Patient-Derived Organoids Functionally Stratify Epithelial Ovarian Cancer into Clinically Relevant Chemotherapy Response Phenotypes

Abstract Background Ovarian cancer (OC) exhibits substantial heterogeneity in response to platinum-based chemotherapy, resulting in variable clinical outcomes and frequent recurrence. Current biomarkers, including serum CA-125 kinetics and BRCA mutational status, incompletely predict therapeutic response. We investigated whether patient-derived organoids (PDOs) could functionally stratify chemotherapy sensitivity and better reflect patient-specific clinical behaviour. Methods Twenty patients with OC treated between January 2024 and May 2026 were included, from whom fourteen PDO lines were successfully established. Eight PDOs with robust low-passage expansion and comprehensive longitudinal follow-up underwent functional profiling against carboplatin, paclitaxel, olaparib, and doxorubicin. Drug responses were assessed using half-maximal inhibitory concentration (IC 50 ) and area under the curve (AUC) analyses and integrated with radiological response, serum CA-125 kinetics, BRCA status, and progression-free survival (PFS). Results Clinical outcomes varied considerably despite similar platinum-taxane regimens. Although post-treatment CA-125 reduction was associated with prolonged PFS, neither CA-125 kinetics nor BRCA mutational status consistently predicted therapeutic response. PDO-guided functional stratification segregated tumours into four clinically relevant platinum-taxane response phenotypes: dual-sensitive, platinum-sensitive/taxane-resistant, platinum-resistant/taxane-sensitive, and dual-resistant. These functional categories closely mirrored radiological response, CA-125 normalisation, and disease progression patterns. PDOs exhibiting low IC 50 and AUC values were associated with durable clinical benefit, whereas resistant PDOs tracked with persistent disease and early recurrence. Conclusions PDO-guided functional stratification captures clinically meaningful therapeutic heterogeneity in OC and complements conventional biomarkers by directly measuring tumour-specific drug susceptibility. Prospective integration of PDO testing may facilitate patient-specific therapeutic selection and support functional precision oncology approaches in ovarian cancer.