Update on the Role of Poly (ADP-Ribose) Polymerase Inhibitors in the DNA Repair-Deficient Pancreatic Cancers: A Narrative Review.

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is the most common cancer found in the pancreas. It has a dismal prognosis and current therapeutic options, including surgical resection, provide only a temporary or limited response due to the development of treatment resistance. Methods: A narrative review of studies investigating poly (ADP-ribose) polymerase (PARP) pathway inhibitors in metastatic PDAC to highlight recent advances. Results: Mutations in BRCA genes confer a higher risk of PDAC, while germ line mutations are found in 4-7% of individuals harboring pancreatic cancer. Although solid tumors with defective DNA damage repair defect (DDR) genes such as BRCA show heightened sensitivity to platinum agents, tumors can exploit the PARP pathway as salvage pathways. Therefore, blocking this pathway will trigger cell death in vulnerable tumor cells with BRCA/DNA repair deficiency. Several drugs with inhibitory activity on the PARP pathway have been approved for breast and ovarian tumors harboring germ line or somatic BRCA mutations. Based on these results, the phase III POLO study showed a significant improvement in progression-free survival compared with placebo in BRCA mutant pancreatic tumors and highlighted the importance of germ line testing in everyone diagnosed with pancreatic cancer. In addition, expansion of the PARP inhibitor indication beyond BRCA mutations to other genes involved in DDR such as ATM and PALB2 merits attention. Conclusion: PARP inhibitors represent a safe and efficacious treatment for a subset of PDAC patients with BRCA mutations. Ongoing trials are evaluating PARP inhibitors in PDAC patients with non-BRCA DDR gene deficiencies as well as PARP inhibitors in combination with other agents, notably immune checkpoint inhibitors to expand the group of patients that derive benefit from this treatment.