DLL3-Targeted Strategies in Advanced Prostate Cancer: Current Evidence and Future Perspectives

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Advanced prostate cancer (PC) typically responds to androgen receptor (AR) signaling inhibition.
• A subset of aggressive PC develops neuroendocrine features (NEPC) or aggressive-variant PC (AVPC) under treatment pressure, characterized by rapid progression and poor prognosis.
• Current treatments for NEPC/AVPC, primarily platinum-based chemotherapy, offer limited benefit.

Purpose of the Study:

• To review the biological rationale, translational evidence, and clinical data for Delta-like ligand 3 (DLL3)-targeted therapies in prostate cancer.
• To highlight DLL3 as a potential therapeutic target and biomarker in NEPC/AVPC.
• To discuss the potential of DLL3-directed strategies to improve outcomes for patients with aggressive prostate cancer.

Main Methods:

• Review of existing literature on DLL3 expression in prostate cancer.
• Analysis of translational evidence and emerging clinical data for DLL3-targeted therapies.
• Examination of various investigational platforms including antibody-drug conjugates, T-cell engagers, and radiopharmaceuticals.

Main Results:

• DLL3 is aberrantly upregulated in neuroendocrine malignancies, including approximately 76.6% of castration-resistant NEPC, compared to 12.5% of castration-resistant adenocarcinoma.
• DLL3-targeted therapies have shown clinical success in small-cell lung cancer, supporting their evaluation in NEPC.
• Early clinical studies indicate that DLL3-directed therapies are most effective in DLL3-expressing neuroendocrine tumors, emphasizing the need for biomarker-guided selection.

Conclusions:

• DLL3 is a promising therapeutic target and biomarker for aggressive-variant prostate cancer, particularly NEPC.
• DLL3-targeted therapies, including antibody-drug conjugates and T-cell engagers, hold potential to reshape treatment paradigms for DLL3-expressing prostate cancer.
• Refining biomarkers and optimizing clinical trial design are crucial for the successful translation of DLL3-directed therapies into clinical practice.