Background: High-risk localised prostate cancer (HRCaP) has high rates of biochemical recurrence; [Lu-177]Lu-PSMA-617 is effective in men with advanced prostate cancer. Objective: To investigate the dosimetry, safety, and efficacy of upfront [Lu-177]Lu-PSMA-617 in men with HRCaP prior to robotic radical prostatectomy (RP). Design, setting, and participants: In this single-arm, phase I/II trial, we recruited men with HRCaP (any of prostate-specific antigen [PSA] >20 ng/ml, International Society of Urological Pathology (ISUP) grade group [GG] 3-5, and >= cT2c), with high tumour uptake on [Ga-68]Ga-PSMA-11 positron emission tomography/computed tomography (PSMA PET/CT), and scheduled for RP. Intervention: Cohort A (n = 10) received one cycle and cohort B (n = 10) received two cycles of [Lu-177]Lu-PSMA-617 (5 GBq) followed by surgery 6 weeks later. Outcome measurements and statistical analysis: The primary endpoint was tumour radiation absorbed dose. Adverse events (AEs; Common Terminology Criteria for Adverse Events (CTCAE) version 5.0), surgical safety (Clavien-Dindo), imaging, and biochemical responses were evaluated (ClinicalTrials.gov: NCT04430192). Results and limitations: Between May 29, 2020 and April 28, 2022, 20 patients were enrolled. The median PSA was 18 ng/ml (interquartile range [IQR] 11-35), Eighteen (90%) had GG >= 3, and six (30%) had N1 disease. The median (IQR) highest tumour radiation absorbed dose after cycle 1 for all lesions was 35.5 Gy (19.5-50.1), with 19.6 Gy (11.3-48.4) delivered to the prostate. Five patients received radiation to lymph nodes. Nine (45%) patients achieved >50% PSA decline. The most common AEs related to [Lu-177]Lu-PSMA-617 were grade 1 fatigue in eight (40%), nausea in seven (35%), dry mouth in six (30%), and thrombocytopenia in four (20%) patients. No grade 3/4 toxicities or Clavien 3-5 complications occurred. Limitations include small a sample size. Conclusions: In men with HRCaP and high prostate-specific membrane antigen (PSMA) expression, [Lu-177]Lu-PSMA-617 delivered high levels of targeted radiation doses with few toxicities and without compromising surgical safety. Further studies of [Lu-177]Lu-PSMA-617 in this population are worthwhile to determine whether meaningful long-term oncological benefits can be demonstrated.
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