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  • Impact of metformin, statins, and beta blockers on survival in patients with primary ovarian cancer: combined analysis of four prospective trials of AGO-OVAR and ENGOT/GCIG collaborators

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Original research
Impact of metformin, statins, and beta blockers on survival in patients with primary ovarian cancer: combined analysis of four prospective trials of AGO-OVAR and ENGOT/GCIG collaborators
  1. Dominik Denschlag1,
  2. Florian Heitz2,
  3. Jacobus Pfisterer3,
  4. Darja Tutschkow4,
  5. Alexander Reuss5,
  6. Werner Meier6,
  7. Philipp Harter7,
  8. Pauline Wimberger8,
  9. Mansoor Raza Mirza9,
  10. Isabelle Ray-Coquard10,11,
  11. Giovanni Scambia12,
  12. Jae-Weon Kim13,
  13. Nicoletta Colombo14,
  14. Ana Oaknin15,
  15. Jalid Sehouli16,
  16. Kristina Lindemann17,18,
  17. Coriolan Lebreton19,
  18. Michael Eichbaum20,
  19. Stefan Spiegelberg21,
  20. Hannah Woopen22 and
  21. Andreas du Bois23
    1. 1OB/GYN, Hochtaunus Kliniken gGmbH, Bad Homburg vor der Hohe, Germany
    2. 2Gynecology and Gynocologic Oncology, Kliniken Essen-Mitte, Essen, Germany
    3. 3Gynecologic Cancer Center, Kiel, Germany
    4. 4University of Marburg, Marburg, Germany
    5. 5Coordinating Center for Clinical Trials, Philipps-Universität Marburg, Marburg, Germany
    6. 6University Hospital of Düsseldorf, Dusseldorf, Germany
    7. 7Department of Gynecology and Gynecologic Oncology, Ev, Kliniken Essen-Mitte, Essen, Germany
    8. 8Gyncology and Obstetrics, Technische Universitat Dresden Medizinische Fakultat Carl Gustav Carus, Dresden, Germany
    9. 9Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
    10. 10Centre Leon Berard, Lyon, France
    11. 11Hesper Lab, Université Claude Bernard Lyon 1, Villeurbanne, France
    12. 12Dipartimento Scienze della Salute della Donna e del Bambino, Fondazione Policlinico Universitario A Gemelli IRCCS, Roma, Italy
    13. 13Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)
    14. 14Medical Gynecologic Oncology Unit, University of Milan Bicocca, European Institute of Oncology, Milano, Italy
    15. 15Vall d'Hebron University Hospital, Barcelona, Spain
    16. 16Gynecology with Center of Oncological Surgery, Charite Universitatsmedizin Berlin, Berlin, Germany
    17. 17Department of Gynecological Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
    18. 18Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
    19. 19Department of Medical Oncology, Institut Bergonié, Bordeaux, France
    20. 20HSK, Wiesbaden, Germany
    21. 21Hochtaunuskliniken, Bad Homburg, Germany
    22. 22Gynecology, Charite-University Medicine of Berlin, European Competence Center for Ovarian Cancer, Berlin, Germany
    23. 23Department of Gynecology and Gynecologic Oncology, KEM, Kliniken Essen Mitte, Essen, Germany
    1. Correspondence to Dr Dominik Denschlag; dominik.denschlag{at}hochtaunus-kliniken.de

    Abstract

    Objective The aim of this study was to investigate the association of co-medication with metformin, a statin, or beta blocker with survival in patients with primary ovarian cancer.

    Methods Individual data from three phase III, randomized controlled trials (AGO-OVAR 11, AGO-OVAR 12, and AGO-OVAR 16) and one phase II trial (AGO-OVAR 15) were pooled and analyzed. Patients were classified as ever user if the specific co-medication was documented at least once during the trial, and were compared with never users as controls. Association of co-medications and outcomes were adjusted for potential confounders (age, International Federation of Gynecology and Obstetrics stage, histology, residual disease after surgery, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index, Charlson Comorbidity Index, and assigned treatment within the trial) in multivariate Cox regression analyses.

    Results Overall, n=2857 patients were included. Ever users were: 100 patients received metformin (3.5%), 226 patients received statins (7.9%), and 475 (16.6%) patients received beta blockers (n=391 selective beta blockers; 84 non-selective beta blockers) as co-medication. There were no significant differences regarding the baseline characteristics except that ever users were significantly older, more obese, and had more comorbidities, according to the Charlson Comorbidity Index, compared with controls. Multivariate analyses for progression free survival and overall survival revealed neither a significant impact of metformin on survival (progression free survival hazard ratio (HR) 0.94, 95% confidence interval CI 0.69 to 1.29, p=0.7; overall survival HR 0.82, 95% CI 0.58 to 1.17, p=0.28) nor for statins (progression free survival HR 0.98, 95% CI 0.82 to 1.18, p=0.87; overall survival HR 0.91, 95% CI 0.74 to 1.12, p=0.37). In contrast, ever users of selective beta blockers had a significantly higher risk for recurrence and death (progression free survival HR 1.22, 95% CI 1.05 to 1.41, p=0.009; overall survival HR 1.25 95% CI 1.06 to 1.47, p=0.009).

    Conclusions In this analysis, co-medication with metformin or statins had no significant impact on survival in patients with primary ovarian cancer. In contrast, co-medication with a beta blocker was associated with worse survival. However, whether this observation is related to the underlying condition rather than a direct negative impact on tumor biology remains unclear.

    • Ovarian Cancer

    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

    https://doi.org/10.1136/ijgc-2024-005663

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      Data availability statement

      All data relevant to the study are included in the article or uploaded as supplementary information.

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      Footnotes

      • DD and FH are joint first authors.

      • DD and FH contributed equally.

