TIDAL: A phase II study of the DLL3-directed T-cell engager tarlatamab in DLL3-positive metastatic prostate cancer.

Abstract

TPS5142 Background: T-cell engagers directed at canonical prostate adenocarcinoma surface antigens (e.g., STEAP1, KLK2) have demonstrated substantial activity in prostate adenocarcinoma; however, alternative tumor-directed targets are needed for pts whose tumors have undergone lineage plasticity. Delta-like ligand 3 (DLL3) is a surface target variably expressed across the spectrum of neuroendocrine/small cell malignancies. Tarlatamab (Imdelltra, Amgen, Thousand Oaks, CA) is a bispecific T-cell engager targeting DLL3 and CD3, with regulatory approval for small cell lung cancer, and emerging evidence of activity in DLL3-positive prostate cancer. TIDAL is a multi-center, prospective, single arm phase II trial (NCT07111507) evaluating the safety and efficacy of tarlatamab in DLL3-positive advanced prostate cancer. Methods: Key eligibility criteria include metastatic prostate cancer with progression on ≥1 prior systemic therapy in the metastatic setting and DLL3-positive disease (IHC ≥50%), irrespective of histologic subtype. Pts without measurable disease by RECIST 1.1 criteria can be enrolled; however, at least 50% of pts enrolled must have measurable disease. Pts will receive tarlatamab in 28-day cycles with a 1 mg priming dose on cycle 1 day 1 (C1D1), followed by a target dose of 10 mg on C1D8, C1D15, and days 1 and 15 of subsequent cycles. All pts are hospitalized for ≥24 hours of monitoring following C1D1 and C1D8 infusions. Mandatory tumor biopsy and circulating tumor DNA (ctDNA) collection are performed at screening and cycle 2, with required ctDNA and optional biopsy at end of treatment (EOT). CT and bone scan are performed every 8 weeks for the first 24 weeks, then every 12 weeks. The primary endpoint is radiographic progression-free survival at 24-weeks. Secondary endpoints include overall response rate (ORR), median duration of response, median rPFS, median composite PFS, median overall survival, and safety. Correlative studies will evaluate associations between tumor DLL3 expression, circulating immune profiles, and clinical outcomes. A subset of pts will be co-enrolled in an imaging biomarker study (NCT04199741) utilizing a novel DLL3 PET tracer ( 89 Zr-DFO-SC16.56). As of January 14, 2026, 4 of the planned 32 pts have been enrolled. Clinical trial information: NCT07111507 .