Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (²²⁵Ac), a potent alpha-emitting radionuclide, may be incorporated into targeting vectors, causing robust and in some cases sustained antitumor responses. The development of radiolabeling techniques involving EDTA, DOTA, DOTPA, and Macropa chelators has laid the groundwork for advancements in this field. At the forefront of clinical trials with ²²⁵Ac in PCa are PSMA-targeted TAT agents, notably [²²⁵Ac]Ac-PSMA-617, [²²⁵Ac]Ac-PSMA-I&T and [²²⁵Ac]Ac-J591. Ongoing investigations spotlight [²²⁵Ac]Ac-hu11B6, [²²⁵Ac]Ac-YS5, and [²²⁵Ac]Ac-SibuDAB, targeting hK2, CD46, and PSMA, respectively. Despite these efforts, hurdles in ²²⁵Ac production, daughter redistribution, and a lack of suitable imaging techniques hinder the development of TAT. To address these challenges and additional advantages, researchers are exploring alpha-emitting isotopes including ²²⁷Th, ²²³Ra, ²¹¹At, ²¹³Bi, ²¹²Pb or ¹⁴⁹Tb, providing viable alternatives for TAT.

We report our initial real-world experience with ¹⁷⁷Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with ¹⁷⁷Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from ¹⁷⁷Lu-PSMA-617 radioligand therapy.