AstraZeneca researchers at AACR 2026 highlighted AZD-4956, a POLθ inhibitor designed to target microhomology-mediated end joining (MMEJ) in HRR-deficient tumors. By suppressing POLθ-driven backup DNA repair, the program aims to increase vulnerability in cancers reliant on error-prone repair pathways. The preclinical concept centers on POLθ as an essential survival mechanism when homologous recombination repair (HRR) is impaired, creating a rationale for combinations with PARP inhibitors and other DNA-damaging regimens. The mechanism frames AZD-4956 as a potential partner to broader DNA damage response strategies rather than a stand-alone therapy. As the data were presented as early translational work, AZD-4956’s value will likely hinge on schedule optimization, biomarker identification, and managing overlapping toxicities typical of DNA repair-targeted combinations. For investors and clinicians tracking the next wave of DNA repair science, the emphasis at AACR on clear pathway logic underscores a continued shift toward mechanism-first combination development in oncology pipelines.