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

Background

Metformin is a widely used, well tolerated anti-diabetic agent. Several studies suggest metformin has anti-cancer activity in different malignancies, including prostate cancer. We hypothesised that metformin also reduces the development of ADT-induced metabolic adverse effects, possibly improving OS via these mechanisms.

Methods

Non-diabetic pts with mHSPC were randomly allocated 1:1 to standard of care (SOC) or SOC+metformin within STAMPEDE. SOC included ADT ± radiotherapy ± docetaxel ± androgen receptor pathway inhibitor (ARPI). The primary outcome was OS. Target hazard ratio (HR) 0.8 (92% power, 2.5% 1-sided significance). 7 subgroup analyses were pre-specified but not pre-powered.

Results

1874 pts with mHSPC were randomised Sep2016-Mar2023. Arms were well balanced: median age 69 years, IQR 63-73; median PSA 84ng/ml, IQR 24-352; de novo 1758 (94%) vs relapsed 116 (6%). Planned SOC included 82% Docetaxel and 3% ARPI. After a median follow-up of 60 months, the HR for OS between arms was 0.91 (p=0.148; 95% CI 0.80-1.03). The median (95%CI) OS was 63 (58-69) and 69 (63-73) months in the SOC and SOC+metformin arms respectively. In patients with high versus low volume disease (CHAARTED def), HR was 0.79 (p=0.006; 0.66-0.93) and 1.0 (p=0.992; 0.79-1.26) respectively. The interaction p-value = 0.086. For progression-free survival: Overall HR was 0.92 (p=0.164; 0.81-1.04) with HRs of 0.76 (p=0.001; 0.64-0.89) and 1.10 (p=0.401; 0.88-1.37) in the high and low volume subgroups respectively, interaction p-value = 0.006. Metabolic parameters that improved significantly with metformin included reduced weight gain, fasting glucose, HbA1c and total and LDL cholesterol. Fewer patients developed a metabolic syndrome. Adverse events (AE) ≥grade 3 were reported in 52% and 57% in the SOC and SOC+metformin arms, respectively; Gastrointestinal AEs increased with metformin.

Conclusions

Metformin does not improve survival in unselected metastatic patients but may improve cancer outcomes and survival in high volume patients. Metabolic parameters were significantly improved overall.

Clinical trial identification

NCT00268476.

Editorial acknowledgement

Legal entity responsible for the study

University College London.

Funding

Cancer Research UK; Medical Research Council; Prostate Cancer UK; Novartis; Sanofi-Aventis; Pfizer; Janssen Pharma NV; Astellas.

