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  • Review Article
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Therapeutic developments in pancreatic cancer

Nature Reviews Gastroenterology & Hepatology volume 21, pages 7–24 (2024)Cite this article

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a rising incidence and is one of the most lethal human malignancies. Much is known regarding the biology and pathophysiology of PDAC, but translating this knowledge to the clinic to improve patient outcomes has been challenging. In this Review, we discuss advances and practice-changing trials for PDAC. We briefly review therapeutic failures as well as ongoing research to refine the standard of care, including novel biomarkers and clinical trial designs. In addition, we highlight contemporary areas of research, including poly(ADP-ribose) polymerase inhibitors, KRAS-targeted therapies and immunotherapies. Finally, we discuss the future of pancreatic cancer research and areas for improvement in the next decade.

Key points

  • Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, with cytotoxic chemotherapy remaining the mainstay of treatment for most patients.

  • Ongoing trials are evaluating ‘classical’ versus ‘basal-like’ expression signatures to inform the therapeutic selection of standard cytotoxic regimens.

  • Small subsets of patients, including those with mutations in BRCA1, BRCA2, PALB2 and KRASG12C, rare fusions (NRG1, NTRK), and mismatch repair deficiency, benefit from targeted therapies.

  • KRAS is a critical target for therapeutic evaluation in PDAC and proof-of-principle approaches have validated targeting in KRASG12C; ongoing trials are evaluating allele-specific inhibitors and pan-(K)RAS inhibitors against the more common allele variants G12D, G12V and G12R.

  • Immune-checkpoint inhibitor blockade and other immune therapies have not had utility for most patients with PDAC; however, select rare individuals beyond mismatch repair deficiency have seen major benefit, leading to optimism that these results can be expanded to a broader patient population.

  • Clinical trial design strategies are changing and PDAC is a prototypic disease to investigate novel drug development paradigms; innovation in clinical trial design has led to the integration of platform-type studies that incorporate novel statistical design, leading to expediencies in drug development, timelines, cost and other resources. Platform studies enable parallel investigation of multiple novel agents, with early signal adjudication of success or failure to allow efficient signal seeking.

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Fig. 1: Treatment strategies for homologous recombination-deficient pancreatic cancers.
Fig. 2: RAS signalling pathway and therapeutic targets in PDAC.
Fig. 3: Immune therapeutic strategies in PDAC.

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Acknowledgements

Cancer Center Support Grant/Core Grant: P30 CA008748. SPORE: 1P50CA257881-01A1.

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  1. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Z. Ian Hu

  2. Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Eileen M. O’Reilly

  3. Weill Cornell Medical College, New York, NY, USA

    Eileen M. O’Reilly

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Hu, Z.I., O’Reilly, E.M. Therapeutic developments in pancreatic cancer. Nat Rev Gastroenterol Hepatol 21, 7–24 (2024). https://doi.org/10.1038/s41575-023-00840-w

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