Case Report: Complete response to the novel NaPi2b-targeting ADC YL205 in heavily pretreated platinum-resistant ovarian cancer

Objectives High-grade serous ovarian carcinoma (HGSOC) remains a formidable challenge in the platinum-resistant setting (PROC). In the post-PARP inhibitor (PARPi) era, prior exposure reshapes resistance mechanisms, necessitating a shift from traditional platinum-free interval definitions to biomarker-driven strategies. We report an exceptional response to a next-generation ADC and review the evolving therapeutic landscape. Case report A 40-year-old woman with FIGO stage IVB, BRCA-wildtype HGSOC developed rapid multi-drug resistance following neoadjuvant chemotherapy, optimal cytoreduction, and progression on maintenance olaparib/bevacizumab, gemcitabine, and a USP1 inhibitor. Following the identification of high NaPi2b expression (83% tumor proportion score), she initiated YL205, a novel NaPi2b-targeting antibody-drug conjugate (ADC) utilizing a topoisomerase I inhibitor payload, at 2.0 mg/kg every 3 weeks. Results The patient achieved a sustained complete radiological response (CR) and CA-125 normalization 3.5U/ml after 24 weeks, remaining stable through 48 weeks treatment. This represents the first clinical instance of CR observed with this agent. Adverse events were limited to manageable grade 1–2 neutropenia symptoms. Conclusions This case underscores the potential of next-generation ADCs featuring optimized linker-payload technologies. By utilizing topoisomerase I inhibitors, agents like YL205 bypass microtubule-stabilization resistance induced by prior taxane exposure, while “bystander effects” address intratumoral heterogeneity. Longitudinal, biomarker-matched strategies and proactive toxicity management are essential to achieving deep tissue clearance in heavily pretreated HGSOC.