Data from The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 After Progression on Rucaparib

Abstract Purpose: 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<0.0001). All patients with reversions received re-challenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (rwTTD 2.4mo vs 5.8mo, p = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second line therapy was significantly lower in those with reversion variants than in those without (5.5mo vs 12.0 mo, p = 0.002). Finally, high levels tumor shedding were independently associated with poor outcomes in patients who received rucaparib. Conclusions: Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA or PALB2 related PDAC who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment and poor overall survival of patients. The identification of such variants in the blood may have both predictive and prognostic value.