HCC1806 and MDA-MB-231 treated with Olaparib and/or AZD1775 for 72 hours in vitro

Novel therapeutic strategies that can effectively combine with immunotherapies are needed in the treatment of triple-negative breast cancer (TNBC). We demonstrate that combined PARP and WEE1 inhibition are synergistic in controlling tumor growth in BRCA1/2-wildtype TNBC preclinical models. The PARP inhibitor (PARPi) olaparib combined with the WEE1 inhibitor (WEE1i) adavosertib triggered significant increases in STING-mediated, anti-tumor immune responses. Combinations with a STING agonist resulted in further improved durable tumor regression and significant improvements in survival outcomes in multiple tumor models of BRCA1/2-wildtype TNBC, even in tumors with low immune infiltration at baseline. These results support the development of combined PARPi, WEE1i and STING agonism in BRCA1/2 wildtype TNBC regardless of baseline levels of T cells. In this study, we have identified baseline TIL levels as a potential predictive biomarker of response to PARPi, WEE1i and immunotherapy in BRCA1/2-wildtype TNBC. Patients with tumors that have moderate levels of T cells may derive benefit from a four-drug combination of PARPi, WEE1i, STING agonist and anti-PD-1, with demonstrated complete tumor clearance and prolonged survival.