TALAVE in Breast Cancer: BRCA1/2 Mutation-Dependent Immune Remodeling after PARP Inhibition with Limited Checkpoint Engagement
- 1Brigham and Women's Hospital
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 H2AX-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.
Related
- Tarloxotinib targets tumor hypoxia to improve therapeutic efficacy of immune checkpoint inhibition in a MyD88-dependent manner.
- Moving Beyond the Plateau in Immune Checkpoint Inhibition-The Imperative of Early Referral and Precision Strategies.
- 418 B cell regulation of anti-PD-1 immune checkpoint inhibition
- Choline Kinase Alpha Inhibition is a Mutation Agnostic Therapeutic Vulnerability in Clonal Hematopoiesis
- Site-specific immune remodeling underlies resistance to dual immune checkpoint blockade in metastatic colorectal cancer
BibTeX
@misc{lynce2026talave,
title = {{TALAVE in Breast Cancer: BRCA1/2 Mutation-Dependent Immune Remodeling after PARP Inhibition with Limited Checkpoint Engagement}},
author = {F. Lynce and K. Shimada and C. Isaacs and X. Geng and E. T. Richardson and A. Nelson and C. Mainor and M. Wei and J. M. Collins and P. R. Pohlmann and A. L. Heeke and K. F. Zheng and M. Townsend and N. Swanson and L. M. Sloat and J. Staunton and S. J. Schnitt and H. Wang and J. S. Brugge and G. I. Shapiro and J. L. Guerriero},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752386},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752386v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - TALAVE in Breast Cancer: BRCA1/2 Mutation-Dependent Immune Remodeling after PARP Inhibition with Limited Checkpoint Engagement
AU - F. Lynce
AU - K. Shimada
AU - C. Isaacs
AU - X. Geng
AU - E. T. Richardson
AU - A. Nelson
AU - C. Mainor
AU - M. Wei
AU - J. M. Collins
AU - P. R. Pohlmann
AU - A. L. Heeke
AU - K. F. Zheng
AU - M. Townsend
AU - N. Swanson
AU - L. M. Sloat
AU - J. Staunton
AU - S. J. Schnitt
AU - H. Wang
AU - J. S. Brugge
AU - G. I. Shapiro
AU - J. L. Guerriero
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752386
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752386v1
AB - 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 H2AX-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.
ER -