{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T03:25:06Z","timestamp":1787973906724,"version":"build-2784847793"},"reference-count":69,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Ther Adv Med Oncol"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related death with a rising incidence in younger individuals and no standard early detection exam. Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated gene of the RAS family, and KRAS mutations are found in approximately 85%\u201390% of PDAC. Long considered undruggable due to its molecular structure, the advent of sotorasib and adagrasib has ushered in multiple novel therapeutics targeting the RAS pathway, including mutation-selective, pan-KRAS, and pan-RAS inhibitors. Combination strategies using chemotherapy and directed against EGFR, SOS1, SHP2, and immune pathways, among others, aim to overcome resistance to RAS inhibitor monotherapy and enhance the depth and duration of clinical benefit. The minority of PDAC tumors that are KRAS-wildtype are enriched for rare, actionable alterations, including Neuregulin-1, HER2, and BRAF amenable to targeted treatments. For patients with metastatic disease carrying a germline BRCA1\/2 or PALB2 pathogenic variant, PARP inhibitors remain an option as maintenance treatment after achieving at least stable disease with platinum-based chemotherapy. Importantly, ongoing and future clinical trials are shifting the use of targeted therapies from the refractory setting to earlier lines and the perioperative setting with promising results. Here, we detail the different areas of investigation targeting KRAS and other precision-based therapies in PDAC, as well as the potential emerging roles of local interventions (radiation, surgery) for select patients with oligometastatic disease. Composite predictive biomarkers using genomic, proteomic, and radiographic factors are needed to refine and individualize treatment selection and ultimately improve patient outcomes.<\/jats:p>","DOI":"10.1177\/17588359261432058","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T01:46:26Z","timestamp":1777254386000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Emerging precision therapeutics for pancreatic ductal adenocarcinoma: KRAS and beyond"],"prefix":"10.1177","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5902-3041","authenticated-orcid":false,"given":"Ani","family":"Misirian","sequence":"first","affiliation":[{"name":"Los Angeles General Medical Center\/University of Southern California, 2020 Zonal Avenue, IRD 620, Los Angeles, CA 90033, USA"},{"name":"USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Pai","sequence":"additional","affiliation":[{"name":"USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA"},{"name":"Los Angeles General Medical Center\/University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana L.","family":"Hanna","sequence":"additional","affiliation":[{"name":"USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA"},{"name":"Los Angeles General Medical Center\/University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,4,26]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.13027"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2023.113471"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4389"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-022-01375-4"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a031435"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1080\/14728214.2022.2134346"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0245-4"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11193175"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.4_suppl.735"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2021.102309"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2308795"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2208470"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.36_suppl.425082"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.00434"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.70056"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2021-1259"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2024.42.3_suppl.94"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.TARG-23-PR014"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg9652"},{"key":"e_1_3_5_21_2","article-title":"Preliminary safety and clinical activity of ASP3082, a first-in-class KRAS G12D selective protein degrader in adults with advanced pancreatic, colorectal, and non-small cell lung cancer","volume":"35","author":"Park W","year":"2024","unstructured":"Park W, Kasi A, Spira AI, et al. Preliminary safety and clinical activity of ASP3082, a first-in-class KRAS G12D selective protein degrader in adults with advanced pancreatic, colorectal, and non-small cell lung cancer. Ann Oncol 2024; 35(Suppl.): S486\u2013S487.","journal-title":"Ann Oncol"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42004-025-01662-4"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2023-526"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.4_suppl.724"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2025.08.1484"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.06.001"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2023.10.025"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25506-6"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.4_suppl.TPS633"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2025-CT265"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2023-0005-OA"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49915-5"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.05.016"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00780-4"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-020-00967-y"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2024.11.009"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.4_suppl.722"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03876-4"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.3390\/ph13050090"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.08.1587"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.TARG-23-A090"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0177"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2022.10.001"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.07.002"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-3930"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1339302"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.17_suppl.LBA4011"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2021.11.003"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.08.2335"},{"key":"e_1_3_5_50_2","article-title":"Clinical response to seribantumab in metastatic pancreatic ductal adenocarcinoma harboring an NRG1 fusion","volume":"6","author":"Thavaneswaran S","year":"2022","unstructured":"Thavaneswaran S, Chan WY, Asghari R, et al. Clinical response to seribantumab in metastatic pancreatic ductal adenocarcinoma harboring an NRG1 fusion. JCO Precis Oncol 2022; 6: e2200263.","journal-title":"JCO Precis Oncol"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2405008"},{"key":"e_1_3_5_52_2","volume-title":"FDA grants accelerated approval to zenocutuzumab-ZBCO","author":"Center for Drug Evaluation and Research","unstructured":"Center for Drug Evaluation and Research. FDA grants accelerated approval to zenocutuzumab-ZBCO. U.S. Food and Drug Administration, n.d."},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2023.216421"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252011090"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2023.04.012"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0190"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06063-y"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2025.102362"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.08.1595"},{"key":"e_1_3_5_60_2","volume-title":"Phase II GLEAM trial did not meet overall survival endpoint in metastatic pancreatic cancer","author":"Astellas Pharma","unstructured":"Astellas Pharma. Phase II GLEAM trial did not meet overall survival endpoint in metastatic pancreatic cancer. Astellas Global, n.d."},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.4_suppl.TPS765"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03037-z"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14040897"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01604"},{"key":"e_1_3_5_65_2","article-title":"Pembrolizumab and olaparib maintenance in metastatic pancreatic cancer: phase II POLAR trial","volume":"35","author":"Park W","year":"2024","unstructured":"Park W, Connor CO, Chou J, et al. Pembrolizumab and olaparib maintenance in metastatic pancreatic cancer: phase II POLAR trial. Ann Oncol 2024; 35: S922.","journal-title":"Ann Oncol"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.4_suppl.TPS793"},{"key":"e_1_3_5_67_2","article-title":"Apollo trial: olaparib versus placebo following curative-intent therapy in resected BRCA-mutated pancreatic cancer","volume":"41","author":"Reiss KA","year":"2023","unstructured":"Reiss KA, Hong SC, Kasi A, et al. Apollo trial: olaparib versus placebo following curative-intent therapy in resected BRCA-mutated pancreatic cancer. J Clin Oncol 2023; 41(4 Suppl.): TPS763.","journal-title":"J Clin Oncol"},{"key":"e_1_3_5_68_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.24.00081"},{"key":"e_1_3_5_69_2","doi-asserted-by":"publisher","DOI":"10.1093\/oncolo\/oyaf154"},{"key":"e_1_3_5_70_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-025-13573-7"}],"container-title":["Therapeutic Advances in Medical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17588359261432058","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/17588359261432058","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17588359261432058","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T22:34:22Z","timestamp":1777588462000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/17588359261432058"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4]]},"references-count":69,"alternative-id":["10.1177\/17588359261432058"],"URL":"https:\/\/doi.org\/10.1177\/17588359261432058","relation":{},"ISSN":["1758-8359","1758-8359"],"issn-type":[{"value":"1758-8359","type":"print"},{"value":"1758-8359","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4]]},"article-number":"17588359261432058"}}