TALAVE in Breast Cancer: BRCA1/2 Mutation-Dependent Immune Remodeling after PARP Inhibition with Limited Checkpoint Engagement
Year: 2026
Type: preprint
Study design: Clinical Trial
Abstract: PARP inhibitors (PARPi) drive efficacy in BRCA-mutant breast cancer (BC) via DNA damage-induced synthetic lethality and immune activation, supporting their combination with immune checkpoint blockade. In the TALAVE study, patients with advanced BRCA-mutant or wild-type (WT) HER2-negative BC received talazoparib followed by talazoparib plus avelumab. Only BRCA-mutant BC responded clinically. Serial multi-omic profiling revealed BRCA-dependent tumor-immune remodeling, including sustained γH2AX-pTBK1 signaling with increased CD8+ T cells, tumor cell depletion, and enrichment of CD163+ macrophages. In contrast, BRCA-WT tumors remained compact and immunosuppressed with reduced T cells after therapy. PD-1+ T cells localized to CD4+-rich neighborhoods and correlated with longer progression-free survival in BRCA-mutant tumors. However, PD-L1+ cells were rapidly depleted or confined to immune-excluded regions, spatially segregating them from PD-1+ T cells, impairing effective checkpoint blockade. These findings suggest limited benefit of PD-1/PD-L1 blockade in augmenting PARPi activity and highlight the need for alternative strategies to sustain PARPi-induced immunity.
Authors: Filipa Lynce, Kenichi Shimada, Claudine Isaacs, Xue Geng, Edward T. Richardson, Adam Nelson, Candace Mainor, Mei Wei, Julie M. Collins, Paula R. Pohlmann, Arielle L. Heeke, Kelly F. Zheng, Madeline G. Townsend, Nicole Swanson, Lauren M. Sloat, Jane Staunton, Stuart J. Schnitt, Hongkun Wang, Joan S. Brugge, Geoffrey I. Shapiro, Jennifer L. Guerriero
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Susan G. Komen for the Cure, Pfizer, Brigham and Women's Hospital, Dana-Farber/Harvard Cancer Center, Merck KGaA, Terri Brodeur Breast Cancer Foundation, National Institutes of Health, Ludwig Center at Harvard, Lombardi Comprehensive Cancer Center, Georgetown University, National Cancer Institute
Awards: G1366430034, G1733809635, G208859497, G2673235985, G3261725791, G3366364652, G431141745, G4561983161, G4850509644, G5442596997, G5544403951, G5603363544, G5916996170, G7394099494, Systems Pharmacology of Therapeutic and Adverse Responses to ImmuneCheckpoint and Small Molecule Drugs, G851536905, G9000008011, G9000032029, G9000154161, G9000177301, G9000211303, G9000226715, Georgetown University Lombardi Comprehensive Cancer Center Support Grant, Immunometabolic pathways enabled by PARP inhibition in breast cancer, Dana Farber/Harvard Cancer Center Specialized Program of Research Excellence in Breast Cancer, Dana-Farber/Harvard Cancer Center
OpenAlex ID: W7213543751