A landmark multicenter clinical trial has reported the first clinical results using terbium-161-labeled PSMA (¹⁶¹Tb-PSMA) in patients with metastatic castration-resistant prostate cancer (mCRPC) who no longer responded to ¹⁷⁷Lu-PSMA radioligand therapy. This pioneering work marks a significant milestone in advanced prostate cancer treatment as it opens the door to an innovative salvage therapy option for a challenging patient group.

Terbium-161 (¹⁶¹Tb) represents a novel theranostic radionuclide that delivers both β⁻ particles and Auger electrons, the latter providing highly localized and potent cytotoxic effects. This dual emission profile is theorized to enhance micrometastatic disease control, potentially offering an edge over the established ¹⁷⁷Lu-PSMA therapies, especially in patients whose disease progresses despite standard radioligand approaches.

This initial study enrolled seven mCRPC patients who had all progressed after standard therapies, including androgen receptor pathway inhibitors, taxane-based chemotherapy, and at least two cycles of ¹⁷⁷Lu-PSMA (Pluvicto). All demonstrated PSMA-positive lesions with no [¹⁸F]FDG-discordant findings—a criterion used to ensure appropriate targeting.

Each participant received two cycles of ¹⁶¹Tb-PSMA administered at 7.4 GBq per cycle, six weeks apart. The response to therapy was assessed using [⁶⁸Ga]PSMA PET/CT imaging per RECIP 1.0 criteria, prostate-specific antigen (PSA) kinetics, and post-treatment organ dosimetry using SPECT/CT.

The results were encouraging.
Objective imaging responses were observed in 57% of participants (4 out of 7).

PSA reduction of at least 50% was achieved in 57% of patients.

Safety profile was excellent: the highest adverse events were mild (grade 1-2), and no grade 3 or higher toxicities were reported.

Dosimetry analysis confirmed favorable absorbed dose distributions to target lesions and acceptable profiles for normal organs.

This report is the first multicenter clinical evidence for ¹⁶¹Tb-PSMA as a therapeutic strategy in ¹⁷⁷Lu-PSMA–refractory mCRPC. The favorable preliminary results suggest that ¹⁶¹Tb-PSMA could represent a next-generation radiopharmaceutical for patients who have exhausted existing options. Given the encouraging safety and molecular efficacy signals, further investigation in larger, controlled studies is warranted.

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