The possibilities of prostate cancer radioligand therapy with low-molecular-weight PSMA inhibitors labeled with actinium-225: a review

INTRODUCTION: The terminal form of prostate cancer known as metastatic castrate-resistant prostate cancer (mCRPC) is a progressive disease with limited therapeutic options and poor survival prognosis. Therefore, there is a high demand for more effective (targeted) strategies of systemic therapy. Radioligand therapy (RLT) offers the possibility to treat mCRPC in a specific and tumor-selective manner by targeting prostate-specific membrane antigen (PSMA), which is overexpressed by prostate tumor cells.

OBJECTIVE: To analyze the efficacy and safety of RLT of mCRPC using low molecular weight PSMA inhibitors labeled with alpha-emitting radionuclide ²²⁵Ac based on the literature data.

MATERIALS AND METHODS: Literature search was performed during a period of 01.04.2024 to 27.04.2024 in Russian and English language in databases Medline/PubMed, Google Scholar, RINC/Elibrary using the following keywords: actinium-225 (²²⁵Ac), PSMA, ²²⁵Ac-PSMA, radioligand therapy of prostate cancer.

RESULTS: This review presents the current worldwide experience of mCRPC RLT using low-molecular-weight PSMA inhibitors labeled with the alpha-emitting radionuclide 225Ac. Data on the efficacy of RLT with ²²⁵Aс-PSMA-617 and ²²⁵Aс-PSMA-I&T as well as the results of tandem therapy are presented. The toxicity of this treatment is discussed in detail, and ways of their avoidance or reduction their intensity are reviewed.

DISCUSSION: RLT with ²²⁵Ac-PSMA ligands is an effective and safe strategy for mCRPC therapy, including tumors, which are resistant to conventional therapies, and also in case of inefficacy of RLT with ¹⁷⁷Lu-PSMA. More than a half of treated patients had PSA levels declined greater than 50%. The most common complication of RLT is xerostomia.

CONCLUSION: RLT with ²²⁵Ac-labeled PSMA-specific ligands is a promising therapy for patients with mCRPC, who have exhausted all possible antitumor therapies.

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