Efficacy, Safety, Blood Kinetics, and 213Bi Distribution Studies of [225Ac]Ac-SibuDAB in Prostate Cancer Patients

²²⁵Ac-labeled (S)-ibuprofen-diaminobutyric acid-PSMA (SibuDAB) is a novel, albumin-binding compound in prostate-specific membrane antigen (PSMA)-targeted α-therapy of prostate cancer. It showed superior preclinical efficacy results to [²²⁵Ac]Ac-PSMA-617. ²²⁵Ac decays via multiple α-particle emissions. The full therapeutic potential requires fast tumor uptake and retention of parent and daughter nuclides, such as ²¹³Bi, in the tumor. High decay energies lead to daughter nuclide recoil of the chelator and, therefore, altered pharmacokinetics and potential irradiation of off-target organs. We hereby present clinical efficacy and safety data for [²²⁵Ac]Ac-SibuDAB, as well as blood kinetics and the ²¹³Bi distribution between blood and urine samples. Methods: Fifteen prostate cancer patients who received [²²⁵Ac]Ac-SibuDAB between December 2021 and August 2024 were included in this retrospective study. Patients were scheduled to receive 6 MBq of [²²⁵Ac]Ac-SibuDAB every 8 wk. The prostate-specific antigen (PSA) response was evaluated, and adverse events were categorized according to Common Terminology Criteria for Adverse Events, version 5.0. Blood pharmacokinetics were determined after blood sampling at different time points and measured in ²²⁵Ac/²²¹Fr equilibrium. The ²¹³Bi distribution was determined in blood and urine samples before reaching ²²⁵Ac/²¹³Bi equilibrium. Results: Fifteen patients received a total of 25 cycles with a median exposure of 6.55 MBq (range, 4.65-30.60 MBq). The Gleason score was available for 12 of the 15 patients, with 10 patients having a Gleason score of 8 or higher. The patients were heavily pretreated, including 13 patients with prior [¹⁷⁷Lu]Lu-PSMA therapy. Nine of the 15 patients showed any PSA decline, and 5 of the 15 patients showed a PSA decline of 50% or more. All patients showed grade 1 xerostomia. Treatment was stopped because of grade 3 thrombocytopenia in 1 of the 15 patients. [²²⁵Ac]Ac-SibuDAB blood kinetics were evaluated in 6 patients. ²¹³Bi blood and urine distribution studies were conducted on 3 patients and showed a vast net ²¹³Bi excess in urine immediately after application, a moderate excess at later time points, and a lack of ²¹³Bi in blood at any time point. Conclusion: [²²⁵Ac]Ac-SibuDAB initial clinical data show efficacy in heavily pretreated prostate cancer patients, with 1 patient experiencing treatment-limiting toxicity. Only limited signs of xerostomia were observed after the treatment. ²¹³Bi generated by recoil is rapidly distributed into urine after application of [²²⁵Ac]Ac-SibuDAB.