Is Terbium-161 the Next Lutetium-177? A New Era for Theranostics on the Horizon

Dear Sir,

The field of radiotheranostics continues to rapidly evolve, and recent developments have sparked a timely reassessment of the radiolanthanide of choice for peptide receptor radionuclide therapy and prostate-specific membrane antigen (PSMA)-targeted therapy. Lutetium-177 (Lu-177) has been the cornerstone of targeted radionuclide therapy and has undergone extensive clinical validation in neuroendocrine tumors and metastatic castration-resistant prostate cancer (mCRPC).[123] However, recent attention has turned to Terbium-161 (Tb-161), which may represent the next major leap in theranostics.[4] The VIOLET trial, recently presented at American Society of Clinical Oncology 2025, marks a watershed moment in this transition. In this multicenter phase I/II study, patients with PSMA-positive mCRPC were treated with Tb-161 PSMA-I and T.[5] PSA response rates of ≥50% and ≥90% were seen in 70% and 40% of patents, respectively. Median PSA-progression-free survival (PFS) and radiographic PFS were 9.0 months (95% confidence interval [CI] 5.7–15.1) and 11.1 months (95% CI 6.6–11.7), respectively. There were no treatment-related deaths and few grade 3 or higher treatment-related adverse events, which included pain flare and lymphopenia only. This trial has established the safety and efficacy of Tb-161 PMSA therapy and many more trials will follow.

Tb-161 shares similar physical characteristics with Lu-177, including a comparable half-life (~6.9 days) and β⁻ emission energy. What sets Tb-161 apart is its co-emission of a significant number of Auger and conversion electrons, which deposit energy over a much shorter range (nanometers). This makes Tb-161 potentially more effective at damaging single tumor cells and micrometastases – an area where Lu-177 therapy has shown limitations.[67] In addition to Tb-161, Tb-152 could also be a promising diagnostic pair for theranostics.[8] With T1/2 of 17.5 h, Eβ+ average of 1140 keV and Iβ+ of 20.3%, Tb-152 can be used for positron emission tomography imaging, offering matched-pair imaging for pretherapy dosimetry in Tb-161–based therapy–similar to the widely used Lu-177/Ga-68 pair but with potentially better pharmacokinetic alignment.

However, the potential clinical use of Tb-161 and Tb-152 will be limited by production challenges. While Lu-177 benefits from well-established reactor-based production centers and commercial availability, the production of Tb isotopes is still not streamlined making them not widely accessible. Nonetheless, initiatives are underway to scale up medical-grade terbium isotope availability. Recently, noncarrier added Tb-161 has been made commercially available with the commercial name Terthera^®.

In conclusion, while Lu-177 remains the current workhorse of theranostic therapy, Tb-161 may offer significant advantages, particularly in targeting small volume or disseminated disease. The VIOLET trial provides the first major clinical validation of this hypothesis. As isotope production capabilities improve, the Lu-177 era may gradually merge with or give way to a Tb-161 based future. It is imperative for the Indian nuclear medicine community, to stay ahead of this curve by investing in cyclotron infrastructure, radiochemistry capabilities, and clinical research in emerging theranostic isotopes.