Phase 2 Study of PARP inhibition and Anti-PD-L1 Therapy in BRCAmt TNBC

Phase 2 Study of PARP inhibition and Anti-PD-L1 Therapy in BRCAmt TNBC

The clinical trial to which this proposal is attached is a randomized, open-label phase II trial exploring the effects of the anti-PD-L1 human monoclonal antibody atezolizumab with the PARP inhibitor Veliparib either alone or in combination in 100 patients with BRCA1/2 TNBC.

This grant will evaluate the mutational load, neoantigens, and anti-tumor immune effects of PARP inhibition and immune-stimulation and determine the possible connection between the biomarkers and patient performance after treatment.

Lay Abstract

Within the past decade, the growth of immunotherapy as a method to treat cancer has been astounding. However, while new immunostimulatory therapies have shown great success in the treatment of many types of breast cancer, not all types of cancer respond. A major challenge remains identification of mechanisms to effectively treat the majority of patients with so-called "non-inflamed" breast tumors. Work in the laboratory has shown that the DNA repair ability of a tumor may impact its potential for immune recognition and sensitivity to immune therapies. We hypothesize that enhanced DNA damage and cell death induced by DNA damage repair inhibition in tumors will also enhance anti-tumor immune responses. To examine this, we are conducting a clinical trial exploring the DNA damage repair inhibitor olaparib either alone or in combination with the human monoclonal antibody atezolizumab in patients with BRCA1/2 mutated locally advanced or metastatic non-HER2-positive breast cancer. In addition to producing a prominent clinical advancement, the Rising Tide award is allowing us to perform experiments to demonstrate fundamental concepts linking DNA repair, specific genomic landscapes, and anti-tumor immune response.  Ultimately, the results from this study have the potential to impact patient care by supporting the clinical development of a novel and biologically driven treatment combination to treat breast cancer.