Abstract
PARP inhibitors in ovarian cancer have been a breakthrough therapy of the past decade, driven by positive trial results, and supported by an original pharmacological rationale. However, with mature data, detrimental survival results led to the withdrawals, in 2022, of all approved PARP inhibitors in the most advanced settings’ indication (as monotherapy in third or subsequent lines) by the US Food and Drug Administration (FDA). Two other indications, as maintenance after relapse, were also restricted. In this work, based on pooled meta-analysis in each setting, we question a unique situation in oncology: a survival benefit is seen in front-line settings, with, at the same time, a survival decrement in later lines. Either this original feature is explained by the unique biological action of PARP inhibitors—through synthetic lethality—in patients with ovarian cancer and homologous repair deficiency. Another explanation may be trial design: decrement in later lines could partly explain why beneficial results were seen in early settings, simply by avoiding late exposure to PARP inhibitors in the experimental arm in those trials. High crossover rates seen in some trials further support this alternate hypothesis. We contend our analysis and recent survival results of PARP inhibitors warrant a whole reassessment of the place of these compounds in the landscape of ovarian cancer treatments.
Data availability
All data used in this work are publicly available.
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Funding
This project was funded by Arnold Ventures, LLC through a grant paid to the University of California, San Francisco (grant number: not available). The funders had no role in the design and conduct of the study.
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TO: conceptualization, writing, original draft, writing, review, and editing. VP: conceptualization, writing, review, and editing.
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Vinay Prasad’s disclosures: research funding: Arnold Ventures; royalties: Johns Hopkins Press, Medscape; honoraria: grand rounds/lectures from universities, medical centers, non-profits, and professional societies; consulting: UnitedHealthcare; speaking fees: Evicore; other: Plenary Session podcast has Patreon backers. Timothée Olivier has no financial nor non-financial conflicts of interest to report.
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Because we used publicly available data, and this is not human subjects’ research in accordance with 45 CFR §46.102(f), we did not submit this study to an institutional review board or require informed consent procedures.
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Olivier, T., Prasad, V. PARP inhibitors and overall survival in ovarian cancer, reevaluation advised in all settings. J Cancer Res Clin Oncol 149, 9509–9512 (2023). https://doi.org/10.1007/s00432-023-04748-5
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DOI: https://doi.org/10.1007/s00432-023-04748-5