Initial Multicenter Experience with [ ¹⁶¹ Tb]Tb-PSMA in [ ¹⁷⁷ Lu]Lu-PSMARefractory Metastatic Castration-Resistant Prostate Cancer: Preliminary Results

161Tb is a theranostic radionuclide that emits both β− particles and Auger electrons with high linear energy transfer, potentially enhancing cytotoxicity in micrometastatic disease. We report the first multicenter clinical experience of [161Tb]Tb-PSMA in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to [177Lu]Lu-PSMA therapy. Methods: This prospective, multicenter study included 7 patients with mCRPC who had progressed despite prior androgen receptor pathway inhibitors, taxane-based chemotherapy, and at least 2 cycles of [177Lu]Lu-PSMA. All patients had PSMA-positive disease without any [18F]FDG-discordant lesions. Each received 2 cycles of [161Tb]Tb-PSMA (7.4 GBq per cycle, 6-wk interval). Response was assessed with [68Ga]Ga-PSMA PET/CT per RECIP 1.0 and prostate-specific antigen kinetics. Posttherapy dosimetry was performed using SPECT/CT imaging at 4 time points. Results: Of the 7 patients, 4 (57%) demonstrated objective imaging response and 4 (57%) showed at least a 50% decline in prostate-specific antigen levels. Treatment was well tolerated, with only mild adverse events (grades 1–2) and no toxicity greater than grade 3. Organ dosimetry confirmed favorable absorbed dose distributions. Conclusion: [161Tb]Tb-PSMA demonstrated promising molecular and biochemical activity with a favorable safety profile in patients who had progressed after [177Lu]Lu-PSMA therapy. These preliminary findings support further investigation of 161Tb-based radiopharmaceuticals as next-generation therapeutic options for mCRPC.