AACR 2021: Talazoparib/Carboplatin Under Study in Triple-Negative Breast Cancer
Posted: Friday, April 23, 2021
Combination therapy using the PARP inhibitor talazoparib and carboplatin showed activity in seven triple-negative breast cancer cell lines, demonstrating high amounts of DNA damage and cell death. Alexia Cotte, MD, of the Université de Montreal, presented these preclinical data on behalf of her colleagues during the virtual edition of the American Association for Cancer Research (AACR) Annual Meeting 2021 (Abstract 1066).
Researchers performed a 10-day chemosensitivity assay using seven triple-negative breast cancer cell lines, both with and without BRCA mutations. They tested nine different concentrations of talazoparib and carboplatin and calculated IC50 (half maximal inhibitor concentration) values for talazoparib alone, combination index values, the DNA damage response, and the apoptotic index. They then performed in vivo studies using a xenograft model of these cancer cells in mice, utilizing a PARP-inhibitor resistant cell line. Mice were treated with either concurrent administration of 35 mg/kg of intraperitoneal carboplatin and 0.03 mg/kg of oral talazoparib or carboplatin 3 days after talazoparib.
Carboplatin and talazoparib demonstrated a synergistic effect in all seven cell lines tested, and the greatest synergy (combination index < 0.65) was noted in the three cell lines resistant to PARP inhibitors. These cells demonstrated a 7- to 16-fold increase in the DNA damage response when talazoparib was used in combination with carboplatin, compared with talazoparib alone. The apoptotic index also increased 4- to 26-fold under these same conditions.
In the mouse xenograft model, concomitant administration of carboplatin and talazoparib resulted in a 53.1% inhibition in primary tumor volume in comparison to the vehicle control (P = .0004). Sequential administration of talazoparib before carboplatin resulted in a 69.2% primary tumor volume inhibition (P < .0001). The sequential administration also resulted in a 53.9% decrease in lung micrometastases (P = .0003).
Disclosure: One of the study authors reported a relationship with Pfizer Canada, and all other authors reported no conflicts of interest.
