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AbstractPurpose: Poly-(ADP-ribose) polymerase inhibitors provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized. Experimental Design: We collected paired cfDNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease. Results: Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (mPFS 3.7mo vs 12.5mo, p=0.001) and poor overall survival (mOS 6.2mo vs 23.0mo, p
Brown et al. (2024) studied this question.