Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2025 Sep 15;31(18):3854-3863.
doi: 10.1158/1078-0432.CCR-25-1211.

Safety and Efficacy of Tarlatamab in Patients with Neuroendocrine Prostate Cancer: Results from the Phase 1b DeLLpro-300 Study

Rahul Aggarwal  1 , Sylvie Rottey  2 , Alice Bernard-Tessier  3 , Begoña Mellado  4 , Takeo Kosaka  5 , Walter M Stadler  6 , Lisa Horvath  7   8 , Richard Greil  9 , Bert O'Neil  10 , Bilal A Siddiqui  11 , Thomas Bauernhofer  12 , Mehmet A Bilen  13 , Ferry Eskens  14 , Shahneen Sandhu  15 , Crystal Shaw  16 , Chia Hsin Ju  16 , Benjamin E Decato  16 , Brian Yu  16 , Ana Aparicio  17
Affiliations
Clinical Trial

Safety and Efficacy of Tarlatamab in Patients with Neuroendocrine Prostate Cancer: Results from the Phase 1b DeLLpro-300 Study

Rahul Aggarwal et al. Clin Cancer Res. .

Abstract

Purpose: Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer with poor prognosis and limited treatment options. As NEPC aberrantly expresses delta-like ligand 3 (DLL3), the activity of tarlatamab, a bispecific T-cell engager that directs cytotoxic T cells to DLL3-positive (DLL3+) cells, was evaluated in the DeLLpro-300 study (NCT04702737).

Patients and methods: This was a phase 1b, open-label study evaluating tarlatamab monotherapy in patients with metastatic de novo or treatment-emergent NEPC defined by histologic, genomic, or IHC criteria. Tarlatamab was administered intravenously every 2 weeks at a dose of 100 mg with a 1-mg step dose. The primary objective was safety, and a secondary objective was objective response rate (ORR) per RECIST v.1.1; DLL3 expression was retrospectively assessed by IHC.

Results: Forty patients were enrolled (DLL3+ tumors, n = 18; DLL3- tumors, n = 14; and DLL3 unknown tumors, n = 8). The most common treatment-related adverse events were cytokine release syndrome (82.5%), dysgeusia (42.5%), and decreased appetite (40.0%). Cytokine release syndrome was predominantly of low grade (grade 1/2/3/4+, 62.5%/15%/5%/0%), occurred exclusively in cycle 1, and was transient in duration (median duration, 3 days). The ORR was 10.5% [95% confidence interval (CI), 2.9-24.8]; the median duration of response was 7.3 months in the overall cohort. Patients with DLL3+ tumors (vs. patients with DLL3-/DLL3 unknown tumors) achieved a higher ORR [22.2% (95% CI, 6.4-47.6) vs. 0% (95% CI, 0-15.4)] and radiographic progression-free survival rate at 6 months [27.7% (95% CI, 8.7-50.9) vs. 0%].

Conclusions: The DeLLpro-300 study provides preliminary evidence for the safety and antitumor activity of tarlatamab in DLL3+ NEPC.

