Combination of PARPi and topoisomerase I inhibitors is highly effective in olaparib-resistant ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) often shows an initial response to poly (ADP-ribose) polymerase inhibitors (PARPi) such as olaparib, particularly in tumors with defects in homologous recombination (HR), but resistance to these drugs is a major clinical challenge. To address this, we screened over 1400 FDA-approved compounds to find agents that could restore olaparib sensitivity in resistant ovarian cancer cells. DNA topoisomerase I inhibitors (TOP1i) emerged as the most effective partner. The combination of TOP1 inhibitors with PARPi showed strong synergistic anticancer effects across multiple murine and human HGSOC models, regardless of HR status, including patient-derived xenografts made resistant to olaparib. The combination was well tolerated and primarily worked by inducing apoptosis and increased DNA damage. These findings suggest that TOP1 inhibitors combined with PARP inhibitors could be a promising treatment strategy for olaparib-resistant ovarian cancer.