Metastatic (and locally advanced) pancreatic
adenocarcinoma (
mPDA) represents a major challenge for the oncology community given the rising mortality burden from the disease and the preponderance of patients diagnosed with unresectable disease. Although systemic
therapies have become more potent with the development of
fluorouracil,
irinotecan, and
oxaliplatin (
FOLFIRINOX) and
gemcitabine plus
nab-paclitaxel as first-line treatments, the median overall survival for patients treated with either of these regimens remains just above 1 year. A significant need exists to build upon the effectiveness of first-line regimens, incorporate tolerable maintenance treatments, and add effective later-line options for patients with this disease. We believe every newly diagnosed
mPDA patient should undergo next-generation sequencing (NGS) testing, preferably from
tumor tissue, to assess for the presence of DNA damage repair (DDR) defects,
microsatellite instability, and other possible actionable molecular alterations (such as neurotrophic tropomysin receptor
kinase (NTRK) fusions,
anaplastic lymphoma kinase (ALK) rearrangements, or
human epidermal growth factor receptor 2 (HER2) amplification). Existing clinical data suggests that patients, whose
tumors harbor DDR defects, benefit from treatment with
platinum-based
chemotherapy and
poly (ADP-ribose) polymerase (
PARP) inhibitors. Preclinically, inhibitors of other critical players in DDR such as
ataxia-telangiectasia and Rad3 related (ATR),
ataxia-telangiectasia mutated (ATM),
DNA-dependent protein kinase (
DNA-PK), and WEE1 have demonstrated promising anti-
tumor activity in PDA cell lines and xenografts. How to move forward the preclinical promise of these newer DDR-targeting
therapies into rational clinical trial combinations and sequence
PARP inhibitors in relation to
platinum chemotherapy remain areas of tremendous clinical research interest. We believe clinical trials should be considered early for
mPDA patients, in all treatment lines, so that novel
therapies may be added to the treatment armamentarium for patients with this disease. Beyond NGS testing from
tumor tissue, we believe it is important to consider germline genetic testing for all patients diagnosed with PDA given recent data suggesting a much stronger hereditary component of the disease than previously understood, and the potential screening implications for family members.