Pilot experience of [¹⁶¹Tb]Tb-PSMA-617 RLT in mCRPC patients after conventional PSMA RLT within a prospective registry

<i>Rationale:</i> The radionuclide ¹⁶¹Tb is an increasingly discussed potential candidate for radioligand therapy (RLT). Through the considerable emitted amount of low-energy Auger and conversion electrons, ¹⁶¹Tb offers physical advantages over the commonly used ¹⁷⁷Lu, resulting in higher locally absorbed doses. In this study, we present initial experience with [¹⁶¹Tb]Tb-PSMA-617 RLT across different clinical settings following initial PSMA RLT. <i>Methods:</i> The study involved n=18 patients with metastasized castration-resistant prostate cancer (mCRPC) participating in a prospective registry (NCT04833517) and receiving [¹⁶¹Tb]Tb-PSMA-617 after initial PSMA RLT with established radionuclides (¹⁷⁷Lu, ²²⁵Ac). In total 47 cycles of [¹⁶¹Tb]Tb-PSMA-617 RLT were administered with a median of 3 cycles (1 - 4 cycles) per patient. The mean administered activity of ¹⁶¹Tb per cycle was 6.2 ± 0.8 GBq, the mean cumulative activity was 16.1 ± 4.9 GBq. Outcome was evaluated by biochemical and molecular imaging response, progression-free survival (PFS), and overall survival (OS). Adverse events were assessed by '<i>Common Terminology Criteria for Adverse Events</i>' (CTCAE v.5.0) grading system. <i>Results:</i> In the heterogeneous cohort of patients previously experiencing insufficient response or progression post RLT with [¹⁷⁷Lu]Lu-PSMA-617, or even after ²²⁵Ac augmentation, biochemical and molecular imaging response rates were 38.9% and 44.4%, median PFS and OS 3.5 and 11.3 months, respectively. The best response and outcome were observed in patients who initially responded to [¹⁷⁷Lu]Lu-PSMA-617 RLT. The majority of all post therapeutically recorded adverse events were mild or moderate (CTCAE °1 or °2); higher grades (CTCAE °3 or °4) were rarely observed (2 cases of thrombocytopenia, 4 cases of anemia and 4 cases of renal impairment). No treatment discontinuation due to therapy related adverse events was recorded. <i>Conclusion:</i> These pilot results confirm ¹⁶¹Tb as a promising radionuclide for PSMA RLT and suggest [¹⁶¹Tb]Tb-PSMA-617 as a potential effective and safe treatment option even in the advanced mCRPC setting after multi-line systemic therapies including standard PSMA RLT. Larger studies are warranted to confirm and extend this initial experience and clinical trials even in earlier CRPC settings appear promising based on our initial impression of this radionuclide-based novelty in PSMA RLT.