Identifying patients eligible for PARP inhibitor treatment: from NGS-based tests to 3D functional assays

Overview & Synopsis

Within the past few years, poly (ADP-ribose) polymerase inhibitors (PARPi) have been added to the standard of care for cancer patients, mainly for those exhibiting specific genomic alterations in the homologous recombination (HR) pathway. Until now, patients who are eligible to receive PARPi have been identified using next-generation sequencing (NGS) of gene panels. However, NGS analyses do have some limitations, with a subset of patients with negative NGS-based results can exhibit a clinical benefit, responding positively to PARPi, despite the failure to detect dynamic and predictive biomarkers such as mutated BRCA1/2 genes. Furthermore, the sequencing of initial tumour does not allow to detect reversions or secondary mutations that can restore proficient HR and lead to PARPi resistance. Therefore, it is crucial to better identify patients who are likely to benefit from PARPi treatment. In this context, tumour models such as patient-derived xenografts or tumour-derived organoids could help to guide clinicians in their decision making as these models accurately mimic phenotypic and genetic tumour heterogeneity, and could reflect treatment response in an integrative manner. In this Perspective article, we provide an overview of the currently available NGS-based tests that enable the identification of patients who might benefit from PARPi, and outline breakthroughs and discoveries to expand this selection using 3D functional assays. Combining NGS with functional assays could facilitate the efficient identification of patients, thereby improving patient survival.