PARP inhibitors olaparib and niraparib trigger cellular senescence in pancreatic cancer cells through the Chk2-p21 pathway, independent of p53 status and BRCA mutations. This senescence mechanism involves both direct DNA damage and reactive oxygen species generation through positive feedback loops. However, these therapy-induced senescent cells express elevated Bcl-2 levels and can resume proliferation when treatment stops, explaining why continuous PARP inhibitor maintenance therapy is clinically necessary. This finding reshapes our understanding of how PARP inhibitors work beyond their established DNA repair interference. The reversible nature of this senescence represents both a therapeutic challenge and opportunity. The researchers demonstrated that sequential combination with navitoclax, a Bcl-2 inhibitor and senolytic drug, can eliminate these senescent cells and enhance treatment efficacy. This approach could transform pancreatic cancer maintenance therapy by preventing the cellular escape mechanism that limits long-term treatment success. The strategy appears promising regardless of BRCA status, potentially expanding treatment options for patients with this notoriously difficult-to-treat cancer. This represents a significant advance in precision oncology, offering a rational combination strategy that targets both active cancer cells and their senescent survivors.