Adaptive Responses to PARP Inhibition Predict Response to Olaparib and Durvalumab: Multi-omic Analysis of Serial Biopsies in the AMTEC Trial
Mitri, Z. I.; Creason, A. L.; Stommel, J. M.; Bottomly, D.; Ozmen, T. Y.; Rames, M. J.; Ozmen, F.; Jeong, B.; Lukashchuk, N.; Ashton, J.; Lim, J. Y.; Sivagnanam, S.; Betre, K.; Lee, J.; Labrie, M.; SMMART Clinical Trials Program, ; Coussens, L. M.; Corless, C. L.; McWeeney, S. K.; Mills, G. B.
Show abstract
In syngeneic murine breast cancer models, poly(ADP-ribose) polymerase inhibitor (PARPi) and anti-PD-L1 combinations induce deep, sustained responses independent of BRCA1 or BRCA2 mutation (BRCAm) status. We therefore investigated this combination in the AMTEC clinical trial, in which a one-month olaparib run-in was followed by combined olaparib and durvalumab in participants with non-BRCAm metastatic triple negative breast cancer. To characterize adaptive responses to olaparib monotherapy, paired biopsies taken before and during the PARPi lead-in were deeply characterized by DNA, RNA, and protein multi-omic analyses, including spatially resolved single-cell proteomics for tumor and immune contexture. We identified multiple potential tumor-intrinsic and microenvironmental biomarkers from pre-treatment and on-olaparib biopsies that robustly predicted participant response to combined olaparib and durvalumab. Notably, the on-olaparib biopsy provided the greatest information content, suggesting that early adaptations of malignant and immune cells to PARPi can serve as a predictor of potential benefit from combined PARPi and anti-PD-L1 therapy.
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