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Abstract Low-grade serous ovarian cancer (LGSOC) typically responds poorly to standard platinum-based chemotherapy and new therapeutic approaches are needed. We describe a remarkable response to targeted therapy in a patient with platinum-resistant, advanced LGSOC who had failed standard-of-care chemotherapy and two surgeries. The patient was in rapid decline and entering hospice care on home intravenous (i.v.) opioid analgesics and a malignant bowel obstruction requiring a G-tube. Genomic analysis of the patient’s tumor did not indicate obvious therapeutic options. In contrast, a CLIA-certified drug sensitivity assay of an organoid culture derived from the patient’s tumor identified several therapeutic choices, including Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, as well as the EGFR inhibitors afatinib and erlotinib. Following off-label administration of daily ibrutinib as monotherapy, the patient had an exceptional clinical turnaround over the following 65 weeks with normalization of CA-125 levels, resolution of the malignant bowel obstruction, halting of pain medications, and improvement of performance status from ECOG 3 to ECOG 1. After 65 weeks of stable disease, the patient’s CA-125 levels began to rise, at which point the patient discontinued ibrutinib and began taking afatinib as monotherapy. The patient’s CA-125 levels remained stable for an additional 38 weeks but due to anemia and rising CA-125 levels, the patient switched to erlotinib and is currently being monitored. This case highlights the clinical utility of ex vivo drug testing of patient-derived tumor organoids as a new functional precision medicine approach to identify effective personalized therapies for patients who have failed standard-of-care treatments.

Background: Homologous recombination deficiencies (HRD) are present in approximately half of epithelial ovarian cancers, for which PARP inhibitors (PARPi) are becoming a preferred treatment option. However, a considerable proportion of these carcinomas acquire resistance or harbour de novo resistance, posing a significant challenge to treatment. Methods: To identify new combinatorial therapeutics to overcome resistance to PARPi, we employed high-throughput conditional RNAi and drug screening of patient-derived ovarian cancer cells. To prioritise clinically relevant drug combinations, we integrated empirical validation with analysis of The Cancer Genome Atlas (TCGA) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets to nominate candidate targets and drugs, reaching three main findings. Findings: Firstly, we found that the PARPi rucaparib enhanced the effect of BET inhibitors (CPI-203 & CPI-0610) irrespective of clinical subtype or HRD status. Additional drug combination screens identified that dasatinib, a non-receptor tyrosine kinase inhibitor, augmented the effects of rucaparib and BET inhibitors, proposing a potential broadly applicable triple-drug combination for high-grade serous and clear cell ovarian carcinomas. Secondly, rucaparib synergised with the BCL2 family inhibitor navitoclax, with preferential activity in ovarian carcinomas that harbour alterations in BRCA1/2, BARD1, or MSH2/6. Thirdly, we identified potentially antagonistic drug combinations between the PARPi rucaparib and vinca alkaloids, anthracyclines, and antimetabolites, cautioning their use in the clinic. Interpretation: These findings propose therapeutic strategies to address PARP inhibitor resistance using agents that are already approved or are in clinical development, with the potential for rapid translation to benefit a broad population of ovarian cancer patients.