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PARP inhibitors for metastatic castration-resistant prostate cancer: Biological rationale and current evidence

Published:February 10, 2022DOI:https://doi.org/10.1016/j.ctrv.2022.102359

      Highlights

      • Up to 25% of mCRPC patients harbor germinal or somatic alterations in HRR genes.
      • PARP inhibitors show antitumor activity in patients with aberrations in HRR genes.
      • PARPi are approved for mCRPC based on their efficacy and acceptable toxicities.
      • Particular HRR alterations may have different impact on PARPi efficacy.
      • PARPi sensitivity assessment is needed to improve patients’ selection.

      Abstract

      Poly(ADP-ribose) polymerase inhibitors (PARPi) are the first clinically approved agents designed to exploit synthetic lethality. Based on the recent approvals, PARPi became available for patients with metastatic castration-resistant prostate cancer (mCRPC). Unlike breast or ovarian cancers, where the approvals are limited to patients with BRCA1/2 alterations, in mCRPC PARPi are offered to patients with a broader spectrum of aberrations. A growing body of data indicates that alterations in specific homologous recombination repair (HRR) genes may confer different sensitivities to PARPi. Another challenging issue is the optimal testing methodology for identifying these aberrations. This comprehensive review presents the current place of PARPi in the treatment of mCRPC, provide biological rationale explaining mechanisms of their action and resistance, and discuss current clinical challenges along with avenues for future research.

      Keywords

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