Testing for homologous recombination repair or homologous recombination deficiency for poly (ADP-ribose) polymerase inhibitors: A current perspective

Poly (ADP-ribose) polymerase inhibitors (PARPis) have demonstrated clinical activity in patients with BRCA1 and/or BRCA2 mutated breast, ovarian, prostate, and pancreatic cancers. Notably, BRCA mutations are associated with defects in the homologous recombination repair (HRR) pathway. This homologous recombination deficiency (HRD) phenotype can also be observed as genomic instability in tumour cells. Accordingly, PARPi sensitivity has been observed in various tumours with HRD, independent of BRCA mutations. Currently, four PARPis are approved by regulatory agencies for the treatment of cancer across multiple tumour types. Most indications are specific to tumours with a confirmed BRCA mutation, mutations in other HRR-related genes, HRD evidenced by genomic insta-bility, or evidence of platinum sensitivity. Regulatory agencies have also approved companion and complementary diagnostics to facilitate patient selection for each PARPi indi-cation. This review aims to summarise the biological basis, clinical validation, and clinical rele-vance of the available diagnostic methods and assays to assess HRD.(c) 2022 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc., Rahway, NJ, USA and The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

PARP inhibitors have shown clinical activity in patients with BRCA1 and/or BRCA2 mutated breast, ovarian, prostate, and pancreatic cancers. The sensitivity to PARPi is not only limited to tumors with BRCA mutations but also observed in tumors with HRD phenotype. Regulatory agencies have approved companion and complementary diagnostics to facilitate patient selection for PARPi treatment. This review aims to summarize the biological basis, clinical validation, and clinical relevance of diagnostic methods and assays to assess HRD.