Filho AM, Laversanne M, Ferlay J, Colombet M, Piñeros M, Znaor A, et al. The GLOBOCAN 2022 cancer estimates: data sources, methods, and a snapshot of the cancer burden worldwide. Int J Cancer. 2025;156(7):1336–46. https://doi.org/10.1002/ijc.35278.

Article  CAS  Google Scholar 

Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA A Cancer J Clinicians. 2025;75(1):10–45. https://doi.org/10.3322/caac.21871.

Article  Google Scholar 

James ND, Tannock I, N’Dow J, Feng F, Gillessen S, Ali SA, et al. The Lancet Commission on prostate cancer: planning for the surge in cases. Lancet. 2024;403(10437):1683–722. https://doi.org/10.1016/S0140-6736(24)00651-2.

Article  PubMed  PubMed Central  Google Scholar 

Spratt DE, Srinivas S, Adra N, Ahmed B, An Y, Bitting R, et al. Prostate cancer, version 3.2026, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2025;23(11):469–93. https://doi.org/10.6004/jnccn.2025.0052.

Article  PubMed  CAS  Google Scholar 

EAU Guidelines. Edn. In: Presented at the EAU annual congress, London. 2026.

Beltran H, Hruszkewycz A, Scher HI, Hildesheim J, Isaacs J, Yu EY, et al. The role of lineage plasticity in prostate cancer therapy resistance. Clin Cancer Res. 2019;25(23):6916–24. https://doi.org/10.1158/1078-0432.CCR-19-1423.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Pedrani M, Salfi G, Pecoraro G, Puglisi M, Turco F, Tortola L, et al. Prognosis and treatment response in aggressive-variant prostate cancer and treatment-related neuroendocrine prostate cancer: a systematic review and meta-analysis. Eur Urol Oncol. 2026. https://doi.org/10.1016/j.euo.2026.01.011.

Article  PubMed  Google Scholar 

Aparicio AM, Shen L, Tapia ELN, Lu JF, Chen HC, Zhang J, et al. Combined tumor suppressor defects characterize clinically defined aggressive variant prostate cancers. Clin Cancer Res. 2016;22(6):1520–30. https://doi.org/10.1158/1078-0432.CCR-15-1259.

Article  PubMed  CAS  Google Scholar 

Chen J, Shi M, Chuen Choi SY, Wang Y, Lin D, Zeng H. Genomic alterations in neuroendocrine prostate cancer: a systematic review and meta‐analysis. BJUI Compass. 2023;4(3):256–65. https://doi.org/10.1002/bco2.212.

Article  PubMed  PubMed Central  Google Scholar 

Yamada Y, Beltran H. Clinical and biological features of neuroendocrine prostate cancer. Curr Oncol Rep. 2021;23(2):15. https://doi.org/10.1007/s11912-020-01003-9.

Article  PubMed  PubMed Central  Google Scholar 

Labrecque MP, Coleman IM, Brown LG, True LD, Kollath L, Lakely B, et al. Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer. J Clin Investig. 2019;129(10):4492–505. https://doi.org/10.1172/JCI128212.

Article  PubMed  PubMed Central  Google Scholar 

Netto GJ, Amin MB, Berney DM, Compérat EM, Gill AJ, Hartmann A, et al. The 2022 World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs—Part B: Prostate and Urinary Tract Tumors. Eur Urol. 2022;82(5):469–482. https://doi.org/10.1016/j.eururo.2022.07.002.

Article  PubMed  Google Scholar 

Rindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, et al. Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocr Pathol. 2022;33(1):115–54. https://doi.org/10.1007/s12022-022-09708-2.

Article  PubMed  CAS  Google Scholar 

Giunta EF, Schepisi G, Bleve S, Serra R, Brighi N, Torresan I, et al. Neuroendocrine prostate cancer (NEPC) in focus: state of the art and future prospectives. Discov Oncol. 2026;17(1):457. https://doi.org/10.1007/s12672-026-04482-7.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Aggarwal R, Huang J, Alumkal JJ, Zhang L, Feng FY, Thomas GV, et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J Clin Oncol. 2018;36(24):2492–503. https://doi.org/10.1200/JCO.2017.77.6880.

