First-in-human results of terbium-161 [161Tb]Tb-PSMA-I&T dual beta-Auger radioligand therapy in patients with metastatic castration-resistant prostate cancer (VIOLET): a single-centre, single-arm, phase 1/2 study

Abstract

Background: Terbium-161 (¹⁶¹Tb) emits beta-radiation similar to lutetium-177 (¹⁷⁷Lu), with additional radiation over ultra-short path lengths from Auger electrons. ¹⁶¹Tb has shown superior in-vitro and in-vivo efficacy compared with ¹⁷⁷Lu. We aimed to evaluate the safety of [¹⁶¹Tb]Tb-PSMA-I&T in patients with metastatic castration-resistant prostate cancer (mCRPC).

Methods: VIOLET was an investigator-initiated, single-centre, phase 1/2 trial, conducted at the Peter MacCallum Cancer Centre (Melbourne, VIC, Australia). Eligible patients were men aged 18 years or older with progressive mCRPC (histologically or cytologically confirmed adenocarcinoma of the prostate or unequivocal diagnosis of metastatic prostate cancer with an elevated serum prostate specific antigen) previously treated with an androgen receptor pathway inhibitor and taxane chemotherapy (unless medically unsuitable), Eastern Cooperative Oncology Group performance status of 0-2, and prostate-specific membrane antigen (PSMA) positivity (maximum standardised uptake value ≥20 on PSMA PET-CT) without discordance on 2-[¹⁸F]fluoro-2-deoxy-D-glucose (FDG) PET-CT. Dose escalation (3 + 3 design) had three prespecified radioactivities (4·4 GBq, 5·5 GBq, and 7·4 GBq). Up to six cycles of [¹⁶¹Tb]Tb-PSMA-I&T were administered intravenously every 6 weeks, reduced by 0·4 GBq for each cycle. Primary endpoints of phase 1 were dose-limiting toxicities, the maximum tolerated dose, and the recommended phase 2 dose, and the primary objective of phase 2 was evaluation of adverse events as defined by Common Terminology Criteria for Adverse Events version 5.0. We present here an interim analysis, with follow-up ongoing and recruitment reopened for an additional dose level (9·5 GBq). The trial is registered at ClinicalTrials.gov (NCT05521412).

Findings: Between Oct 14, 2022 and Feb 15, 2024, 30 eligible patients were enrolled. Median age was 69·0 years (IQR 66·0-74·8), screening PSA 26·9 ng/mL (10·1-70·0), PSMA mean standardised uptake value 8·2 (7·4-10·8), and 20 (67%) of 30 patients had received previous docetaxel. There were no dose-limiting toxicities. The maximum administered dose and recommended phase 2 dose was 7·4 GBq. Grade 3 treatment-related adverse events (TRAEs) were limited to pain (one [3%] of 30; the only serious TRAE) and lymphopenia (one [3%] of 30). No grade 4 TRAEs or treatment-related deaths occurred. No dose reductions or treatment discontinuation occurred for toxicity.

Interpretation: [¹⁶¹Tb]Tb-PSMA-I&T is safe at the maximum administered dose of 7·4 GBq. Further investigation of this promising radionuclide is warranted in larger, randomised clinical trials.

Funding: Prostate Cancer Foundation, Peter MacCallum Cancer Foundation, National Health and Medical Research Council Investigator Grant, Isotopia Molecular Imaging.