Objective <p>This prospective, open-label, single-arm, phase 2 study evaluated the efficacy, safety, pharmacokinetics (PK) and dosimetry of [¹⁷⁷Lu]Lu-PSMA-617 in Japanese patients with progressive PSMA+ mCRPC.</p> Methods <p>This is a PK/dosimetry analysis of [⁶⁸Ga]Ga-PSMA-11 and [¹⁷⁷Lu]Lu-PSMA-617 in patients from Parts 1, 2, and 3 of the 4-part study. Blood and urine samples, serial PET/CT, planar, and SPECT/CT scans were collected post-administration of [⁶⁸Ga]Ga-PSMA-11 (111–259&#xa0;MBq) at screening and [¹⁷⁷Lu]Lu-PSMA-617 (7.4&#xa0;GBq ± 10%) during cycle 1. External radiation exposure in medical personnel and family members was measured once in each cycle from cycle 1 to 6, excluding the cycle where dosimetry was performed.</p> Results <p>Of 35 patients included, 3 patients each had evaluable data for PK/dosimetry of [⁶⁸Ga]Ga-PSMA-11 and [¹⁷⁷Lu]Lu-PSMA-617. Both [⁶⁸Ga]Ga-PSMA-11 and [¹⁷⁷Lu]Lu-PSMA-617 showed a bi-exponential decline in blood concentrations post-dosage, with an initial rapid phase followed by a slower phase. For [⁶⁸Ga]Ga-PSMA-11, terminal half-life (T_1/2; geometric mean) was 3.93&#xa0;h, total systemic clearance (CL) was 5.52 L/hr, and an apparent volume of distribution (V_z) was 31.3 L. For [¹⁷⁷Lu]Lu-PSMA-617, these values were 28.9&#xa0;h, 1.71 L/hr, and 71.2 L, respectively. For [⁶⁸Ga]Ga-PSMA-11 dosimetry, kidneys received the largest absorbed doses (0.23 ± 0.14&#xa0;mGy/MBq), and effective dose was 0.030&#xa0;mSv/MBq. For a full six-cycle cumulative injected activity of 44.4&#xa0;GBq of [¹⁷⁷Lu]Lu-PSMA-617, the lacrimal glands received the largest estimated absorbed dose of 90 ± 45&#xa0;Gy. The mean absorbed dose to the kidneys (critical organ) was 0.34&#xa0;Gy/GBq, resulting in a cumulative absorbed dose of 15&#xa0;Gy for the full six-cycles. The radiation exposure was evaluated among 13 medical personnel, 8 who participated in administration, and family members. Measurements were taken at 8 sites including patients’ home. External radiation exposure to medical personnel and family members was minimal, with 0 μSv in 6/7 patients and 60 μSv in 1 patient.</p> Conclusion <p>This is the first prospective Japanese study to demonstrate the use of [⁶⁸Ga]Ga-PSMA-11 and [¹⁷⁷Lu]Lu-PSMA-617 in patients with mCRPC. The absorbed doses in various organs for both radiopharmaceuticals were consistent with previously reported data. Minimal radiation exposure observed for medical personnel and caregivers highlights the safety of [¹⁷⁷Lu]Lu-PSMA-617 during treatment, ensuring a secure treatment environment.</p> Trial registration <p>This study is a prospective, open-label, multicenter, single-arm, phase 2 trial of [¹⁷⁷Lu]Lu-PSMA-617 in patients with progressive PSMA + mCRPC in Japan (NCT05114746). The trial was initiated on 25-Jan-2022 (first patient first visit), with a primary analysis data cut-off on 8-Dec-2023. The study is ongoing. A total of 35 patients were screened and received [⁶⁸Ga]Ga-PSMA-11, of whom 30 were included for efficacy and safety assessments of [¹⁷⁷Lu]Lu-PSMA617 across Part 1 (safety run-in), Part 2 (post-taxane), and Part 3 (pre-taxane). Additionally, 3 patients each had evaluable data for PK and dosimetry assessments of [⁶⁸Ga]Ga-PSMA-11 and [¹⁷⁷Lu]Lu-PSMA-617. Informed consent was obtained from all participants before conducting any study-specific procedures.</p>