Article  PubMed  PubMed Central  CAS  Google Scholar 

EAU Guidelines. Edn. In: Presented at the EAU annual congress, Madrid. 2025.

Von Amsberg G, Emmenegger U, Robbrecht DG, Arslan C, Mehra N, Gonzalez-Billalabeitia E, et al. Phase 1b/2 KEYNOTE-365 cohort I: pembrolizumab (pembro) plus carboplatin and etoposide chemotherapy (chemo) or chemo alone for metastatic neuroendocrine prostate cancer (NEPC). JCO. 2025;43(16_suppl):5059–5059. https://doi.org/10.1200/JCO.2025.43.16_suppl.5059.

Article  Google Scholar 

Owen DH, Giffin MJ, Bailis JM, Smit MAD, Carbone DP, He K. DLL3: an emerging target in small cell lung cancer. J Hematol Oncol. 2019;12(1):61. https://doi.org/10.1186/s13045-019-0745-2.

Article  PubMed  PubMed Central  Google Scholar 

Paz-Ares L, Champiat S, Lai WV, Izumi H, Govindan R, Boyer M, et al. Tarlatamab, a first-in-class DLL3-targeted bispecific T-cell engager, in recurrent small-cell lung cancer: an open-label, phase I study. J Clin Oncol. 2023;41(16):2893–903. https://doi.org/10.1200/JCO.22.02823.

Article  PubMed  PubMed Central  CAS  Google Scholar 

The Human Protein Atlas. DLL3 (delta like canonical Notch ligand 3). [Internet]. https://www.proteinatlas.org/ENSG00000090932-DLL3.

Ladi E, Nichols JT, Ge W, Miyamoto A, Yao C, Yang LT, et al. The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol. 2005;170(6):983–92. https://doi.org/10.1083/jcb.200503113.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Zhou B, Lin W, Long Y, Yang Y, Zhang H, Wu K, et al. Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther. 2022;7(1):95. https://doi.org/10.1038/s41392-022-00934-y.

Article  PubMed  PubMed Central  Google Scholar 

Weinmaster G, Kintner C. Modulation of notch signaling during somitogenesis. Annu Rev Cell Dev Biol. 2003;19(1):367–95. https://doi.org/10.1146/annurev.cellbio.19.111301.115434.

Article  PubMed  CAS  Google Scholar 

Yao J, Bergsland E, Aggarwal R, Aparicio A, Beltran H, Crabtree JS, et al. DLL3 as an emerging target for the treatment of neuroendocrine neoplasms. Oncologist. 2022;27(11):940–51. https://doi.org/10.1093/oncolo/oyac161.

Article  PubMed  PubMed Central  Google Scholar 

Wang H, Zheng T, Xu D, Sun C, Huang D, Liu X. Targeting DLL3: innovative strategies for tumor treatment. Pharmaceutics. 2025;17(4):520. https://doi.org/10.3390/pharmaceutics17040520.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Ajkunic A, Sayar E, Roudier MP, Patel RA, Coleman IM, De Sarkar N, et al. Assessment of TROP2, CEACAM5 and DLL3 in metastatic prostate cancer: expression landscape and molecular correlates. NPJ Precis Onc. 2024;8(1):104. https://doi.org/10.1038/s41698-024-00599-6.

Article  CAS  Google Scholar 

Ku SY, Wang Y, Garcia MM, Yamada Y, Mizuno K, Long MD, et al. Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer. J Clin Investig. 2024;134(17):e175217. https://doi.org/10.1172/JCI175217.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Puca L, Gavyert K, Sailer V, Conteduca V, Dardenne E, Sigouros M, et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med. 2019;11(484):eaav0891. https://doi.org/10.1126/scitranslmed.aav0891.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Thoma C. Targeting DLL3 in neuroendocrine prostate cancer. Nat Rev Urol. 2019;16(6):330–330. https://doi.org/10.1038/s41585-019-0190-6.

Article  PubMed  Google Scholar 

Ku SY, Yamada Y, Ng P, Sun L, Beltran H. Abstract 2896: DLL3-targeted T cell engager therapy (HPN328) for neuroendocrine prostate cancer. Cancer Res. 2022;82(12_Supplement):2896–2896. https://doi.org/10.1158/1538-7445.AM2022-2896.

Article