Collection of diagnostic tissue blocks from the STAMPEDE metformin trial in advanced prostate cancer

Background: Pre-clinical and observational studies have proposed a tumour suppressive effect for the anti-diabetic drug metformin in prostate cancer (PCa).

The CRUK-funded Phase III STAMPEDE metformin trial is the largest trial (n=3,019) evaluating the impact of metformin on advanced PCa.

It will provide a seminal dataset to conclusively determine whether metformin suppresses disease progression in non-diabetic men with locally advanced (M0) or metastatic (M1) hormone-sensitive PCa. Patients were randomised 1:1 to receive contemporary standard-of-care (SOC) or SOC with metformin. The primary outcome is overall survival.

The study will report in 2024 when ~473 M1 control arm deaths have been reported. >95% of patients have consented to translational research on their tumours.

Aims: We propose to collect archived prostate tissue blocks surplus to diagnostic requirements from ~2,000 metformin trial patients (646 M0 patients, 1054 M1 patients) recruited across 106 UK sites.

Methods: We will utilise the infrastructure and standard operating procedures of our STRATOSPHERE programme, which collected samples from ~3,200 PCa patients randomised in the STAMPEDE abiraterone and docetaxel Phase 3 trials for testing prognostic and predictive biomarkers.

Pseudo-anonymised tumour blocks will enter a research work-flow to obtain digitised pathology images, pan-transcriptome data, and molecular phenotyping.

Tests for associations of molecular biomarkers with clinical outcome will be performed by the MRC CTU statisticians following a pre-specified statistical analysis plan.

How the results of this research will be used: Data generated will be used to test several hypotheses including: (1) response to metformin is enriched in low NKX3.1-expressing cancers, mediated by reduction in oxidative stress and rescue of mitochondrial function, (2) metformin supresses cancer progression via O-GlycNAcylation of transcription factors including c-Myc, (3) metformin mediates response to prostate radiotherapy by modifying tumour oxygenation and DNA-damage response, (4) metformin mitigates treatment-related toxicity in a sub-set of patients defined by host-tumour interactions.

If metformin improves survival, its low cost and known toxicity profile will allow rapid implementation into routine clinical practice internationally.

However, if no improvement in survival is observed, this collection will generate a deeply characterised cohort managed with a contemporary SOC to validate multi-modal biomarkers.

These data will be integrated with parallel studies in the same cohort including longitudinal blood sampling, imaging biomarkers, and linkage with routinely collected healthcare data.

Together, this unique and valuable resource will help identify the sub-group of PCa patients most likely to derive benefit from metformin and generate hypotheses for the targeted development of novel therapies.