PARP inhibitors and overall survival in ovarian cancer, reevaluation advised in all settings.

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 survivalbenefit is seen in front-line settings, with, at the same time, a survivaldecrement 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.