Neuroendocrine prostate cancer, a particularly aggressive form of the disease that often emerges after treatment with androgen deprivation therapy, is showing vulnerability to new therapies targeting Delta-like ligand 3 (DLL3). DLL3, a protein rarely expressed in healthy tissues or localized prostate cancer, sees its expression surge in castrate-resistant prostate cancer, especially when cells undergo neuroendocrine diversion. This makes it an attractive target for novel therapeutic strategies.
The Promise of DLL3-Targeted Therapies
At the 2024 European Society of Medical Oncology (ESMO) Annual Congress, Dr. Himisha Beltran highlighted the potential of DLL3 as a therapeutic target. DLL3's role in Notch signaling, particularly its overexpression in neuroendocrine tumors, makes it a compelling target. Unlike adenocarcinoma, neuroendocrine prostate cancer often exhibits low PSMA expression, rendering traditional treatments less effective.
Several DLL3-targeted therapies are under development, including T cell engagers, next-generation antibody-drug conjugates (ADCs), radionuclides, bispecific antibodies, and CAR-T cell therapies. One notable example is tarlatamab, a DLL3-targeted bispecific T cell engager, which received approval for previously treated small cell lung cancer in May 2024. However, its efficacy in neuroendocrine prostate cancer is still under investigation.
Clinical Trial Results and Ongoing Research
While the NCCN guidelines recommend platinum-based chemotherapy for neuroendocrine prostate cancer, the results of a study evaluating tarlatamab in this setting were presented at ASCO 2024. The trial included patients with neuroendocrine prostate cancer who had progressed on prior systemic treatments. The objective response rate in the overall cohort was only 10.5%, but increased to 22.2% in the DLL3-positive subgroup. This suggests that patient selection based on DLL3 expression is crucial.
MK-6070, another DLL3-targeting T cell engager, has shown more promising results. In a phase I/II trial, MK-6070 demonstrated an overall response rate of 58% and a disease control rate of 83% among 12 evaluable patients with genitourinary neuroendocrine cancer. One patient experienced an ongoing response for over 50 weeks, indicating durable anti-tumor activity.
The Role of Imaging and Biomarkers
Dr. Beltran emphasized the importance of patient selection for DLL3-targeted therapies, given the heterogeneous nature of prostate cancer. DLL3 is not typically expressed in most prostate adenocarcinomas, leading to mixed responses in unselected patient populations. To address this, researchers are exploring the use of imaging techniques, such as PET scans with the tracer 89Zr-SC16, to detect and quantify DLL3 expression in tumors. This could help identify patients who are most likely to benefit from DLL3-targeted treatments.
Future Directions
DLL3-targeted therapies represent a promising avenue for treating aggressive neuroendocrine prostate cancer. Ongoing research focuses on refining patient selection strategies, understanding resistance mechanisms, and developing rational combination therapies to improve treatment outcomes. The integration of imaging biomarkers and a deeper understanding of tumor heterogeneity will be crucial for maximizing the potential of these novel therapies.
