Terbium-161 PSMA Therapy Delivers High Tumor Doses With Tolerable Organ Exposure

A new dosimetry study has delivered the most detailed quantitative picture yet of what happens inside the bodies of men with advanced prostate cancer when they receive a next-generation radioligand built around the isotope terbium-161. The research, conducted at Saarland University Medical Center in Germany and published in the European Journal of Nuclear Medicine and Molecular Imaging, measured exactly how much radiation the experimental therapy deposits in tumor metastases compared with the healthy organs most at risk. The results are striking: tumors absorbed several times more radiation per unit of injected activity than the kidneys or salivary glands, yielding tumor-to-organ ratios that substantially exceed those reported for the current clinical standard, lutetium-177.

Radioligand therapy has transformed the treatment landscape for metastatic castration-resistant prostate cancer, or mCRPC, a stage of disease in which tumors no longer respond to hormone deprivation. The approved therapy, lutetium-177 labeled PSMA-617, homes in on prostate-specific membrane antigen, a molecule abundantly displayed on the surface of prostate cancer cells, and delivers beta radiation directly to metastatic deposits. Clinical trials demonstrated improved survival and tolerability, leading to regulatory approval in both Europe and the United States. Yet not every patient responds, and resistance eventually emerges in many. This therapeutic gap has driven a search for alternative radionuclides capable of packing more lethal energy into tumor cells, and terbium-161 has quickly become one of the most compelling candidates.

The appeal of terbium-161 lies in its distinctive decay physics. It closely mimics lutetium-177 in the ways that matter for clinical logistics: nearly identical half-lives of 6.9 versus 6.6 days, similar mean beta particle energies of 154 versus 133 kiloelectronvolts, and gamma emissions suitable for post-treatment imaging and dosimetry. But terbium-161 also emits a far greater abundance of conversion electrons and low-energy Auger electrons. These particles travel less than 500 nanometers in tissue and deposit energy at a high linear energy transfer of 4 to 26 kiloelectronvolts per micrometer. In principle, this means intense, highly localized irradiation precisely where the radioligand binds, particularly damaging for microscopic tumor deposits and single tumor cells that beta particles from lutetium-177 may spare. Preclinical studies and simulation work have consistently suggested a dosimetric advantage for terbium-161, and an initial head-to-head comparison in six patients corroborated the theory.

What has been missing is rigorous dosimetry in a larger patient cohort. The new study addresses that gap by analyzing 15 men with mCRPC enrolled in a prospective therapeutic registry who received terbium-161 labeled PSMA-617, typically as a second-line radioligand option after prior therapy with lutetium-177 or actinium-225. Patients received a median of two treatment cycles with a mean administered activity of 6.0 plus or minus 1.3 gigabecquerels per cycle, for a cumulative mean activity of 12.3 plus or minus 4.6 gigabecquerels. The radiolabeling process, adapted from established lutetium-177 methodology, achieved radiochemical yields and purity consistently above 99 percent, and administered activities were individually tailored to each patient’s tumor burden, renal function, and blood counts.

Dosimetric assessment relied on a hybrid two-dimensional and three-dimensional imaging protocol. Planar whole-body scans were acquired at roughly 24, 48, and at least 69 hours after injection, supplemented by SPECT/CT imaging of the head and neck on day one and of the abdomen on day two. Using a 74.6 kiloelectronvolt photopeak window, scatter and attenuation corrections, partial-volume corrections derived from terbium-161 phantom measurements, and automated Bayesian volume segmentation, the physics team calculated absorbed doses with the OLINDA/EXM software following the internationally recognized MIRD schema. This combination of planar kinetics rescaled by quantitative SPECT values represents a methodologically sound middle ground between speed and accuracy, and it allowed the researchers to track 43 individual metastatic lesions alongside the kidneys, liver, parotid glands, and submandibular glands.

