Effective treatments for de novo and treatment-emergent small cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from advanced cancer patients, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a positron-emission tomography (PET) agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life-extended bispecific T cell engager (BiTE®) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable anti-tumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE® immunotherapy has significant anti-tumor activity in this aggressive prostate cancer subtype.
Cancer research. 2022 Nov 09 [Epub ahead of print]
Jonathan Chou, Emily A Egusa, Sinan Wang, Michelle L Badura, Fei Lee, Anil P Bidkar, Jun Zhu, Tanushree Shenoy, Kai Trepka, Troy M Robinson, Veronica Steri, Jiaoti Huang, Yuzhuo Wang, Eric J Small, Emily Chan, Bradley A Stohr, Alan Ashworth, Brant Delafontaine, Sylvie Rottey, Keegan S Cooke, Nooshin Hashemi Sadraei, Brian Yu, Mark Salvati, Julie M Bailis, Felix Y Feng, Robert R Flavell, Rahul Aggarwal
University of California, San Francisco, San Francisco, CA, United States., University of California, San Francisco, San Francisco, California, United States., Amgen Inc., South San Francisco, CA, United States., Memorial Sloan Kettering Cancer Center, New York, NY, United States., Duke University School of Medicine, Durham, United States., University of British Columbia, Vancouver, BC, Canada., Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, United States., University of California, San Francisco, San Franciso, United States., UCSF Helen Diller Family Comprehensive Cancer Centre, San Francisco, CA, United States., Ghent University Hospital, Ghent, Belgium., Ghent University Hospital - 4B11, Ghent, Belgium., Amgen Inc., Thousand Oaks, CA, United States., Amgen (United States), Thousand Oaks, California, United States., Bristol-Myers Squibb (United States), Princeton, NJ, United States., Amgen, Inc., South San Francisco, CA, United States.