(UroToday.com) The 2025 Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting held in New Orleans, LA between June 21st and 24th, 2025, was host to a session on non-beta emitter PSMA radioligand therapy. Dr. James Buteau discussed the use of Terbium-161 (161Tb) for the treatment of advanced prostate cancer.
Dr. Buteau began by noting that 177Lu-PSMA is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC) delivering high radiation doses to cancer cells and low doses to normal cells, which minimizes potential side effects. However, even with a radiologic complete response of the macroscopically visible disease, mCRPC eventually progresses. This is likely related to the persistence of energy-sheltered micrometastases in this setting.
There are 3 main types of radiation particles:
- Beta emitters: Have a low linear energy transfer (LET) of ~0.2 keV/µm with a long range of 1.8–10 mm
- Alpha emitters: The ‘bowling ball’ of radiation particles – Have a higher LET of ~5-230 keV/µm with a shorter range of 40-100 nm
- Radiation particles that emit Auger and conversion electrons: A ‘middle ground’ between α and β emitters with an LET of 4-26 keV/µm and a range of 2-500 nm.
One such example of an Auger and conversion electron emitter is 161Tb:
161Tb attaches to PSMA receptors and emits β-particles, similar to 177Lu, killing larger sized tumors with abundant crossfire. It also emits additional Auger and conversion electrons that delivers higher concentrations of radiation over very short path lengths, which may kill micrometastases better than 177Lu.
As seen in the graph below, 161Tb is able to achieve significantly higher radiation doses to the nucleus, compared to 177Lu, highlighting the higher lethality of 161Tb.1
Pre-clinical studies support that this increased radiation dose to the nucleus may better kill micrometastases.2
How do the physical characteristics of 177Lu and 161Tb compare? They have similar half-lives of 6.7–6.9 days. 161Tb is associated with a higher β- mean energy (154.3 vs 133.3 keV), which is associated with improved lethality. Significantly, the conversion electrons (CE) and Auger electrons (AE) emitted per radioactive decay are significantly higher for 161Tb:
- CE: 39.3 versus 13.5 keV
- AE: 8.94 versus 1.13 keV
Ongoing work from multiple groups is evaluating quantitative 161Tb SPECT/CT in the advanced prostate cancer space:
At the recent ASCO 2025 meeting, the first-in-human results of Terbium-161[161Tb]Tb-PSMA-I&T radioligand therapy in mCRPC patients were presented. The VIOLET trial (NCT05521412) is a single-center, investigator-initiated phase I/II study designed to evaluate a novel therapeutic approach in mCRPC patients. Eligible participants were those who progressed on ≥1 taxane (unless medically unsuitable) and an androgen receptor pathway inhibitor (ARPI) and demonstrated PSMA-positive disease on PET imaging (SUVmax ≥20) with no discordant FDG uptake. Eligible participants were also required to have adequate bone marrow, hepatic, and renal function, with an ECOG performance status of 0–2.
The trial incorporated dose-escalation and dose-expansion portions. A standard 3+3 dose-escalation approach was employed, with three radioactivity levels evaluated: 4.4 GBq, 5.5 GBq, and 7.4 GBq administered intravenously every six weeks, with an added 0.4 GBq per cycle. In phase I, the goal was to identify the recommended phase II dose. In phase II, patients received up to six cycles of therapy while continuing their background androgen deprivation therapy.
A total of 33 patients were assessed for eligibility in the VIOLET trial, with 3 excluded due to low PSMA uptake or FDG discordance. Notably, enrollment was completed 8 months ahead of schedule. Among those treated, 3 patients received radioactivity level 1, 3 received level 2, and 6 received level 3. An additional 18 patients were treated in the dose expansion cohort. Overall, 21 patients (70%) completed all 6 treatment cycles, with a median total administered radioactivity of 38 GBq (IQR: 21.1–38.5).
No dose-limiting toxicities were observed. Treatment-related Grade 3/4 adverse events occurred in only 2 patients (7%), with no instances of radioactivity dose reduction, no cycle delays, and no treatment-related deaths.
The PSA50 and PSA90 response rates were 70% and 40%, respectively.
The median PSA progression-free survival (PSA-PFS) was 9 months (95% CI, 5.7–15.1), while the median radiographic progression-free survival (rPFS) was 11 months (95% CI, 6.6–11.7).
The key takeaway points from this trial were as follows:
- This is the first-in-human use of Terbium-161 across any cancer type
- In patients with progressive mCRPC, Terbium-161 PSMA-I&T had a low toxicity rate (up to 7.4 GBq) and promising activity
- Treatment-related grade 3-4 adverse events: 7%
- No treatment-related dose reductions, delays, or deaths
- PSA90 response rate: 40%
- Radiographic PFS, median: 11.1 months
Presented by: James Buteau, MD, FRACP, FRCPC, Nuclear Medicine Physician, Peter MacCallum Cancer Cenre, Victoria, Australia
Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2025 Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting, New Orleans, LA, June 21st – 24th, 2025
References:
- Alcocer‑Ávila ME, Ferreira A, Quinto MA, et al. Radiation doses from 161Tb and 177Lu in single tumour cells and micrometastases. EJNMMI Phys. 2020; 7(1):33.
- Müller C, Singh A, Umbricht CA, et al. Preclinical investigations and first-in-human application of ¹⁵²Tb-PSMA-617 for PET/CT imaging of prostate cancer. EJNMMI Res. 2019; 9(1):68.