Novel Radioactive Drug Shows Promise Against Advanced Prostate Cancer in First Human Trial

Australian researchers report that terbium-161-based radioligand therapy is safe and shows encouraging early results in men with metastatic castration-resistant prostate cancer

Researchers at the Peter MacCallum Cancer Centre in Melbourne, Australia, have published the first-ever human trial results for a novel cancer-fighting isotope called terbium-161 (¹⁶¹Tb), paired with a prostate-cancer-targeting molecule called PSMA-I&T. The findings, published in The Lancet Oncology, come from a phase 1/2 study known as VIOLET and mark a significant step for a radionuclide many hope could eventually outperform the current standard treatment.

Why terbium-161 is generating interest

For several years, doctors have used lutetium-177 (¹⁷⁷Lu) attached to PSMA-targeting molecules to treat metastatic castration-resistant prostate cancer (mCRPC) — cancer that has spread and stopped responding to hormone therapy. This approach, sold as [¹⁷⁷Lu]Lu-PSMA-617, has been shown in multiple trials to extend survival and improve quality of life, but it does not cure the disease, and progression eventually returns.

Terbium-161 works on a similar principle: it is attached to a molecule that seeks out and binds to PSMA, a protein found on the surface of prostate cancer cells, then delivers radiation directly to the tumor. But unlike lutetium-177, terbium-161 also emits a shower of extremely short-range particles called Auger and conversion electrons. Laboratory and animal studies have suggested this additional radiation could make terbium-161 more effective at destroying small clusters of cancer cells and even single stray cancer cells — the kind that traditional beta radiation may not fully reach.

Despite that promise, until now, terbium-161 had never been tested in a clinical trial for any cancer type.

Inside the trial

The VIOLET trial enrolled 30 men with progressive mCRPC between October 2022 and February 2024. All had already been treated with hormone-blocking drugs and, in most cases, chemotherapy. Patients were confirmed to have PSMA-positive disease using PET imaging before being accepted into the study.

The trial used a dose-escalation design, starting participants on lower radioactivity levels (4.4 GBq) and gradually increasing to a higher dose (7.4 GBq) as safety was confirmed at each step. Patients received up to six treatment cycles, each six weeks apart, with the dose slightly reduced with each subsequent cycle.

Key safety findings

The headline result is a reassuring one: no dose-limiting toxicities occurred at any radioactivity level tested, and the maximum dose used, 7.4 GBq, was confirmed as safe and recommended for further study. Serious side effects were rare — only one patient experienced a severe (grade 3) adverse event related to treatment, in the form of pain, and one patient had severe low lymphocyte counts. No patients experienced life-threatening (grade 4) side effects related to the drug, and no one had to reduce their dose or stop treatment because of toxicity. Common but mild side effects included dry mouth, fatigue, and mild anemia — patterns broadly similar to those seen with lutetium-177 treatments.

Signs the treatment is working

While the trial's main goal was to establish safety, the results also hinted at meaningful anti-cancer activity. Seven out of ten patients (70%) had their PSA levels — a blood marker of prostate cancer activity — drop by half or more, and 40% saw a 90% or greater reduction. Among patients with measurable tumors on scans, half showed a partial shrinkage of their disease.

Patients went a median of about 11 months before their cancer progressed on scans, and survival without any sign of worsening disease lasted a median of just over 8 months.

What comes next

Because VIOLET was a single-arm study without a comparison group, the researchers caution that these results cannot yet prove terbium-161 is better than the existing lutetium-177 treatments — that question awaits larger, randomized trials. The Melbourne team has already expanded the study to test an even higher radioactivity dose (9.5 GBq) in an additional group of patients, and researchers say the infrastructure used for existing lutetium-177 treatment programs could be readily adapted for terbium-161, easing any future rollout to other cancer centers.

The study's authors say the results support moving forward with larger, randomized phase 3 trials, and suggest terbium-161 could eventually be explored earlier in the course of prostate cancer treatment — including in patients whose disease has not yet become resistant to hormone therapy.

Source: 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." The Lancet Oncology, published online July 2, 2025. Trial registration: ClinicalTrials.gov NCT05521412.