Beyond classical synthetic lethality: how PARP inhibitor pharmacology contributes to antitumor activity in HR-proficient cancers

PARP inhibitors were developed on the principle of synthetic lethality, which predicts enhanced sensitivity in tumors with homologous recombination deficiency (HRD). Clinical trials have demonstrated benefits beyond germline BRCA-mutated disease (NOVA and ARIEL3), including modest progression-free survival improvements in genomically HRD-negative subgroups (PRIMA). However, negative genomic HRD testing does not necessarily indicate functional HR proficiency, and these findings do not establish mechanisms independent of synthetic lethality. This Review examines the pharmacological mechanisms that may contribute to PARP inhibitor activity beyond established BRCA-associated HRD. The four agents have distinct pharmacological profiles—differences in PARP trapping potency, off-target activities against kinases (DYRK1A/1B, PIM3, CDK16) and the non-kinase PARP16, and immune-modulatory effects—that extend activity beyond HRD. Beyond canonical BRCA-associated HRD, these activities map onto distinct conditional dependencies in individual tumor contexts: lineage-dependent oncoprotein stability in small cell lung cancer, genotype-dependent immune vulnerability in SPOP-mutant prostate cancer, and pharmacologically induced HR impairment in hepatocellular carcinoma, where a direct c-Met–PARP1 mechanism remains to be verified. On-target mechanisms (PARP trapping and downstream DNA-damage effects) are directly demonstrated, whereas individual off-target contributions to clinical efficacy remain largely correlative and require prospective validation. By organizing these mechanisms into a unifying framework, this review aims to guide off-target-aware PARP inhibitor selection, rational combination design, and the development of next-generation compounds, providing a framework for investigating context-dependent PARP inhibitor strategies beyond established HRD-associated indications.