Abstract B095: Sacituzumab govitecan-based drug combinations overcome platinum/PARP inhibitor resistance in ovarian cancer models

Abstract

Background: Ovarian cancer causes more deaths than any other gynaecological cancer per year in the USA. Sacituzumab govitecan (SG) is a TROP2-targeted antibody-drug conjugate, approved for the treatment of triple-negative and hormone receptor-positive breast cancers. TROP2 is commonly overexpressed in ovarian cancer and represents an attractive, potential therapeutic target in ovarian cancer. This study investigated the in vitro activity of SG alone and in combination with targeted therapies/chemotherapies in ovarian cancer cell line models.

Methods: This study utilized the PEO1 and PEO4 cell lines, which were derived from the same patient, with PEO4 acquiring a secondary restorative BRCA2 mutation to confer platinum resistance. Olaparib-resistant PEO1 (PEO1-Ola) cells were generated through continuous exposure to olaparib, to a maximum 13 μM, for four months. The anti-proliferative effects of SG, talazoparib, olaparib, carboplatin, and paclitaxel were tested in PEO1, PEO1-Ola, and PEO4 cell lines. 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.

Results: Olaparib and carboplatin resistance did not result in their cross-resistance. PEO1-Ola showed similar sensitivity to carboplatin as PEO1 parental cells, while carboplatin-resistant PEO4 cells displayed clinically achievable sensitivity to olaparib and talazoparib. SG was highly effective in all models tested. SG in combination with carboplatin or talazoparib was synergistic across all cell lines and resulted in induction of apoptosis.

Conclusions: This pre-clinical study showed that TROP2-targeting ADC-based drug combinations warrant further investigation for the treatment of ovarian cancer.

Citation Format: Neil T Conlon, Elena Möhrle, Luna Stockmann, John Crown. Sacituzumab govitecan-based drug combinations overcome platinum/PARP inhibitor resistance in ovarian cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B095.