PubMed Disclaimer

Conflict of interest statement

R. Aggarwal reports grants from Amgen during the conduct of the study, as well as personal fees from MJH Health, Lumanity, EcoR1 Capital, PCCTC, Scitaris, Curio Sciences, Boxer Capital, Slingshot Capital, Research To Practice, Xencor, Alessa Therapeutics, AbbVie, Oric Pharmaceuticals, Auron Therapeutics, Peptone Therapeutics, Pfizer, Daiichi Sankyo, and DAVA Oncology and grants and personal fees from AstraZeneca, Johnson & Johnson, Merck, BioeXcel Therapeutics, Novartis, and Fibrogen outside the submitted work. A. Bernard-Tessier reports personal fees and nonfinancial support from Novartis and Bayer; grants from Servier; and personal fees from Janssen, AstraZeneca, Astellas, MSD, and Bouchara-Recordati outside the submitted work. B. Mellado reports grants and nonfinancial support from Bayer, Janssen, and Astellas; grants, nonfinancial support, and other support from Pfizer; grants and other support from AstraZeneca; nonfinancial support and other support from Novartis; and personal fees from Ipsen outside the submitted work. W.M. Stadler reports grants from Amgen during the conduct of the study, as well as personal fees from Merck, Bayer, Caremark/CVS, and Fortress Biotech and grants from Astellas, Bayer, Johnson & Johnson, and Pfizer outside the submitted work. L. Horvath reports other support from Amgen during the conduct of the study, as well as grants and other support from Astellas and Bayer and other support from Janssen and MSD outside the submitted work; in addition, L. Horvath has a patent for International (PCT) Patent Application No. PCT/AU2023/050849 pending to Chris O’Brien Lifehouse/Baker Institute. R. Greil reports other support for the financing of scientific research from Celgene, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz Gilead, and Roche during the conduct of the study as well as other support for advisory role or expert testimony from Celgene, Novartis, Roche, BMS, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Merck, Gilead, and Daiichi Sankyo outside the submitted work. In addition, R. Greil reports traveling support from Roche, Amgen, Janssen, AstraZeneca, Novartis, MSD, Celgene, Gilead, Bristol Myers Squibb, AbbVie, and Daiichi Sankyo; honoraria from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, Sanofi, and Pfizer; and stock ownership in Novo Nordisk, Lilly, Regeneron, and Vertex. B. O’Neil reports personal fees from Amgen outside the submitted work. B.A. Siddiqui reports personal fees from Cancer Expert Now, Curio Science, Merck, Pfizer, Amgen, and Johnson & Johnson and grants from ASCO-Conquer Cancer Foundation, Prostate Cancer Foundation, and Cancer Research Institute outside the submitted work. T. Bauernhofer reports grants from Ipsen and AstraZeneca and personal fees from Johnson & Johnson, Astellas, AstraZeneca, Bayer, Pfizer, Bristol Myers Squibb, MSD, and ESAI outside the submitted work. M.A. Bilen reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai Inc., EMD Serono, Exelixis Inc., Genomic Health, Janssen, Nektar, Pfizer, Seagen, and Sanofi and grants from AAA, AstraZeneca, Bayer, Bristol Myers Squibb, Genentech/Roche, Genome & Company, Incyte, Merck, Nektar, Peloton Therapeutics, Pfizer, Seagen, Tricon Pharmaceuticals, and Xencor outside the submitted work. C. Shaw reports being an employee of and stockholder at Amgen, Inc. C.H. Ju reports other support from Amgen outside the submitted work. B.E. Decato reports employment with Amgen and possession of company stock. B. Yu reports personal fees from Amgen during the conduct of the study and outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Occurrence of CRS and ICANS during tarlatamab treatment in patients with NEPC.
Figure 2.
Figure 2.
Duration of treatment, response rates, and Kaplan–Meier plots of survival outcomes in NEPC with tarlatamab. A, Duration of treatment and DLL3 H-scores in patients with evaluable DLL3 expression. Six other patients discontinued tarlatamab prior to the first scheduled restaging scan (8 weeks after initiation of tarlatamab) because of disease progression (n = 2), ICANS (n = 1), atrial flutter (n = 1), physician decision (n = 1), and principal investigator’s decision (n = 1). B, Distribution of tumor regression and DLL3 expression (H-score) in relation to treatment response. C, rPFS, (D) OS, and (E) rPFS in patients with DLL3+ tumors with small cell histology vs. all other patients. F, OS in patients with DLL3+ tumors with small cell histology vs. all other patients. *, Percent change in the SLD of the target lesions. H-score was calculated as (0 × % cells at 0 staining intensity) + (1 × % cells at 1+ staining intensity) + (2 × % cells at 2+ staining intensity) + (3 × % cells at 3+ staining intensity). Median H-score = 125 (range, 0–300). CR, complete response; SLD, sum of the longest diameter. Data cutoff: August 1, 2024.
Figure 3.
Figure 3.
Pharmacodynamics of tarlatamab as assessed by DLL3 expression in NEPC. A, Induction of inflammatory cytokines as assessed by DLL3 expression. B, T-cell margination and redistribution of T cells as assessed by DLL3 expression. DLL3+ is defined as ≥1% DLL3 tumor positivity by IHC. Data cutoff: August 1, 2024. CxDx, cycle x day x; HRx, hour x.
See this image and copyright information in PMC

References

    1. Nadal R, Schweizer M, Kryvenko ON, Epstein JI, Eisenberger MA. Small cell carcinoma of the prostate. Nat Rev Urol 2014;11:213–9. - PMC - PubMed
    1. Eule CJ, Hu J, Al-Saad S, Collier K, Boland P, Lewis AR, et al. Outcomes of second-line therapies in patients with metastatic de novo and treatment-emergent neuroendocrine prostate cancer: a multi-institutional study. Clin Genitourin Cancer 2023;21:483–90. - PMC - PubMed
    1. Wishahi M. Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer: identification, prognosis and survival, genetic and epigenetic factors. World J Clin Cases 2024;12:2143–6. - PMC - PubMed
    1. 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:eaav0891. - PMC - PubMed
    1. Henke RM, Meredith DM, Borromeo MD, Savage TK, Johnson JE. Ascl1 and Neurog2 form novel complexes and regulate delta-like3 (Dll3) expression in the neural tube. Dev Biol 2009;328:529–40. - PMC - PubMed

Publication types

MeSH terms

Substances

Associated data