-5.jpg

Metabolic parameters that improved significantly with metformin included reduced weight gain (-2.5, 95% CI -3.6 to -1.4), fasting glucose (-0.17, 95% CI -0.29 to -0.05), and HbA1c (-1.0, 95% CI -1.6 to -0.5):

image-6.jpg

Additionally, the metformin arm decreased total (-0.16, 95% CI -0.29 to -0.03) and LDL cholesterol (-0.17, 95% CI -0.29 to -0.05):

image-7.jpg

Importantly, all of the aforementioned parameters statistically significantly improved at 6, 12, and 24 months. Adverse events ≥ grade 3 were reported in 52% and 57% in the standard of care and standard of care + metformin arms, respectively. Gastrointestinal adverse events increased with metformin. 

image-8.jpg

Dr. Gillessen concluded her presentation by discussing results from STAMPEDE assessing the addition of metformin to ADT for patients with mHSPC with the following take-home points:

  • There is no clear evidence that adding metformin to standard of care increases overall survival in unselected patients with mHSPC
  • There is some evidence of benefit for outcomes in the pre-specified, but not pre-powered, subgroup with high-volume compared to low-volume disease, which requires further evaluation
  • Most metabolic parameters improved significantly with metformin, irrespective of disease volume, which may translate to reduced cardiovascular deaths in the future
  • Future research is warranted for patients treated with an ADT-androgen receptor pathway inhibitor doublet backbone

Presented by: Silke Gillessen, MD, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 European Society of Medical Oncology (ESMO) Annual Meeting, Barcelona, Spain, Fri, Sept 13 – Tues, Sept 17, 2024. 

Related content: Metformin Study Reveals Weight Management Benefits for ADT Therapy - Silke Gillessen