While therapies such as Lutetium-177 (¹⁷⁷Lu) radioligand treatments have marked a significant advancement, researchers are now exploring next-generation options to improve outcomes. This is the case with the ACCEL trial, a groundbreaking phase I clinical study presented at the ASCO Genitourinary Cancers Symposium (ASCO GU) 2025. This trial investigates Actinium-225-PSMA-62 (Ac-225-PSMA-62), an innovative radioligand therapy that could redefine how we approach prostate cancer.

The ACCEL trial is a phase Ia/Ib/II clinical study designed to evaluate the efficacy, safety, tolerability, and dosimetry (radiation distribution) of Ac-225-PSMA-62 in two distinct groups of prostate cancer patients: those with oligometastatic hormone-sensitive prostate cancer (OmHSPC) and those with metastatic castration-resistant prostate cancer (mCRPC).

Currently in its early phase (phase I), the trial focuses on patients who have progressed after androgen deprivation therapy (ADT) and at least one chemotherapy agent, such as Docetaxel or Cabazitaxel. Notably, at this stage, the trial excludes patients previously treated with Lu-177-based therapies, a decision that reflects its intent to establish a baseline understanding of Ac-225-PSMA-62’s effects in a specific patient population before expanding to more complex cases.

At the heart of the ACCEL trial is Ac-225-PSMA-62, a radioligand therapy combining Actinium-225, an alpha-emitting radioisotope, with PSMA-62, a targeting ligand. Prostate-specific membrane antigen (PSMA) is a protein overexpressed on the surface of prostate cancer cells, making it an ideal target for precision therapies. The PSMA-62 ligand is engineered for enhanced cellular internalization, meaning it can more effectively deliver its radioactive payload directly into cancer cells.
Actinium-225 stands out due to its alpha-particle emissions.

Unlike beta particles (used in Lu-177 therapies), alpha particles deliver high-energy radiation over a very short distance—typically just a few cell diameters. This precision allows Ac-225 to cause significant damage to cancer cells (via double-strand DNA breaks) while minimizing harm to surrounding healthy tissue. Compared to earlier Actinium-based therapies, Ac-225-PSMA-62 is designed with improved biodistribution, potentially reducing side effects like salivary gland damage (xerostomia), a common issue with radioligand treatments.

For patients with oligometastatic hormone-sensitive disease—where cancer has spread to only a few sites—Ac-225-PSMA-62 could delay progression to more aggressive stages. For those with mCRPC, who often face limited options after failing standard treatments, this therapy might provide a lifeline by targeting cancer cells more effectively than existing methods.

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