Dosimetry of ¹⁷⁷Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: Correlations Between Pretherapeutic Imaging and Whole-Body Tumor Dosimetry with Treatment Outcomes

¹⁷⁷Lu-prostate-specific membrane antigen (PSMA)-617 enables targeted delivery of β-particle radiation to prostate cancer. We determined its radiation dosimetry and relationships to pretherapeutic imaging and outcomes. <b>Methods:</b> Thirty patients with prostate cancer receiving ¹⁷⁷Lu-PSMA-617 within a prospective clinical trial (ACTRN12615000912583) were studied. Screening ⁶⁸Ga-PSMA-11 PET/CT demonstrated high PSMA expression in all patients. After therapy, patients underwent quantitative SPECT/CT at 4, 24, and 96 h. Pharmacokinetic uptake and clearance at a voxel level were calculated and translated into absorbed dose using voxel S values. Volumes of interest were drawn on normal tissues and tumor to assess radiation dose, and a whole-body tumor dose was defined. Correlations between PSMA PET/CT parameters, dosimetry, and biochemical and therapeutic response were analyzed to identify relationships between absorbed dose, tumor burden, and patient physiology. <b>Results:</b> Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (<i>P</i> < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. On screening PSMA PET, whole-body tumor SUV_mean correlated with mean absorbed dose (<i>r</i> = 0.62), and SUV_max of the parotids correlated with absorbed dose (<i>r</i> = 0.67). There was an inverse correlation between tumor volume and mean dose to the parotids (<i>r</i> = -0.41) and kidneys (<i>r</i> = -0.43). The mean parotid dose was also reduced with increasing body mass (<i>r</i> = -0.41) and body surface area (<i>r</i> = -0.37). <b>Conclusion:</b>¹⁷⁷Lu-PSMA-617 delivers high absorbed doses to tumor, with a significant correlation between whole-body tumor dose and PSA response. Patients receiving less than 10 Gy were unlikely to achieve a fall in PSA of at least 50%. Significant correlations between aspects of screening ⁶⁸Ga-PET/CT and tumor and normal tissue dose were observed, providing a rationale for patient-specific dosing. Reduced salivary and kidney doses were observed in patients with a higher tumor burden. The parotid dose also reduced with increasing body mass and body surface area.