Abstract 2958: SAR408701: An anti-CEACAM5-maytansinoid antibody-drug conjugate to treat CEACAM5-positive neuroendocrine prostate cancer (NEPC)

Abstract Background: Neuroendocrine prostate cancer (NEPC) is a very aggressive subtype of metastatic castration-resistant prostate cancer (mCRPC), for which therapeutic strategies are currently lacking. NEPC is rare de-novo (<1% of the cases) but can represent 15 to 20% of cases after failure of the treatment targeting the androgen receptor (AR) axis (such as enzalutamide, abiraterone) in. Carcinoembryogenic antigen-related cell adhesion molecule 5 (CEACAM5) has been previously identified as an attractive NEPC cell surface antigen. Here, we investigate its expression in NEPC patient specimens and its therapeutic potential as a target for Antibody-Drug Conjugate (ADC) therapy. Methods: Tumor biopsy specimens were obtained from the prospective trial MATCH-R (NCT02517892). Patient-derived xenografts (PDX) were established and both patient biopsies (n=59) and PDX (n=16) were characterized by RNAseq and immunohistochemistry (IHC). 5 PDX from our 16 models were selected based on their CEACAM5 expression for our pharmacological assay: 2 NEPC models with a high expression of CEACAM5, 1 NEPC model with a mild (weak) expression of CEACAM5, 1 NEPC model with no expression of CEACAM5 and 1 mCRPC with a luminal phenotype and no expression of CEACAM5. SAR408701, an anti-CEACAM5 ADC or an irrelevant ADC with no specific target was administrated to immunodeficient mice. Tumor growth and body weight were monitored twice a week for 21 days post-injection. Results: 54 patient biopsies were collected for IHC and 59 for RNAseq analysis. 33 cases out of the 54 presented evidence of neuroendocrine differentiation (in IHC analysis)tusamitamab and 21 expressed synaptophysin in more than 50% of the tumor cells. CEACAM5 expression in tumor cells was detected in 12 cases which all expressed synaptophysin (>50%), suggesting a strong correlation between CEACAM5 expression and neuroendocrine differentiation. An unsupervised hierarchical clustering based on RNAseq analysis of patient samples showed an enriched neuroendocrine cluster, in which CEACAM5 was significantly overexpressed. In the 5 PDX models selected to test the activity of Tusamitamab Ravtansine based on CEACAM5 expression, a strong correlation between CEACAM5 expression in the PDX models and response to Tusamitamab Ravtansine was observed, with Tusamitamab Ravtansine showing a strong antitumoral activity on CEACAM5 expressing PDX models and no efficacy in models lacking CEACAM5 expression. Conclusion: Overall, these results demonstrate the efficacy and specificity of SAR408701 against NEPC tumors harboring CEACAM5.This study provides preclinical evidence of the antitumor activity of SAR408701 in CEACAM5-positive NEPC. Funding: Gustave Roussy, Cancer Campus, Grand Paris Citation Format: Loic Poiraudeau, Bigot Ludovic, Cedric Pobel, Naoual Menssouri, Marine Aglave, Catline Nobre, Alice Bernard-Tessier, Natacha Naoun, Anna Patrikidou, Claudio Nicotra, Maud Ngocamus, Benjamin Besse, Karim Fizazi, Jean-Yves Scoazec, Anne-Marie Lefebvre, Celine Nicolazzi, Nathalie Mace, Anne-Laure Bauchet, Yohann Loriot. SAR408701: An anti-CEACAM5-maytansinoid antibody-drug conjugate to treat CEACAM5-positive neuroendocrine prostate cancer (NEPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2958.