First-in-human results of terbium-161[ ¹⁶¹ Tb]Tb-PSMA-I&T radioligand treatment in patients with metastatic castration-resistant prostate cancer (VIOLET): A single-centre, single-arm, phase I/II study.

5010 Background: Terbium-161 ( 161 Tb) is a novel radionuclide emitting beta-radiation comparable to lutetium-177 ( 177 Lu), with additional higher-energy, ultra-short path-length Auger electrons which may better target micrometastases. 161 Tb has superior in-vitro and in-vivo efficacy in comparison with 177 Lu. We aim to evaluate the safety and effectiveness of [ 161 Tb]Tb-PSMA-I&T in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: Eligible patients in this investigator-initiated, single-centre, single-arm, phase I/II trial had progressive mCRPC previously treated with taxane chemotherapy (unless medically unsuitable) and an androgen receptor pathway inhibitor, PSMA-positive disease on PSMA PET/CT (SUVmax ≥20), no sites of discordance on FDG PET/CT, adequate bone marrow, hepatic and renal function, and ECOG performance status ≤2. The dose-escalation followed a 3+3 design to establish safety of three prespecified administered radioactivities of [ 161 Tb]Tb-PSMA-I&T (4.4, 5.5, and 7.4 GBq). Up to six cycles of [ 161 Tb]Tb-PSMA-I&T were administered intravenously every six weeks, with each subsequent radioactivity per cycle reduced by 0.4 GBq. The co-primary objectives were to establish the maximum tolerated dose (MTD) and safety profile (CTCAE v5.0) of [ 161 Tb]Tb-PSMA-I&T. Key secondary objectives for this interim analysis were PSA ≥50% and ≥90% response rates (PSA50-RR and PSA90-RR), PSA and radiographic progression-free survival (PSA-PFS and rPFS). Results: Between October 14, 2022 and February 15, 2024, 30 eligible patients were enrolled. Median (IQR) age 69.0 years (66.0-74.8), median baseline PSA 26.9 ng/mL (10.1-70.0), PSMA SUVmean 8.2 (7.4-10.8) and 20 patients (67%) had received prior docetaxel. There were no dose-limiting toxicities. The MTD and recommended phase 2 dose was 7.4 GBq. There were no treatment-related deaths and few grade 3 or higher treatment-related adverse events, which included pain flare and lymphopenia only. The remaining AEs are summarised in the table. PSA50-RR and PSA90-RR occurred in 21 (70% [95%CI 51-85]) and 12 (40% [95%CI 23-59]). Median PSA-PFS and rPFS were 9.0 months (95%CI 5.7-15.1) and 11.1 months (95%CI 6.6-11.7) with median follow-up of 11.2 and 11.0 months, respectively. Conclusions: [ 161 Tb]Tb-PSMA-I&T displayed highly encouraging efficacy with few Grade 3 or 4 adverse events. An additional cohort to assess a higher administered radioactivity is planned. Clinical trial information: NCT05521412 . Main treatment-related adverse events. Adverse event Grade 1 Grade 2 Grade 3 Grade 4 Total Lymphocyte count decreased 8 10 1 0 19 (63%) Pain 3 0 1 0 4 (13%) Anemia 16 4 0 0 20 (67%) Neutrophil count decreased 3 3 0 0 6 (20%) Fatigue 12 1 0 0 13 (43%) Dry mouth 21 0 0 0 21 (70%) Nausea 7 0 0 0 7 (23%) Platelet count decreased 6 0 0 0 6 (20%) Any adverse event 13 14 2 0 29 (97%)