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ABSTRACT
Introduction
Pancreas ductal adenocarcinoma (PDAC) is a frequently lethal malignancy that poses unique therapeutic challenges. The current mainstay of therapy for metastatic PDAC (mPDAC) is cytotoxic chemotherapy. NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, oxaliplatin) is an emerging standard of care in the metastatic setting. An evolving understanding of PDAC pathogenesis is driving a shift toward targeted therapy. Olaparib, a poly-ADP-ribose polymerase (PARP) inhibitor, has regulatory approval for maintenance therapy in BRCA-mutated mPDAC along with other targeted agents receiving disease-agnostic approvals including for PDAC with rare fusions and mismatch repair deficiency. Ongoing research continues to identify and evaluate an expanding array of targeted therapies for PDAC.
Areas covered
This review provides a brief overview of standard therapies for PDAC and an emphasis on current and emerging targeted therapies.
Expert opinion
There is notable potential for targeted therapies for KRAS-mutated PDAC with opportunity for meaningful benefit for a sizable portion of patients with this disease. Further, emerging approaches are focused on novel immune, tumor microenvironment, and synthetic lethality strategies.
Article highlights
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that poses unique therapeutic challenges.
Cytotoxic chemotherapy remains the mainstay of treatment for most patients with this disease. An evolving knowledge of PDAC pathogenesis, the tumor microenvironment and immunotherapy are driving a shift toward targeted therapies.
A notable focus has been on targeting mutant KRAS, where multiple therapeutic modalities including small and large-molecule enzyme inhibitors, siRNA, and vaccines have converged on this target, and which hold the potential to advance therapeutic paradigms.
There are emerging data to support the role of immune checkpoint blockade (ICB) in combination with other targeted strategies such as poly-ADP-ribose polymerase (PARP) inhibitors, vaccines, or tumor microenvironment (TME)-directed therapies in PDAC.
Many novel therapeutic agents are under evaluation, including strategies capitalizing on synthetic lethality through targeting protein arginine methyltransferases 5 (PRMT5) in methylthioadenosine phosphorylase (MTAP)-deficient PDAC, and targeting claudin 18.2.
Refined tumor molecular subtyping systems (classical and basal-like), subtype surrogate markers such as GATA6 expression and development of signature tools such as PurIST, are anticipated to inform future treatment selection and clinical trial design.
Declaration of interests
E O’Reilly declares the following: research funding to institution: Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, Digestive Care. Consulting/DSMB: Arcus, Alligator, Agenus, BioNTech, Ipsen, Merck, Novartis, Syros, Leap Therapeutics, Astellas, BMS, Fibrogen, Revolution Medicine, Merus, Agios (spouse), Genentech-Roche (spouse), Eisai (spouse) Servier (Spouse).The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.