New data show that >75% of castration-resistant small-cell neuroendocrine prostate cancers (CRPC-NE) express the Notch ligand delta-like protein 3 (DLL3), which can be targeted by the antibody–drug conjugate SC16LD6.5 (rovalpituzumab tesirine). Treatment with this agent resulted in complete and durable responses in DLL3+ prostate cancer xenograft models and clinical and radiological responses in a patient in a phase I basket trial.

Credit: RM/Alamy

Prostate cancer treatment with androgen receptor pathway inhibitors can result in drug resistance and the emergence of tumours with neuroendocrine features. These aggressive tumours have molecular similarities to small-cell lung cancers (SCLCs). SC16LD6.5 has shown promising efficacy in early-phase SCLC trials.

In this new study, the researchers investigated DLL3 expression of CRPC-NE and antitumour activity of SC16LD6.5 in DLL3-expressing prostate cancer models. First, the team evaluated DLL3 expression in different prostate tissues. None of the benign and only 0.52% of localized prostate cancer samples were DLL3+. By contrast, 12.5% of CRPC adenocarcinomas and 76.6% of CRPC-NE expressed DLL3, and 10.37% and 63.95% of cells in these samples were DLL3+, respectively. Survival analyses showed that patients with DLL3+ tumours had worse overall survival both from the time of prostate cancer diagnosis (35 months versus 81.5 months) and from the time of metastasis (11.8 months versus 71.6 months).

The timing and mechanisms of neuroendocrine phenotype acquisition in prostate cancer remain unclear. In this study, the team evaluated temporal, intrapatient and interpatient heterogeneity of tumour DLL3 expression. In one patient, the primary tumour at diagnosis was DLL3–, a metastatic bone CRPC adenocarcinoma sample 1 year before death was DLL3+ and all metastases and the primary tumour at autopsy were highly DLL3+ and had small-cell features, indicating acquisition of DLL3 expression with time and treatment resistance. Data from two other patients showed heterogeneity of DLL3 expression and/or small-cell features.

Using cell line and patient-derived prostate cancer xenograft models, the researchers observed complete responses at 35 days after a single dose of SC16LD6.5 in DLL3+ models but no response in DLL3– models. Notably, in a patient with DLL3+ neuroendocrine prostate cancer receiving SC16LD6.5 every 6 weeks in an ongoing phase I trial, target nodal metastases shrunk from 42 mm to 24 mm and nontarget lesions showed complete or partial responses after 1 treatment cycle, remaining stable and without new lesions after 2 cycles.

in a patient with DLL3+ neuroendocrine prostate cancer … target nodal metastases shrunk from 42 mm to 24 mm

The team also tested whether circulating tumour cell (CTC) analysis might enable noninvasive detection of emerging DLL3 expression, which could inform trial eligibility. DLL3 expression status of CTCs and matched metastatic biopsy samples was concordant in 13 of 15 patients (87%).