TALAVE in Breast Cancer: BRCA1/2 Mutation-Dependent Immune Remodeling after PARP Inhibition with Limited Checkpoint Engagement
Lynce, F.; Shimada, K.; Isaacs, C.; Geng, X.; Richardson, E. T.; Nelson, A.; Mainor, C.; Wei, M.; Collins, J. M.; Pohlmann, P. R.; Heeke, A. L.; Zheng, K. F.; Townsend, M.; Swanson, N.; Sloat, L. M.; Staunton, J.; Schnitt, S. J.; Wang, H.; Brugge, J. S.; Shapiro, G. I.; Guerriero, J. L.
Show 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.
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