Ovarian cancer (OC) is the 5th leading cause of cancer deaths in women worldwide. Datopotamab deruxtecan (Dato-DXd) is a novel TROP2-directed antibody-drug conjugate (ADC) with a topoisomerase I inhibitor payload that is FDA approved for the treatment of hormone receptor-positive, HER2-negative breast cancer that has been previously treated with systemic therapy. TROP2 is commonly overexpressed in OC, making it an attractive therapeutic target. PARP inhibitors (PARPi) target the DNA damage response (DDR) and are used to treat different cancer types, especially cancers with DDR deficiency. Olaparib is a PARPi approved for the treatment of several different cancer types. Saruparib (AZD5305) is a PARP1-selective inhibitor in clinical development. This preclinical study examines the efficacy of Dato-DXd alone and in combination with PARPi olaparib and saruparib in OC cell lines in 2D and 3D culture conditions.

This study utilised a panel of six OC cell lines with different BRCA2 mutation and HR deficiency status. The anti-proliferative effects of Dato-DXd and olaparib/saruparib were determined using a 5-day acid phosphatase assay. Synergism was assessed using Combenefit software with the Loewe additivity model. Induction of caspase 3/7 activation, a marker of apoptosis, was tested with single agents and combinations using kinetic, fluorescent microscopy with the Incucyte S3 imaging system. Internalisation rates of Dato-DXd were monitored using the Incucyte. Single agent and combination anti-proliferative effects were assessed in 3D bioprinted culture conditions utilising the RASTRUM platform. Comparison of image-based analysis and metabolic readout with Cell Titer Glo 3D was carried out.

The combinations of Dato-DXd + olaparib/saruparib were highly synergistic in the TROP2-high cell line models tested with no antagonism observed (concentration range 0.008 – 5 µg/mL and 0.625 – 10 µM, respectively). Lower levels of synergy were still observed in TROP2-low cell lines. Treatment response of PEO1 and PEO4 cells was further functionally characterised. Dato-DXd in combination with PARPi synergistically induced apoptosis. Combinations were effective in 3D models of cancer growth with comparable efficacy to 2D models. Dato-DXd is internalised in a time- and concentration-dependent manner in TROP2 expressing cells. Internalisation assays revealed increased levels of Dato-DXd internalisation when combined with olaparib.

This study provides a preclinical rationale for the clinical investigation of Dato-DXd in combination with PARPi olaparib or saruparib in OC.