Drugging the DNA damage response in the clinic: going beyond PARP

Introduction Targeting the DNA damage response (DDR) has emerged as a promising therapeutic strategy in oncology. This review highlights the growing clinical relevance of DDR inhibitors beyond PARP inhibitors, focusing on novel targets, biomarker-driven patient selection, and rational combination strategies.Areas Covered A comprehensive literature search was conducted using PubMed and ClinicalTrials.gov through May 2025, using terms such as ‘DDR inhibitors,’ ‘synthetic lethality,’ and the names of specific DDR targets. This review summarizes preclinical and clinical data on next-generation DDR inhibitors, including agents targeting ATR, ATM, APE1, DNA-PK, WEE1, CHK1/2, CDC7, PLK4, PKMYT1, Polθ, USP1, PARG, WRN, and ALC1. It discusses mechanistic rationale, clinical activity, and safety profiles, with emphasis on combination strategies involving chemotherapy, immunotherapy, radiotherapy, and other DDR agents. Key challenges such as resistance, cumulative toxicity, and the need for predictive biomarkers are also addressed.Expert Opinion DDR-targeting agents hold significant promise, especially when guided by predictive biomarkers and combined with other therapies. As these agents move into later-phase trials, future development should emphasize biomarker-driven design, toxicity mitigation through dose optimization, and expansion into non-canonical tumor types to maximize clinical impact.