Recently, promising results of the antitumor effects were observed in patients with metastatic castration-resistant prostate cancer treated with ¹⁷⁷Lu-labeled PSMA-ligands. Radionuclide therapy efficacy may even be improved by using the alpha emitter Ac-225. Higher efficacy is claimed due to high linear energy transfer specifically towards PSMA positive cells, causing more double-strand breaks. This study aims to manufacture [²²⁵Ac]Ac-PSMA-I&T according to good manufacturing practice guidelines for the translation of [²²⁵Ac]Ac-PSMA-I&T into a clinical phase 1 dose escalation study. Quencher addition during labeling was investigated. Quality control of [²²⁵Ac]Ac-PSMA-I&T was based on measurement of Fr-221 (218 keV), in equilibrium with Ac-225 in approximately six half-lives of Fr-221 (T½ = 4.8 min). Radio-(i)TLC methods were utilized for identification of the different radiochemical forms, gamma counter for concentration determination, and HPGe-detector for the detection of the radiochemical yield. Radiochemical purity was determined by HPLC. The final patient dose was prepared and diluted with an optimized concentration of quenchers as during labeling, with an activity of 8–12 MBq (±5%), pH > 5.5, 100 ± 20 μg/dose, PSMA-I&T, radiochemical yield >95%, radiochemical purity >90% (up to 3 h), endotoxin levels of <5 EU/mL, osmolarity of 2100 mOsmol, and is produced according to current guidelines. The start of the phase I dose escalation study is planned in the near future.

For patients with metastatic castration-resistant prostate cancer (mCRPC), the survival benefit of classic treatment options with chemotherapy and drugs targeting androgen signaling is limited. Therefore, beta and alpha radionuclide therapy (RNT) have emerged as novel treatment options for patients with mCRPC. Radioligands target the prostate-specific membrane antigen (PSMA) epitopes, which are upregulated up to a thousand times more in prostate cancer cells compared to the cells in normal tissues. For this reason, PSMA is an excellent target for both imaging and therapy. Over the past years, many studies have investigated the treatment effects of lutetium-177 labeled PSMA (¹⁷⁷Lu-PSMA) and actinium-225 labeled PSMA (²²⁵Ac-PSMA) RNT in patients with mCRPC. While promising results have been achieved, this field is still in development. In this review, we have summarized and discussed the clinical data of ¹⁷⁷Lu-PSMA and ²²⁵Ac-PSMA RNT in patients with mCRPC.