5012 Background: NEPC is an aggressive form of prostate cancer with poor prognosis and no standard treatment approach. NEPC can be characterized by late, treatment-emergent transformation from adenocarcinoma to high-grade neuroendocrine carcinoma (NEC), in 10–15% of mCRPC patients (pts). DLL3 is overexpressed in high-grade NECs, including NEPC, and minimally expressed on normal tissue. Tarlatamab, a bispecific T-cell engager immunotherapy with clinical activity in small cell lung cancer (SCLC), binds DLL3 and CD3 resulting in T-cell mediated tumor lysis. Here, we report primary analysis data of tarlatamab in NEPC (NCT04702737). Methods: This is an open-label phase 1b study evaluating tarlatamab monotherapy in adult (≥18 years y) pts with metastatic de novo or treatment-emergent NEPC by histologic, genomic, or immunohistochemistry (IHC) criteria. The starting dose was the highest safe and tolerable dose in the phase 1 SCLC trial (NCT03319940). Safety was the primary objective; anti-tumor activity and pharmacokinetics were secondary objectives. Exploratory analysis of DLL3 expression was assessed by IHC using the Ventana SP347 assay. Results: As of 28 March 2023, 40 pts received ≥1 tarlatamab dose (1 mg step dose, 100 mg target dose). Median (range) age was 64.5 (43–83) y, prior lines of therapy was 3 (1–9), prostate specific antigen at baseline was 0.2 (0.0–5000.0) μg/L. Treatment-related adverse events (TRAE) occurred in all patients, with no fatal TRAE. Most common TRAEs were cytokine-release syndrome (CRS; 65.0%), pyrexia (52.5%) and dysgeusia (42.5%). CRS occurred primarily in treatment cycle 1; events were mostly grade 1–2 (one grade 3 event). Treatment discontinuation due to TRAE was low (7.5%). Tarlatamab serum exposures were consistent with tarlatamab SCLC studies. Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) was 10.5% (95% CI, 2.9, 24.8); median progression free survival (mPFS) was 1.9 months (m) (95% CI, 1.7, 3.5). Retrospective DLL3 IHC analysis showed that 18 of 32 (56.3%) biopsy evaluable pts had ≥1% DLL3 tumor positivity (DLL3+). As of 24 January 2024, ORR in DLL3+ pts was 22.2% (95% CI, 6.4, 47.6); durations of response in the 4 pts with response were 25.8 m, 9.2 m, 5.5 m, 3.7 m; mPFS in DLL3+ pts was 3.75 m (95% CI, 1.87, 11.01). Efficacy is shown in Table. Conclusions: Findings from this phase 1 study of tarlatamab in pts with NEPC demonstrated manageable safety with encouraging anti-tumor activity in DLL3 expressing NEPC. Further investigation is ongoing. Clinical trial information: NCT04702737 . Table: see text