Background: Maintenance PARP inhibition (PARPi) extends progression-free survival and improves quality of life for patients (pts) with advanced, platinum-sensitive pancreatic cancer (PC) and BRCA or PALB2 variants. However, most will experience progression. PARPi resistance mechanisms are poorly defined in PC. Cell-free (cf)DNA analysis can detect some known classes of resistance mechanisms, like reversion mutations, and other potentially prognostic and predictive genomic features. Methods: Pts with advanced, platinum-sensitive pancreatic cancer and pathogenic germline or somatic BRCA1, BRCA2, or PALB2 variants were treated with maintenance rucaparib on clinical trial. cfDNA was collected at baseline and progression and analyzed with the GuardantOMNI 500-gene liquid biopsy. Time to event analysis was performed from index date of enrollment until endpoint (PFS, OS, and PFS2). Associations were tested by the log-rank test with adjustment. Results: The trial enrolled 42 pts, of whom 31 have progressed. cfDNA was available for 41 pts at baseline and 30 pts at progression; 88% had baseline detectable cfDNA. Two pts had baseline reversion mutations, 5 had new reversion mutations at progression. Of 21 pts who had tissue NGS, 17 pts had a KRAS variant in the tumor, 12 of whom had detectable cfDNA at either baseline or progression. Of the 41 patients with cfDNA samples, 10 pts had baseline KRAS mutations detected in plasma; an additional 10 pts had a detectable plasma KRAS mutation at progression. Outcomes are shown. Of those who had progressed, pts with acquired reversion mutations had shorter OS (p<0.001) and PFS (p = 0.018) on rucaparib than those without reversion mutations. Of those who received chemo after progression (n=23), PFS2 was shorter for pts with acquired reversions compared to those with no reversions (p = 0.038). KRAS mutation detection at baseline was observed with higher overall somatic allele fraction in cfDNA and a trend toward shorter PFS and OS. Conclusions: Acquired reversion mutations were infrequent but associated with worse outcomes. Other causes of resistance may be dominant. Detection of KRAS mutation in the peripheral blood may be associated with disease burden and clinical outcome.