Abstract A115: DNA repair biomarkers to guide usage of combined PARP inhibitors and chemotherapy: A meta-analysis and systematic review

Abstract Background: The addition of PARP inhibitors to chemotherapy has been assessed in 90 clinical trials across multiple malignancies, on the premise that PARP inhibitors will increase chemotherapy effectiveness regardless of whether cancers have underlying disruption of DNA repair pathways. Consequently, the majority of combination therapy trials have been performed on patients without biomarker selection, despite the use of homologous recombination deficiency to dictate use of PARP inhibitors in the maintenance setting. An unresolved question is whether biomarkers are needed to identify patients who respond to combination PARP inhibitors and chemotherapy. Objective: To provide the first synthesized analysis of the benefit of PARP inhibitors plus chemotherapies across multiple malignancies, and whether any benefit is dependent upon the presence of a DNA repair biomarker. Methods: A systematic literature review identified studies using PARP inhibitors in combination with chemotherapy versus chemotherapy alone, where the study included a biomarker of DNA repair function (BRCA1, BRCA2, BRCAPRO, ATM, ERCC1, SFLN11). Hazard ratios (HR) of identified studies were pooled in a meta-analysis using generic inverse-variance and fixed or random effects modelling. Subgroup analyses were conducted based on biomarker selection and type of malignancy. Results: Nine studies comprising 2, 084 patients met the inclusion criteria. Progression-free survival (PFS) was significantly better in patients selected with a DNA repair biomarker (HR 0. 52, 95% confidence interval (CI) 0. 43-0. 63; p 0. 00001), but there was no benefit in patients who lacked a biomarker (HR 0. 94, 95% CI 0. 82–1. 08; p = 0. 38). Subgroup analysis showed that BRCA mutation and SFLN11 biomarkers could predict benefit, and biomarker-driven benefit occurred in all malignancies (ovarian, breast and non-small cell lung cancers). The addition of PARP inhibitors was associated with more grade 3/4 side effects, and particularly neutropenia. Conclusions: Combination therapy only increases PFS in patients with identifiable DNA repair biomarkers. This indicates that PARP inhibitors do not sensitize patients to chemotherapy treatment, except where their cancer has a homologous recombination defect, or an alternative biomarker of impaired DNA repair. While effective in patients with DNA repair biomarkers, there is a risk of high-grade haematological side-effects with the use of combination therapy. Thus, the benefit in PFS from combination therapy must be weighed against potential adverse effects, as individual arms of treatment can also confer benefit. Citation Format: Zoe Phan, Caroline E. Ford, Elizabeth Caldon. DNA repair biomarkers to guide usage of combined PARP inhibitors and chemotherapy: A meta-analysis and systematic review abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr A115.