Abstract
Purpose: Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer with poor prognosis and limited treatment options. As NEPC aberrantly expresses delta-like ligand 3 (DLL3), the activity of tarlatamab, a bispecific T-cell engager that directs cytotoxic T cells to DLL3-positive (DLL3+) cells, was evaluated in the DeLLpro-300 study (NCT04702737). Patients and methods: This was a phase 1b, open-label study evaluating tarlatamab monotherapy in patients with metastatic de novo or treatment-emergent NEPC defined by histologic, genomic, or IHC criteria. Tarlatamab was administered intravenously every 2 weeks at a dose of 100 mg with a 1-mg step dose. The primary objective was safety, and a secondary objective was objective response rate (ORR) per RECIST v.1.1; DLL3 expression was retrospectively assessed by IHC. Results: Forty patients were enrolled (DLL3+ tumors, n = 18; DLL3- tumors, n = 14; and DLL3 unknown tumors, n = 8). The most common treatment-related adverse events were cytokine release syndrome (82.5%), dysgeusia (42.5%), and decreased appetite (40.0%). Cytokine release syndrome was predominantly of low grade (grade 1/2/3/4+, 62.5%/15%/5%/0%), occurred exclusively in cycle 1, and was transient in duration (median duration, 3 days). The ORR was 10.5% [95% confidence interval (CI), 2.9-24.8]; the median duration of response was 7.3 months in the overall cohort. Patients with DLL3+ tumors (vs. patients with DLL3-/DLL3 unknown tumors) achieved a higher ORR [22.2% (95% CI, 6.4-47.6) vs. 0% (95% CI, 0-15.4)] and radiographic progression-free survival rate at 6 months [27.7% (95% CI, 8.7-50.9) vs. 0%]. Conclusions: The DeLLpro-300 study provides preliminary evidence for the safety and antitumor activity of tarlatamab in DLL3+ NEPC.