LAUSR

DLL3 is overexpressed in neuroendocrine prostate cancer and is a potential therapeutic target. Lessons from one tumor help with another Neuroendocrine prostate cancer is an aggressive tumor subtype that can arise late in the course of the disease and drive therapeutic resistance. Puca et al. demonstrate the feasibility of targeting it with an antibody-drug conjugate against delta-like protein 3 (DLL3), a recently identified therapeutic being tested in small cell lung cancer, another aggressive neuroendocrine tumor. The authors confirmed the presence of DLL3 in most neuroendocrine prostate cancers, but not in localized tumors or normal prostate, and showed its association with aggressive clinical features. They then demonstrated the effectiveness of targeting DLL3 in multiple mouse models as well as a human patient. Histologic transformation to small cell neuroendocrine prostate cancer occurs in a subset of patients with advanced prostate cancer as a mechanism of treatment resistance. Rovalpituzumab tesirine (SC16LD6.5) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) and was initially developed for small cell lung cancer. We found that DLL3 is expressed in most of the castration-resistant neuroendocrine prostate cancer (CRPC-NE) (36 of 47, 76.6%) and in a subset of castration-resistant prostate adenocarcinomas (7 of 56, 12.5%). It shows minimal to no expression in localized prostate cancer (1 of 194) and benign prostate (0 of 103). DLL3 expression correlates with neuroendocrine marker expression, RB1 loss, and aggressive clinical features. DLL3 in circulating tumor cells was concordant with matched metastatic biopsy (87%). Treatment of DLL3-expressing prostate cancer xenografts with a single dose of SC16LD6.5 resulted in complete and durable responses, whereas DLL3-negative models were insensitive. We highlight a patient with neuroendocrine prostate cancer with a meaningful clinical and radiologic response to SC16LD6.5 when treated on a phase 1 trial. Overall, our findings indicate that DLL3 is preferentially expressed in CRPC-NE and provide rationale for targeting DLL3 in patients with DLL3-positive metastatic prostate cancer.