Disclosure

S. Gillessen: Financial Interests, Institutional, Advisory Board, 2022: Amgen, AstraZeneca, Bayer, MSD Merck Sharp & Dohme, Myriad Genetic, Orion; Financial Interests, Institutional, Advisory Board, 2023: BMS, Daiichi Sankyo, Innomedica, Ipsen, Boehringer Ingelheim, Innomedica, Bayer; Financial Interests, Institutional, Invited Speaker, 2022: ESMO, Silvio Grasso Consulting; Financial Interests, Institutional, Other, Interview 2022: PeerVoice; Financial Interests, Institutional, Invited Speaker, 2023: SAKK, Meister ConCept GmbH, ASCO GU, EPG Health, S. Grasso Consulting, AdMeTech Foundation; Financial Interests, Institutional, Other, Faculty activity 2022: WebMD-Medscape; Financial Interests, Personal, Other, Travel support 2022: AstraZeneca; Financial Interests, Personal, Invited Speaker, 2022: DESO, SAKK; Financial Interests, Personal, Other, Travel support 2023: Bayer; Financial Interests, Institutional, Invited Speaker, 2024: Intellisphere LLC; Financial Interests, Personal, Other, Travel support 2024: Gilead; Financial Interests, Personal, Invited Speaker, Speaker OncoSummit 02.2024: Meister ConCept GmbH; Financial Interests, Personal, Other, Travel Support 2024: Intellisphere LLC; Financial Interests, Institutional, Other, Scientific Committee Pfizer Forschungspreis 2022/2023: Pfizer; Financial Interests, Institutional, Other, Consulting Agreement: TOLREMO; Financial Interests, Personal, Invited Speaker, 2023/2024: ESMO; Financial Interests, Institutional, Advisory Board, 2024: Ipsen, Macrogenics; Financial Interests, Personal, Other, Part of a patent for a biomarker, but (for the moment) no income, but I could not write none in the dropdown menu: Proteomedix/Onconetix; Financial Interests, Institutional, Funding, 2021, Unrestricted grant for a Covid related study as co-investigator: Astellas; Non-Financial Interests, Advisory Role, Continuing: ProteoMediX. N.D. James: Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors: AstraZeneca; Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Janssen, Clovis, Novartis; Financial Interests, Institutional, Advisory Board, Assisted with submissions regarding licencing for abiraterone: Janssen; Financial Interests, Personal, Advisory Board, Docetaxel: Sanofi; Financial Interests, Institutional, Advisory Board, Providing STAMPEDE trial data to facilitate licence extensions internationally for docetaxel: Sanofi; Financial Interests, Personal, Advisory Board, Bladder cancer therapy: Merck; Financial Interests, Personal, Advisory Board, Advice around novel hormone therapies for prostate cancer: Bayer; Financial Interests, Personal, Invited Speaker, Lecture tour in Brazil August 2022 - speaking on therapy for advanced prostate cancer: Merck Sharp & Dohme (UK) Limited; Financial Interests, Institutional, Coordinating PI, Funding for STAMPEDE trial: Janssen, Astellas; Financial Interests, Institutional, Coordinating PI, Funding for RADIO trial bladder cancer: AstraZeneca. G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion, Novartis, Blue Earth Therapeutics; Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone: Institute of Cancer Research; Financial Interests, Institutional, Advisory Board: Artera, Veracyte; Financial Interests, Institutional, Research Grant: Janssen, Astellas, Novartis; Financial Interests, Institutional, Coordinating PI: Janssen; Financial Interests, Institutional, Local PI: Novartis, Pfizer; Non-Financial Interests, Principal Investigator: Janssen, Astellas; Non-Financial Interests, Advisory Role: Janssen, AstraZeneca; Non-Financial Interests, Project Lead: Artera, Veracyte. R.J. Jones: Financial Interests, Personal, Advisory Board, advisory board attendance: AstraZeneca, Astellas; Financial Interests, Personal, Invited Speaker, Honoraria for speaking: Astellas; Financial Interests, Personal, Advisory Board: Bayer, Clovis, Exelixis, Ipsen, Bristol Myers Squipp, Merck Serono, Merck Sharpe Dome, Roche, Janssen, Novartis / AAA, MSD, Astellas, Gilead, AstraZeneca, pfizer; Financial Interests, Personal, Invited Speaker: Bayer, Ipsen, Bristol Myers Squibb, Merck Serono, Merck Sharpe Dome, Pfizer, Roche, Janssen, Pfizer; Financial Interests, Institutional, Other, IDMC membership: Roche; Financial Interests, Institutional, Other, IDMC member: Stab; Financial Interests, Personal, Other, promotional video: Astellas, astellas, astellas, bayer; Financial Interests, Institutional, Local PI: Janssen, Pfizer, Tail, AstraZeneca, BioXcel, Bristol Myers Squibb; Financial Interests, Institutional, Coordinating PI: Novartis / AAA, Roche, MSK. M. Varughese: Financial Interests, Personal, Advisory Board: Janssen, Pfizer; Financial Interests, Personal, Invited Speaker, To educational event: MSD; Financial Interests, Personal, Other, To attend educational event: Astellas; Financial Interests, Personal, Other, To attend international congress: Janssen; Financial Interests, Personal, Other, to attend international congress: Roche; Financial Interests, Institutional, Local PI: Pfizer, Roche, Astellas. N.N. Srihari: Financial Interests, Personal, Non financial benefits, registration fees: Jansen. C. Murphy: Financial Interests, Institutional, Full or part-time Employment: University College London. M.K. Parmar: Financial Interests, Institutional, Full or part-time Employment, Director at MRC Clinical Trials Unit at UCL: Medical Research Council Clinical Trials Unit at UCL; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, Astellas, Janssen, Baxter, GSK; Financial Interests, Institutional, Research Grant: Clovis, Abcodia Pvt Ltd, Akagera, Amgen, Aspirin Foundation, Bayer, BMS US, Bri-BioCepheid, Cipla, CSL Behring, Eli-Lilly, Emergent Biosolutions, Gilead Sciences, Grifols, Johnson & Johnson, Pfizer, Sanofi, ViiVHealthcare, Micronoma, Modus Theraputics, Mylan, Serum Institute of India, shionogi, SyntenyBiotechnology, Takeda, Tibotec, Transgene, Virco and Xenothera; Non-Financial Interests, Advisory Role, Euro Ewing Consortium: University College London; Non-Financial Interests, Advisory Role, rEECur: University of Birmingham; Non-Financial Interests, Advisory Role, CompARE Trial: University of Birmingham; Non-Financial Interests, Advisory Role, ROSSINI Trial Platform: University of Birmingham. L.C. Brown: Financial Interests, Institutional, Research Grant, £170k educational grant for the FOCUS4-C Trial from June 2017 to Dec 2021: AstraZeneca; Financial Interests, Institutional, Funding, Various grants awarded to my institution for work undertaken as part of the STAMPEDE Trial: Janssen Pharmaceuticals; Financial Interests, Institutional, Funding, Grant funding to my institution for the STAMPEDE2 trial: Novartis AAA; Non-Financial Interests, Other, I am a member of the CRUK CERP funding advisory panel and my Institution also receive grant funding from CRUK for the STAMPEDE and FOCUS4 trials: Cancer Research UK. N. Clarke: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca; Financial Interests, Personal, Invited Speaker: Ipsen, Bayer, Pfizer, Janssen; Non-Financial Interests, Leadership Role, Principal Investigator The Propel Trial: AstraZeneca. All other authors have declared no conflicts of interest.