The organ dosimetry results place terbium-161 therapy squarely within the safety envelope established for lutetium-177. Kidneys received the highest mean absorbed dose at 0.70 plus or minus 0.41 gray per gigabecquerel, followed by the parotid glands at 0.40 plus or minus 0.20 and the submandibular glands at 0.36 plus or minus 0.14 gray per gigabecquerel, with the liver absorbing the least at 0.13 plus or minus 0.08 gray per gigabecquerel. Absorbed doses did not change significantly between the first and second treatment cycles, and no deterioration in renal toxicity was observed even in the two patients with the highest kidney doses, both of whom entered the study with pre-existing renal risk factors. The reported kidney dose range overlaps the published spectrum for lutetium-177 PSMA-617, which spans roughly 0.39 to 0.99 gray per gigabecquerel across major studies.

The tumor findings are where the therapy’s promise becomes most visible. Across 43 analyzed metastases, predominantly bone lesions, the mean absorbed tumor dose was 5.95 plus or minus 3.60 gray per gigabecquerel, with individual lesions ranging from 0.68 to 32.34 gray per gigabecquerel. Bone metastases absorbed 5.89 plus or minus 4.20 gray per gigabecquerel and lymph node metastases 5.46 plus or minus 2.97 gray per gigabecquerel, with lesions retaining the tracer for a mean effective half-life of 44 hours. These figures compare favorably with meta-analytic data for lutetium-177 PSMA ligands, which reported mean bone lesion doses of about 3.6 to 4.1 gray per gigabecquerel and soft-tissue doses of about 2.9 to 4.2 gray per gigabecquerel. Translated into therapeutic indices, the tumor-to-kidney ratio reached 10.55 plus or minus 8.32 and the tumor-to-parotid ratio 16.15 plus or minus 11.85, well above the kidney therapeutic indices of 3.6 to 5.3 previously published for lutetium-177-based approaches.

The study also probed the relationship between dose and response, finding a suggestive but statistically non-significant trend. Patients whose disease progressed biochemically tended to have received lower tumor absorbed doses, averaging 3.15 plus or minus 1.62 gray per gigabecquerel, than patients with stable disease at 5.81 plus or minus 2.64 or partial PSA remission at 6.52 plus or minus 3.27 gray per gigabecquerel, with a moderate correlation between tumor dose and PSA change. The authors attribute the lack of statistical significance to the small, heterogeneous, and heavily pretreated cohort rather than to any absence of a dose-response relationship, which earlier work in PSMA radioligand therapy has supported. Importantly, no severe adverse events or treatment discontinuations occurred in the cohort, reinforcing the emerging picture from the independent VIOLET phase 1/2 trial of terbium-161 PSMA-I&T that this radionuclide is safe and clinically active.

The investigators are careful to note the limitations: the cohort was small, all patients had undergone multiple prior radioligand therapy cycles that may have altered tracer kinetics, red marrow dosimetry was not feasible, and lesion selection was constrained by imaging criteria that could introduce bias. Nonetheless, as the largest terbium-161 PSMA dosimetry study published to date, the work provides a quantitative foundation for a therapy that could ultimately serve not only prostate cancer patients but also those receiving peptide receptor radionuclide therapy or FAP-targeted treatments. The favorable tumor-to-organ ratios reported here support continued clinical development, and the authors argue that individualized dosimetry will be central to future treatment planning, allowing clinicians to adapt activity prescriptions per patient to maximize tumor kill while protecting kidneys and salivary glands. Larger prospective trials will determine whether terbium-161’s physical advantages translate into a survival benefit, but the dosimetric arithmetic now clearly favors it.

Subject of Research: Organ and tumor dosimetry of terbium-161 PSMA-617 radioligand therapy in metastatic castration-resistant prostate cancer

Article Title: Organ and tumor dosimetry of [161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC

Article References: Schaefer-Schuler, A., Blickle, A., Ganz, S., Petto, S., Burgard, C., Speicher, T., Bastian, M. B., Maus, S., Bartholomä, M., Ezziddin, S., & Rosar, F. (2026). Organ and tumor dosimetry of [161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08171-z

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08171-z

Keywords: terbium-161, PSMA-617, radioligand therapy, dosimetry, prostate cancer, mCRPC, Auger electrons, SPECT/CT, tumor-to-organ ratio, nuclear medicine, theranostics, kidney dose