A new Phase I clinical trial is investigating ²²⁵Ac-ETN029 as a potential treatment for neuroendocrine prostate cancer (NEPC), a rare and aggressive form of prostate cancer. This radiopharmaceutical therapy uses Actinium-225, an alpha-emitting isotope, to target DLL3, a protein found in about 77% of NEPC cases. The trial, is actively recruiting 65 patients with advanced, DLL3-expressing solid tumors, including locally advanced, unresectable, or metastatic de novo or treatment-emergent NEPC.
Patients must have confirmed neuroendocrine differentiation through local histology and expression of markers like DLL3, synaptophysin, or chromogranin A, and must have progressed after platinum-based chemotherapy.

The study is split into two phases. Phase 1a tests escalating doses to find the safest and most effective dose, using 111In-ABD147 imaging to track how the drug spreads in the body. Phase 1b expands the selected dose to gather more data on safety and early signs of effectiveness, such as tumor response rates and progression-free survival. The therapy’s alpha particles aim to deliver precise, high-energy radiation to DLL3-positive tumor cells, potentially sparing healthy tissue, which is critical for NEPC patients with limited treatment options.

While the trial is in its early stages, it addresses a critical gap in NEPC treatment, where standard therapies like hormone treatments often fail. DLL3’s high expression in NEPC makes it a promising target, supported by prior research on DLL3-targeted therapies showing activity in preclinical models.

Clinical trial.