PARP Inhibitor Sensitivity in Tumors Harboring Non-BRCA Homologous Recombination Gene Alterations - Current Evidence Across Ovarian, Breast, Prostate, and Pancreatic Cancers

Sep 22, 2026

Poly(ADP-ribose) polymerase inhibitors (PARPis) show strong efficacy in tumors with BRCA1/2 pathogenic variants via synthetic lethality, yet the predictive value of non-BRCA homologous recombination (HR) gene alterations remains unclear and may differ by gene and cancer type. This narrative review synthesizes evidence on how non-BRCA HR pathogenic variants relate to PARPi sensitivity across ovarian, breast, prostate, and pancreatic cancers, analyzing clinical trials and preclinical data reported from 2023 to 2025.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages42

Reading Time1 h 46 min

AccessFree to download

Abstract

Introduction

Keywords

Review Methods and Evidence Summary

Preclinical findings

Clinical evidence and gene-specific associations

Limitations and future directions

Review PARP Inhibitor Sensitivity in Tumors Harboring Non-BRCA Homologous Recombination Gene Alterations: Current Evidence Across Ovarian, Breast, Prostate, and Pancreatic Cancers Elizabeth Santana dos Santos 1,2, André Luiz Cicilini 1, Maria Fernanda Evangelista Simões 3, Maria Baz 4, Sandrine M. Caputo 5,† and Etienne Rouleau 4, *,† Academic Editor: Roberto Piergentili Received: 11 April 2026 Revised: 21 July 2026 Accepted: 25 July 2026 Published: 28 July 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Department of Clinical Oncology, A.C. Camargo Cancer Center, São Paulo 01509-010, Brazil; [elizabeth.santanadossantos@gmail.com](elizabeth.santanadossantos@gmail.com) (E.S.d.S.); [andre.cicilini@accamargo.org.br](andre.cicilini@accamargo.org.br) (A.L.C.) 2 Department of Oncogenetics, Hospital Sírio Libanês, São Paulo 01308-050, Brazil 3 Department of Clinical Oncology, Hospital Sírio Libanês, São Paulo 01308-050, Brazil; [mf_simoes@hotmail.com](mf_simoes@hotmail.com) 4 Gustave Roussy Cancer Genetics Laboratory, Department of Medical Biology and Pathology, 94800 Villejuif, France; [maria.baz.baz@hotmail.com](maria.baz.baz@hotmail.com) 5 Department of Genetics, Institut Curie, Paris Sciences and Lettres (PSL) University, 75005 Paris, France; [sandrine.caputo@curie.fr](sandrine.caputo@curie.fr) * Correspondence: [etienne.rouleau@gustaveroussy.fr](etienne.rouleau@gustaveroussy.fr)[ ](etienne.rouleau@gustaveroussy.fr)† These authors contributed equally to this work. Abstract Poly(ADP-ribose) polymerase inhibitors (PARPis) have demonstrated remarkable efficacy in tumors carrying BRCA1/2 pathogenic variants (PVs) through the mechanism of synthetic lethality. PVs in other homologous recombination (HR) genes may also impair homologous recombination repair and confer sensitivity to PARPis; however, their predictive value remains uncertain and appears to vary according to the affected gene and tumor type. We review and critically discuss the current evidence regarding the predictive value of non-BRCA HR gene pathogenic variants as biomarkers of PARPi sensitivity across ovarian, breast, prostate, and pancreatic cancers. A narrative review was conducted between October 2023 and December 2025, first identifying pivotal clinical trials of PARP inhibitors across ovarian, breast, prostate, and pancreatic cancers, followed by a targeted search of PubMed, Embase, Web of Science, and Google Scholar for relevant preclinical and clinical studies. Seventeen clinical studies and multiple preclinical reports were analyzed regarding genomic frequency, HRD association, and treatment response. Preclinical studies consistently demonstrated increased PARPi sensitivity in models with alterations in several non-BRCA HR genes. Clinical evidence, however, was heterogeneous. PALB2 demonstrated the strongest and most consistent association with PARPi benefit across tumor types, while RAD51C and RAD51D also showed clinically meaningful activity, particularly in ovarian cancer. In contrast, evidence supporting PARPi sensitivity in tumors harboring ATM, CHEK2, CDK12, and several other HR gene alterations remained limited or inconsistent. Differences in gene function, biallelic inactivation, variant type, and current limitations of HRD companion diagnostic assays likely contribute to the observed variability in clinical response. Non-BRCA HR gene alterations represent promising predictive biomarkers for PARPi therapy but should not be considered a homogeneous group. Future biomarkerdriven studies integrating comprehensive genomic profiling and functional assessment of homologous recombination deficiency are needed to refine patient selection and optimize the clinical application of PARPis beyond BRCA1/2-associated cancers. Keywords: neoplasms; prostate cancer; breast can

FAQs

What is the central question of this review?

How non-BRCA homologous recombination gene pathogenic variants predict PARPi sensitivity across ovarian, breast, prostate, and pancreatic cancers, and how this evidence compares across tumor types and genes.

What do preclinical studies generally show about PARPi sensitivity?

Models with alterations in several non-BRCA HR genes consistently demonstrate increased PARPi sensitivity compared with models without such alterations.

Which non-BRCA genes show the strongest clinical association with PARPi benefit?

PALB2 shows the strongest and most consistent association across tumor types. RAD51C and RAD51D also show clinically meaningful activity, particularly in ovarian cancer, while evidence for ATM, CHEK2, CDK12, and other HR genes is more limited or inconsistent.

Sep 22, 2026

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