Purpose <p>To evaluate tumour and normal organ dosimetry of PSMA-targeted RLT ¹⁷⁷Lu-rhPSMA-10.1.</p> Methods <p>PSMA-positive mCRPC patients experiencing disease progression following standard-of-care treatment were enrolled and underwent ≤ 3 cycles of 5.55 or 7.40 GBq ¹⁷⁷Lu-rhPSMA-10.1 at 6-week intervals. Multi-bed SPECT/CT was conducted 3-, 24-, 48-, and 168-hours post-administration to calculate tumour and organ absorbed doses. Two methods (activity- and anatomy-based) were used for selecting and delineating tumours for dosimetry. Venous blood was collected for radioactivity measurement 30&#xa0;min before ¹⁷⁷Lu-rhPSMA-10.1 administration, and 0.5-, 1.5-, 4-, 24-, and 48-hours post-administration.</p> Results <p>Thirteen patients were enrolled; three received 5.55 GBq/cycle and 10 received 7.40 GBq/cycle. Mean absorbed doses were 0.266, 0.130 and 8.87&#xa0;Gy/GBq in kidneys, salivary glands, and tumours (activity-method), respectively, giving mean tumour-to-kidney and tumour-to-salivary ratios of 32.1 and 73.2, respectively. Tumour dose estimates were consistently higher with the activity-method vs. anatomy-method. Tumour absorbed doses decreased each cycle; Cycle 2 and 3 doses were ~ 37% and ~ 56% lower than Cycle 1 estimates, respectively. ¹⁷⁷Lu-rhPSMA-10.1 was rapidly cleared from the blood (effective half-life, 2.2&#xa0;h). Imaging data showed mean effective half-lives to be 91.4, 33.7 and 45.4&#xa0;h in tumours, kidneys, and salivary glands, respectively.</p> Conclusion <p>¹⁷⁷Lu-rhPSMA-10.1 delivers high radiation doses to tumours vs. normal organs, facilitated by its favourable pharmacokinetics. Cumulative doses to normal organs were well within established tolerable limits, suggesting higher cumulative radioactivity could be administered in clinical trials. The observation of decreasing tumour absorbed dose with subsequent cycles also supports the exploration of front-loading radioactivity in Phase II.</p>