TY - JOUR
T1 - The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 after Progression on Rucaparib
AU - Brown, Timothy J.
AU - Yablonovitch, Arielle
AU - Till, Jacob E.
AU - Yen, Jennifer
AU - Kiedrowski, Lesli A.
AU - Hood, Ryan
AU - O’Hara, Mark H.
AU - Teitelbaum, Ursina
AU - Karasic, Thomas B.
AU - Schneider, Charles
AU - Carpenter, Erica L.
AU - Nathanson, Katherine
AU - Domchek, Susan M.
AU - Reiss, Kim A.
N1 - Publisher Copyright:
c2023 American Association for Cancer Research.
PY - 2023/12/15
Y1 - 2023/12/15
N2 - Purpose: PARP inhibitors (PARPi) 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 cell-free DNA 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 (median PFS, 3.7 vs. 12.5 months; P ¼ 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P ¼ 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 (5.5 vs. 12.0 months, P ¼ 0.002). Finally, high levels of 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 pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value.
AB - Purpose: PARP inhibitors (PARPi) 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 cell-free DNA 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 (median PFS, 3.7 vs. 12.5 months; P ¼ 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P ¼ 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 (5.5 vs. 12.0 months, P ¼ 0.002). Finally, high levels of 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 pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value.
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U2 - 10.1158/1078-0432.CCR-23-1467
DO - 10.1158/1078-0432.CCR-23-1467
M3 - Article
C2 - 37486343
AN - SCOPUS:85173781961
SN - 1078-0432
VL - 29
SP - 5207
EP - 5216
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -