VIOLET Trial: A Promising Advancement in Prostate Cancer Therapy
Patients with metastatic castration-resistant prostate cancer (mCRPC) often face limited treatment options, especially after standard therapies like chemotherapy and \[177Lu]Lu-PSMA radioligand therapy stop working. The VIOLET trial is a new clinical study that is testing an advanced radiopharmaceutical called 161Tb] Tb-PSMA-I &T. This therapy uses Terbium-161, a next-generation radioisotope that may offer greater tumor-killing ability, particularly in small or resistant cancer sites.
The VIOLET trial is being conducted at the Peter MacCallum Cancer Centre in Melbourne, Australia, and is the first human trial to evaluate this specific therapy for mCRPC.
Why Lu-177 Is Not Always Enough
Lu-PSMA has become an established treatment option for patients with mCRPC by targeting prostate-specific membrane antigen (PSMA) found on prostate cancer cells. It works by delivering beta radiation that kills tumor cells. However, Lu-177 has a physical limitation. Its radiation path length (about 0.7 mm) may not be enough to kill very small clusters of cancer cells, known as micrometastases, or single cancer cells. These small cancer sites often receive insufficient radiation, allowing the cancer to return over time.
Micrometastases are a major challenge in prostate cancer progression. They may survive treatment and cause the cancer to spread again. Studies show that while larger tumors may shrink or disappear with Lu-177, the smallest cancer deposits are often left behind and continue to grow later.
Source: https://pubmed.ncbi.nlm.nih.gov/36175742/
What Makes Terbium-161 A Better Option
Terbium-161 (Tb-161) emits not only beta particles but also a significant number of Auger and conversion electrons. These electrons have higher energy density and deposit radiation over a much shorter distance. This makes Tb-161 more effective at destroying cancer cells that are too small or too energy-shielded for Lu-177 to affect.
Preclinical studies have shown that Tb-161 delivers approximately 35–40% more radiation energy per decay than Lu-177, specifically to micrometastases and single cells.
Source: [https://jnm.snmjournals.org/content/65/8/1231]
Tb-161 has similar chemical behavior and imaging capabilities as Lu-177, so the same PSMA-targeting molecules (PSMA-I\&T) can be used to deliver the radiation.
What Is the VIOLET Trial?
The VIOLET trial
(ClinicalTrials.gov ID: [NCT05521412]
(https://clinicaltrials.gov/study/NCT05521412) is an investigator-initiated, single-center, open-label Phase I/II trial. It is led by a team of clinicians and scientists at the Peter MacCallum Cancer Centre and the University of Melbourne, including:
Dr. James P. Buteau
Dr. Michael S. Hofman
Dr. Shahneen Sandhu
Dr. Arun Azad
The goal of the trial is to assess the safety and preliminary effectiveness of Tb-PSMA-I&T in patients with mCRPC.
Who Is Eligible?
The trial enrolled men with metastatic castration-resistant prostate cancer who had:
- Disease progression after at least one line of taxane-based chemotherapy
- Prior treatment with androgen receptor pathway inhibitors (e.g., enzalutamide, abiraterone)
- PSMA-positive disease as confirmed on PET imaging
- No prior treatment with radiopharmaceuticals like Lu-177 or Radium-223
- Adequate kidney, liver, and bone marrow function
How Is the Treatment Given?
Each patient can receive up to six intravenous injections of Tb-PSMA-I\&T, one every six weeks. The dose level is adjusted depending on the patient’s response and side effects. Blood tests and imaging scans are done at regular intervals to monitor safety and effectiveness.
Treatment is given in an outpatient setting, with additional hydration during administration. Imaging with SPECT/CT is performed after each cycle to measure radiation dose delivery to tumors and normal organs.
Recent Updates on the VIOLET Trial
As of April 2025, the VIOLET trial has completed its Phase I dose-escalation stage and has moved to Phase II, where the focus is on evaluating the treatment’s effectiveness in a larger group of patients. In Phase I, the maximum tolerated dose was established at 7.4 GBq, with subsequent cycles reduced by 0.4 GBq to reduce side effects.
According to [trials.cancervic.org.au](https://trials.cancervic.org.au/details.aspx?ID=feed-cta-trial468), the treatment was well tolerated. The study is now assessing response to therapy, including prostate-specific antigen (PSA) reduction, radiographic progression-free survival, overall survival, and patient-reported outcomes such as pain and quality of life.
Challenges and Innovations
One of the challenges in this trial was the lack of commercial imaging tools for Tb-161. The research team developed in-house solutions to accurately measure and track radiation using advanced SPECT/CT imaging. These innovations were critical for ensuring precise radiation dosing and patient safety.
Dr. Michael Hofman discussed these challenges in a presentation at the 2025 UCSF-UCLA PSMA Conference. He emphasized that Terbium-161 could provide better outcomes in patients whose cancer is resistant to Lu-177 due to its ability to target micrometastases more effectively.
Source:https://www.urotoday.com/video-lectures/2025-ucsf-ucla-psma-conference/video/mediaitem/4752-beyond-lutetium-psma-exploring-terbium-161-for-treatment-resistant-prostate-cancer-presentation-michael-hofman.html
Safety and Side Effects
No serious adverse effects from Tb-161 have been reported so far in the VIOLET trial. Side effects are being tracked using standard criteria (CTCAE v5.0), and dose adjustments are made when necessary. Expected side effects include fatigue, temporary decrease in blood counts, dry mouth, and mild kidney or liver changes, which are similar to those observed with Lu-177.
Patients are closely monitored before each treatment cycle to ensure that their blood parameters meet minimum safety thresholds.
Why This Trial Matters
- Tb-161 may be more effective than Lu-177 in targeting small, hard-to-treat cancer deposits
- It has shown promising results in early studies without significant added toxicity
- If successful, it could become a new standard of care for patients who relapse after Lu-177 therapy
The VIOLET trial is the first step in bringing Tb-161 therapy into clinical practice and could open the door for more personalized and effective prostate cancer treatments.
Conclusion
The VIOLET trial is one of the most closely watched studies in nuclear oncology today. Its focus on a new radionuclide, Tb-161, reflects the next chapter in radioligand therapy for prostate cancer. Early results suggest that Tb-161 may improve treatment outcomes for patients who have limited options. The trial is currently ongoing, and final results are expected in late 2025.
For more information or updates, refer to:
https://trials.cancervic.org.au/details.aspx?ID=feed-cta-trial468
https://clinicaltrials.gov/study/NCT05521412
https://jnm.snmjournals.org/content/65/8/1231
https://www.urotoday.com/video-lectures/2025-ucsf-ucla-psma-conference/video/mediaitem/4752-beyond-lutetium-psma-exploring-terbium-161-for-treatment-resistant-prostate-cancer-presentation-michael-hofman.html
https://jnm.snmjournals.org/content/jnumed/65/8/1231.full.pdf