First-in-Human Results of Terbium-161 PSMA Radioligand Therapy in mCRPC: Insights from the VIOLET Study

Highlights

• [161Tb]Tb-PSMA-I&T, a dual beta- and Auger electron-emitting radioligand, was administered safely in men with metastatic castration-resistant prostate cancer (mCRPC), with no dose-limiting toxicities at doses up to 7.4 GBq.
• Serious treatment-related adverse events were rare, and no grade 4 toxicities or treatment-related deaths occurred.
• This first-in-human trial supports further investigation of terbium-161-based theranostics in advanced prostate cancer.

Clinical Background and Disease Burden

Metastatic castration-resistant prostate cancer (mCRPC) remains a major therapeutic challenge, with limited survival and quality-of-life benefits from conventional therapies after androgen receptor pathway inhibitors and taxane chemotherapy. Targeted radioligand therapy (RLT) with prostate-specific membrane antigen (PSMA) ligands has emerged as a promising strategy, exemplified by the clinical impact of [177Lu]Lu-PSMA agents. However, disease progression and resistance are common, highlighting the need for next-generation RLTs with improved efficacy and manageable toxicity profiles.

Research Methodology

The VIOLET study was an investigator-initiated, single-centre, open-label phase 1/2 trial conducted at the Peter MacCallum Cancer Centre, Melbourne, Australia. Eligible participants were men aged 18 or older with histologically or cytologically confirmed mCRPC, progression after androgen receptor pathway inhibitors and (where suitable) taxane chemotherapy, ECOG performance status 0-2, and PSMA PET positivity (SUVmax ≥20) without discordance on FDG PET-CT.

The study employed a 3+3 dose escalation design, with three predefined radioactivity cohorts (4.4 GBq, 5.5 GBq, 7.4 GBq), and an interim plan to explore a higher dose (9.5 GBq). Patients could receive up to six cycles of [161Tb]Tb-PSMA-I&T intravenously every 6 weeks, with each subsequent dose reduced by 0.4 GBq.

Primary phase 1 endpoints were dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), and recommended phase 2 dose. The key phase 2 endpoint was the incidence and severity of adverse events, graded using CTCAE v5.0. Efficacy endpoints such as PSA response and radiological outcomes were exploratory in this interim analysis.

Key Findings

Between October 2022 and February 2024, 30 eligible patients (median age 69 years, IQR 66-74.8) were treated. Baseline characteristics reflected a heavily pretreated population: median PSA 26.9 ng/mL (IQR 10.1-70.0), mean PSMA SUV 8.2, and 67% had prior docetaxel exposure.

No dose-limiting toxicities were observed in any cohort. The highest tested dose, 7.4 GBq, was established as both the maximum administered and recommended phase 2 dose. Grade 3 treatment-related adverse events (TRAEs) were rare: severe pain (1/30, 3%) and lymphopenia (1/30, 3%). Notably, there were no grade 4 TRAEs, no treatment-related deaths, and no dose reductions or discontinuations due to toxicity. These findings underscore a favorable safety profile, especially in a fragile, refractory population.

Further recruitment is ongoing for an exploratory higher dose (9.5 GBq), reflecting continued interest in optimizing the therapeutic window.

Mechanistic Insights and Biological Plausibility

Terbium-161 is a radiolanthanide that, like lutetium-177, emits beta particles suitable for targeting micrometastatic disease. However, the key differentiator is its emission of a high number of short-range Auger electrons, which deposit energy over nanometer distances, potentially causing lethal DNA damage in proximity to the radiolabeled target. Preclinical studies have shown that 161Tb delivers greater cytotoxicity than 177Lu, particularly in cell models with high PSMA expression or micrometastatic disease, where cross-fire effects are limited.

This dual emission mechanism may be especially advantageous in eradicating small-volume or heterogeneous prostate cancer lesions, which often seed resistance and relapse after conventional therapies. The safety observed in this trial, even at higher administered activities, suggests that the additional Auger component does not confer unacceptable off-target toxicity, at least in the short- to mid-term.

Expert Commentary

The VIOLET trial represents a significant translational milestone in PSMA-targeted theranostics. According to Prof. Michael S. Hofman and colleagues (Lancet Oncol. 2025), these first-in-human data “provide a strong rationale for randomized trials of terbium-161-based RLT, not only as salvage therapy but potentially in earlier disease settings or in combination regimens.” Emerging expert consensus emphasizes the importance of head-to-head trials comparing 161Tb with 177Lu to clarify the relative benefit, optimal patient selection, and real-world tolerability.

Controversies and Limitations

This interim analysis is limited by its single-centre, single-arm design and relatively small sample size (n=30). While the safety profile is reassuring, efficacy data (PSA response rates, radiological outcomes, survival) remain preliminary and will require longer follow-up and larger, randomized cohorts. Generalizability to broader mCRPC populations (e.g., those with lower PSMA expression or poorer performance status) is uncertain. Additionally, the duration and spectrum of potential late toxicities, particularly marrow suppression or renal effects, are not yet fully characterized.

Comparison with [177Lu]Lu-PSMA therapies is indirect at this stage; randomized head-to-head studies are essential to establish superiority or non-inferiority, especially with regard to long-term outcomes and quality of life. The ongoing escalation to a 9.5 GBq dose will further inform the therapeutic window and risk-benefit balance.

Conclusion

The VIOLET phase 1/2 trial demonstrates that [161Tb]Tb-PSMA-I&T, a next-generation dual beta-Auger PSMA-targeted radioligand, is safe and well-tolerated at doses up to 7.4 GBq in men with heavily pretreated mCRPC. These findings justify further evaluation in randomized clinical trials to determine the efficacy, optimal dosing, and comparative advantage of terbium-161-based therapy over established lutetium-177 protocols. As the landscape of prostate cancer treatment evolves, terbium-161 RLT holds promise for improving outcomes in this difficult-to-treat population.

References

1. Buteau JP, Kostos L, Jackson PA, et al. 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. Lancet Oncol. 2025 Aug;26(8):1009-1017. doi: 10.1016/S1470-2045(25)00332-8. Epub 2025 Jul 3. PMID: 40617237.
2. Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomized, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804.
3. Rahbar K, Bodei L, Morris MJ. Radioligand therapy of metastatic prostate cancer: current status and future directions. Clin Cancer Res. 2022;28(6):1169-1177.