      • Presented at The manuscript was presented as an oral presentation at the ESGO meeting in 2021.

      • Contributors All authors substantially contributed to the conception and design of the work or the acquisition, analysis, and interpretation of data for the work. All authors drafted the work and revised it critically for important intellectual content; finally approved the current version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DD is the guarantor.

      • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.

      • Competing interests DD: honoraria: AstraZeneca, GSK, Intuitive, KLS Martin, Merck Sharp & Dohme (MSD); travel/accommodation/expenses: AstraZeneca; Data Safety Monitoring Board/Advisory Board: AstraZeneca, Eisai, GSK, KLS Martin, MSD, PharmaMar, Seagen. FH: personal fees and non-financial support: AstraZeneca, Roche, Tesaro, GSK, Clovis; personal fees: Zailabs and PharmaMar, outside the submitted work. JF: honoraria: Medupdate, Decision Resources, Simon-Kucher and Partners, Juniper, Bionest Partner, Vox Bio, Axiam Healthcare Strategies, Prosapient, Lilly, MedPartners; research funding: Roche Pharma AG, GSK/Tesaro; travel/accommodation/expenses: Roche Pharma AG. PH: grants, personal fees and non-financial support: Astra Zeneca, GSK; grants and personal fees: Roche, MSD, Clovis, Immunogen; personal fees: Sotio, Stryker, Zai Lab, Mersana, Miltenyi; grants: Boehringer lngelheim, Medac, Genmab, Deutsche Krebshilfe, Deutsche Forschungsgemeinschaft, outside the submitted work. PW: Advisory Board Member and received honoraria: Amgen, AstraZeneca, MSD, Novartis, Pfizer, Lilly, Roche Pharma, Eisai, Clovis, GSK, Daiichi Sankyo. MRM: honoraria: Astra Zeneca, Eisai, Genmab, GSK, Mersana, Takeda, Zailab; travel/accommodation/expenses: AstraZeneca, GSK, Takeda; Advisory Board: Allarity Therapeutics, Astra Zeneca, Biontech, Daiichi-Sankyo, Eisai, Genmab, GSK, lmmunogen, Incyte, Merck/MSD, Mersana, Regeneron, Zailab; Chairman (2020-2022) of the European Network of Gynaecological Oncology Trials group; Vice-President of the European Society of Gynaecological Oncology; Faculty member of the European Society of Medical Oncology; Scientific Chair of the International Gynecologic Cancer Society; stock options: Karyopharm Therapeutics, Sera Prognostics. IRC: grants/contracts: Astra Zeneca, Clovis, GSK, Mersana, BMS, MSD; honoraria: Astra Zeneca, Clovis, GSK, Mersana, BMS, MSD, Roche, PharmaMar, Seagen, ESAI, Novartis; travel/accommodation/expenses: Roche, GSK, Astra Zeneca, PharmaMar, MSD; Data Safety Monitoring Board/Advisory Board: Clovis, Deciphera, AdaptImmune, Sutro, Immunogen. GS: grants: MSD Italia S.r.l; consulting fees: Tesaro Bio Italy S.r.l, Johnson & Johnson; payment for expert testimony: Clovis Oncology Italia S.r.l; NC: grants: GSK, Astrazeneca; consulting fees: AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, Pieris, Roche; honoraria: AstraZeneca, Novartis, Clovis Oncology,GSK, MSD/Merck; Data Safety Monitoring Board/Advisory Board: AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, Pieris, Roche. AO: Grants to institution: AbbVie Deutschland, Advaxis Inc., Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Clovis Oncology Inc., Eisai Ltd, F. Hoffmann-La Roche Ltd, Regeneron Pharmaceuticals, lmmunogen Inc, Merck, Sharp & Dohme de Esparsia SA, Millennium Pharmaceuticals Inc, PharmaMar SA, Tesaro Inc., Bristol Myers Squibb; consulting fees and honoraria: AstraZeneca, Clovis Oncology, Deciphera, Genmab, GSK, lmmunogen, Mersana Therapeutics, PharmaMar, MSD de Esparia SA, Agenus, Sutro, Corcept Therapeutics, EMD Serono, Novocure, Sattucklabs, Itheos, Eisai; travel/accommodation/expenses: AstraZeneca, PharmaMar, Roche; Data Safety Monitoring Board/Advisory Board: AstraZeneca, Clovis Oncology, Deciphera, Genmab, GSK, Immunogen, Mersana Therapeutics, PharmaMar, MSD de Esparia SA, Agenus, Sutro, Corcept Therapeutics, EMD Serono, Novocure, Sattucklabs, Itheos, Eisai; JS: study funding to institution: GSK, AstraZeneca, MSD, Clovis, Tesaro; consulting fees: GSK, Astra Zeneca, Tesaro, MSD, Elisei, Clovis, Riemser, Roche; travel/accomodation/expenses: Roche; Data Safety Monitoring Board/Advisory Board: GSK, PharmaMar, Novocure, Astra Zeneca, Clovis, GSK, Tesaro; ESGO Faculty; NOGGO President; PARSGO President. KL: grants: GSK; honoraria: Eisai; Data Safety Monitoring Board/Advisory Board: Eisai, MSD, Nycode, Astra Zeneca, GSK. CL: honoraria: IMSD, GSK, Eisai, Clovis Oncology; travel/accommodation/expenses: MSD, GSK; Data Safety Monitoring Board/Advisory Board: GSK. ME: stock/stock options: GSK. AdB: honoraria: Zodiac, AMGEN, GSK/Tesaro; Data Safety Monitoring Board/Advisory Board: AstraZeneca/MSD, AMGEN, Pfizer, GSK/Tesaro. All other authors declare no competing interests.

      • Provenance and peer review Not commissioned; externally peer reviewed.

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