Antibody-drug conjugates (ADCs) provide a novel treatment modality for target anti-cancer drug delivery. In this study, we investigated the in vitro efficacy of ADC-containing drug combinations in ovarian (OC) and endometrial (EC) cancers. As TROP2 and HER2 are commonly over-expressed in OC and EC, respectively, the TROP2 targeting datopotamab deruxtecan (Dato-DXd) and HER2-targeting trastuzumab deruxtecan (T-DXd) were chosen. As both ADCs use a potent topoisomerase I inhibitor payload (DXd), which induces irreparable DNA double-strand breaks, we aimed to uncover potential synergies between Dato-DXd and T-DXd and DNA damage response inhibitors (DDRis), targeting ATM (AZD1390) and ATR (AZD6378), and chemotherapeutic agents in 2D cancer cell models. This study aimed to determine the potential of DXd-ADCs in combination with DDRis and current first line chemotherapies.

This study utilised a panel of six OC (PEO1, PEO4, IGROV-1, SKOV3, OVCAR4, COV318) and three EC lines (AN3CA, HEC1B, MFE280) cell lines. The anti-proliferative effects of Dato-DXd and T-DXd was assessed in their respective panels by 5-day acid phosphatase assay. Synergy with the DDRis, AZD1390 and AZD6738, and chemotherapies, carboplatin and paclitaxel, were assessed by matrix proliferation assays and analysed by Combenefit software. TROP2 and HER2 protein expression was examined by Western blotting.

Dato-DXd showed single agent efficacy in the three highest TROP2 expressing OC cell lines (PEO1, PEO4, OVCAR4). Dato-DXd demonstrated synergy with carboplatin in these three cell lines and additivity in the lower TROP2 expressing cell lines. Paclitaxel did not enhance the anti-proliferative effect of Dato-DXd in the OC panel. However, synergy was observed across all cell lines with AZD1390 and in 4/6 cell lines with AZD6738. MFE280 showed the highest HER2 expression and sensitivity to T-DXd. Both AZD1390 and AZD6738 plus T-DXd were synergistic in all cell lines and outperformed carboplatin and paclitaxel.

Our findings indicate that combining Dato-DXd and T-DXd with specific DDR inhibitors potentially enhances anti-tumour activity in ovarian and endometrial cancer models, which offers potential pathways for clinical translation. These combinations, particularly those involving ATM and ATR inhibitors, support the need for further investigation in clinical settings.