OBJECTIVE: This prospective, open-label, single-arm, phase 2 study evaluated the efficacy, safety, pharmacokinetics (PK) and dosimetry of [Lu]Lu-PSMA-617 in Japanese patients with progressive PSMA+ mCRPC. METHODS: This is a PK/dosimetry analysis of [Ga]Ga-PSMA-11 and [Lu]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 [Ga]Ga-PSMA-11 (111-259 MBq) at screening and [Lu]Lu-PSMA-617 (7.4 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. RESULTS: Of 35 patients included, 3 patients each had evaluable data for PK/dosimetry of [Ga]Ga-PSMA-11 and [Lu]Lu-PSMA-617. Both [Ga]Ga-PSMA-11 and [Lu]Lu-PSMA-617 showed a bi-exponential decline in blood concentrations post-dosage, with an initial rapid phase followed by a slower phase. For [Ga]Ga-PSMA-11, terminal half-life (T; geometric mean) was 3.93 h, total systemic clearance (CL) was 5.52 L/hr, and an apparent volume of distribution (V) was 31.3 L. For [Lu]Lu-PSMA-617, these values were 28.9 h, 1.71 L/hr, and 71.2 L, respectively. For [Ga]Ga-PSMA-11 dosimetry, kidneys received the largest absorbed doses (0.23 ± 0.14 mGy/MBq), and effective dose was 0.030 mSv/MBq. For a full six-cycle cumulative injected activity of 44.4 GBq of [Lu]Lu-PSMA-617, the lacrimal glands received the largest estimated absorbed dose of 90 ± 45 Gy. The mean absorbed dose to the kidneys (critical organ) was 0.34 Gy/GBq, resulting in a cumulative absorbed dose of 15 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. CONCLUSION: This is the first prospective Japanese study to demonstrate the use of [Ga]Ga-PSMA-11 and [Lu]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 [Lu]Lu-PSMA-617 during treatment, ensuring a secure treatment environment. TRIAL REGISTRATION: This study is a prospective, open-label, multicenter, single-arm, phase 2 trial of [Lu]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 [Ga]Ga-PSMA-11, of whom 30 were included for efficacy and safety assessments of [Lu]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 [Ga]Ga-PSMA-11 and [Lu]Lu-PSMA-617. Informed consent was obtained from all participants before conducting any study-specific procedures.