Maintenance therapy for ATM-deficient pancreatic cancer by multiple DNA repair pathway inhibition after platinum-based chemotherapy

Mutations in DNA-damage repair (DDR) genes can ascribe vulnerability toward PARP1 inhibitors allowing tailored interventions in certain cancer types. Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancies albeit PDAC-related death is projected rising over the next decade. Most recently, PARP1-inhibitor maintenance therapy after platinum-based induction improved progression-free survival in germline BRCA1/2 mutated PDAC. Transferability of such concept to other mutant DDR genes is unclear. We conducted a placebo-controlled, three-armed preclinical trial to evaluate the efficacy of multi-DDR interference (mDDRi) as a maintenance therapy vs. FOLFIRINOX-ongoing implemented with ATM-deficient PDAC lines upon orthotopic transplantation. Kaplan-Mayer analysis, time resolved cross-sectional imaging by MRI, histology as well as in vitro analysis was applied as analytical readout.

Median overall survival was significantly longer in the maintenance arm followed by FOLFIRINOX-ongoing and placebo. Survival benefit in the maintenance arm was mirrored in highest DNA damage load, accompanied by reduced primary cancer size and metastatic load. In vitro analysis suggests FOLFIRINOX-driven selection of more invasive subclones, erased by the subsequent mDDRi treatment, in line with reduced metastatic burden in vivo.

Collectively, this preclinical trial substantiates mDDRi as novel therapeutic option in PDAC and extends the concept to non-BRCA1/2 mutant PDAC.

Publication History

Article published online:
08 September 2020