Emerging DLL3-targeted therapies are showing promise in treating neuroendocrine prostate cancer, an aggressive subtype with limited treatment options. DLL3, or delta-like ligand 3, is a cell surface protein highly expressed in neuroendocrine and small cell prostate cancers, making it an attractive therapeutic target. Recent clinical trials of DLL3-targeted T-cell engagers, including Tarlatamab and MK-6070, have demonstrated potential efficacy in treating neuroendocrine carcinomas.
DLL3 as a Therapeutic Target
DLL3 is not typically expressed in healthy adult tissues, making it a promising target for cancer therapy. In prostate cancer, DLL3 expression is minimal in benign or localized tumors but increases significantly as tumors progress to castration-resistant prostate cancer, particularly in neuroendocrine or small cell carcinomas, where it is expressed in up to 76% of cases. This lineage plasticity, where tumors switch from an adeno to a neuroendocrine phenotype, presents both a challenge and an opportunity for targeted therapies.
Clinical Evidence and Ongoing Trials
The DLL3-targeted T-cell engager Tarlatamab has already received FDA approval for previously treated small cell lung cancer, based on a phase 2 trial that showed a 40% response rate and promising overall survival. This approval raises the question of whether Tarlatamab could also benefit patients with neuroendocrine prostate cancer, given the shared expression of DLL3. However, data from a trial of Tarlatamab in prostate cancer, which included patients with neuroendocrine differentiation or tumor suppressor losses, showed a less impressive overall objective response rate of 10.5%.
Merck is developing another DLL3-targeted T-cell engager called MK-6070, a trispecific antibody that also binds albumin to extend half-life and minimize nonspecific T-cell activation. Interim results from an ongoing phase 1 study of MK-6070 in small cell lung cancer, neuroendocrine prostate cancer, and other high-grade neuroendocrine carcinomas have shown responses across the spectrum of neuroendocrine carcinomas. Notably, some patients with neuroendocrine prostate cancer in this trial were treated beyond radiographic progression due to clinical benefit, suggesting the potential for durable responses in select patients.
Challenges and Future Directions
Patient selection is crucial for optimizing the use of DLL3-targeted therapies in prostate cancer. DLL3 is not expressed in most adenocarcinomas, and heterogeneous tumor features may lead to mixed responses. Biomarkers that capture heterogeneity may help improve patient selection and inform rational combination strategies. Researchers are also developing DLL3 PET imaging to complement PSMA PET and F-18 FDG PET in diagnosing neuroendocrine prostate cancer and understanding resistance patterns.
Tumor heterogeneity in prostate cancer also suggests the potential for co-targeting. Given the incomplete overlap in the expression of various cell surface targets across castration-resistant prostate cancer, combining drugs or using bispecific therapies that target multiple antigens may lead to more robust antitumor activity. Clinical trials and research are essential to improve our understanding of this aggressive cancer subtype and develop more effective treatments.
