Rashid Sayyid: Hello everyone and thank you for joining us today in this UroToday Journal Club recording. I'm Rashid Sayyid, a robotic urological oncology fellow at the University of Southern California. And as always, I'm delighted to be joined by Zach Klaassen, associate professor and program director at Wellstar MCG Health in Augusta, Georgia. And today we'll be discussing the exciting results of the VIOLET trial, which is a phase 1/2 trial that looks at terbium-161 PSMA-I&T in patients with mCRPC. This trial was published in The Lancet Oncology led by Dr. James Buteau as the first author, with Michael Hofman at the Peter Mac Center as the senior author.

So as our listeners will know in 2022, FDA approved Pluvicto or lutetium-177 for PSMA-positive mCRPC patients who were previously treated with an androgen receptor pathway inhibitor and a taxane chemotherapy. And this approval is based on the results of two seminal phase 2 trials, we have the VISION trial that looked at lutetium-177 PSMA-617 plus standard of care versus standard of care alone in patients who received both an ARPI and taxane or ineligible for a taxane and demonstrated a four-month overall survival benefit from just under a year to 15 months.

Similarly, the TheraP trial compared lutetium-177 PSMA-617 to cabazitaxel here as an active control arm. And although there was no difference in overall survival with lutetium-177 compared to cabazitaxel, lutetium-177 did show superior PSA progression-free survival as well as superior PSA 50 response 66 versus 37%, so almost double. And more recently, in March of 2025, the FDA approved for PSMA-positive mCRPC patients lutetium-177 for those who were previously treated with an ARPI, but those who were considered appropriate for delaying taxane-based chemotherapy. And so this is the difference compared to before the taxane-based chemotherapy component.

And this was based on the results of the PSMAfore trial that compared ARPI pre-treated mCRPC patients, lutetium-177 versus an ARPI switch and showed an almost four-month improvement in radiographic progression-free survival. So very exciting results with approvals that followed thereafter for a very high-risk cohort with poor prognosis.

But why do we need another radionuclide if we already have Pluvicto and what limitations would new radionuclides try to overcome? And so this leads us to terbium. What is terbium-161? It's a beta-emitting radionuclide with similar energy and a half-life to lutetium-177. And so, as such, it targets a larger tumor volume just like lutetium does. But additionally it emits conversion and Auger electrons. And so what these two components do is they deposit energy over a much shorter distance, in nanometers to micrometers, and it better targets micrometastatic deposits. And so these micrometastatic deposits have been theorized to be a mechanism of resistance. So if we can target them in theory, we can overcome one of these mechanisms of resistance and increase double-strand DNA damage that may lead to improved outcomes.

What is the evidence that supports this alternate mechanism of action or additional mechanism of action in this case? So terbium-161 PSMA-617 has shown superior in vitro and in vivo efficacy in tumor-bearing mice when compared to lutetium. And this supports the theory that additional emission of conversion Auger electrons from this terbium can contribute to enhanced therapeutic effect. And we can see quite clearly here on the left we have the lutetium, on the right the terbium, how the cell growth is much lower with the tumor volume.

Additionally, in dosimetric symmetric model studies, terbium is consistently been shown to lead or be associated with higher absorbed doses across the components of the cell, but in particular the nucleus, we see it's almost fourfold higher. And so this increased absorbed dose is associated likely with increased double-strand DNA breaks and thus superior efficacy. Really the early evidence from these smaller studies really does support that this additional factor of emitting these conversion Auger electrons may lead to enhanced efficacy and thus in theory, superior outcomes.

And so based on this rationale, the objective of this study was to investigate the safety and activity of terbium-161 PSMA I&T in mCRPC patients. And so this was a single-center investigator-initiated phase 1/2 trial that was conducted at the Peter MacCallum Cancer Center in Australia and was very generously supported by the Prostate Cancer Foundation. This study included patients with progressive mCRPC previously receiving at least one ARPI and taxane or unfit for taxane chemotherapy. And they also had PSMA-positive disease on a PSMA PET-CT, be it gallium-68 or be it a Pylarify PET. And when we say PSMA-positive disease, we mean an SUV max of at least 20 in one lesion and an SUV max of at least 10 in measurable soft tissue metastasis. And importantly, just like we saw with the eligibility criteria for PET, the patients are required to have no discordant findings on FDG PET, meaning FDG PET positive and PSMA PET negative. Patients, as is typical for these trials, had excellent performance status, ECOG zero to two and adequate bone marrow, hepatic and renal function.

This study employed both dose escalation phase 1 and dose expansion phase 2 design. In the phase 1 portion, it followed a standard three plus three dose escalation approach with three radioactivity levels for the terbium-161 PSMA-I&T, 4.4, then 5.5 and then later 7.5. And up to six cycles were administered intravenously every six weeks, and this dose was reduced by 0.4 gigabecquerels for each cycle. And the reason it's decreased with each cycle is you would expect that this agent would work and with each cycle you would have a lower tumor burden and thus require a lesser dose. And by that, you maintain the efficacy while minimizing cumulative toxicity. It's important to note that this terbium-161 PSMA-I&T was produced on-site at the center and all patients continued ADT during the study.

In terms of the study endpoints. For the phase 1, typical dose-limiting toxicities as well as maximum tolerated dose, which was defined as the highest dose at which less than one-third or less than two out of six patients experienced a dose-limiting toxicity, and also you have the recommended phase 2 dose. With phase 2 we see more of the efficacy outcomes. In addition to the adverse events, you have the radiation absorbed dose, the PSA response rate, radiographic progression-free survival, PSA progression-free survival, overall survival response rates, and also looking at patient-reported outcomes.

This study mandated a pre-specified sample size of 30 to 36 patients based on the sample size calculations. And this sample size would in theory allow for 24 patients to be treated at the maximum tolerated dose. And this is assuming a probability of at least one dose-limiting toxicity of 64%. The safety population included all patients who received at least one cycle in the dose escalation or expansion phases. And similarly, the activity analysis was conducted for all patients who received at least one cycle of the terbium-161 PSMA-I&T. And as is usual, time-to-event outcomes in this trial were reported using Kaplan-Meier curves with survival analysis.

At this point, I'll turn it over to Zach. We'll go over the results of this exciting trial and then we'll contextualize these results in our discussion and what it means for our patients and for clinical trial design moving forward.

Zachary Klaassen: Rashid, great introduction as always, and I'm going to take a minute here to go through some of the baseline characteristics. So as you mentioned, there were 30 patients in this trial, the median age was 69 years, and these are patients that have had prostate cancer for a long time, median time since diagnosis, 6.5 years. And we look at de novo metastatic disease at diagnosis, this was 50%. The PSA at the time of screening for the VIOLET trial was 26.9. Excellent performance status for all of these patients. We look at majority of these patients had radiotherapy in the past, about three-quarters. About two-thirds of these patients had taxane chemotherapy, most commonly docetaxel. Part of the trial design was all patients having had an ARPI with about half having abiraterone, slightly over half having enzalutamide and a handful of patients having darolutamide. When we look at the PSMA SUV max, the median was 8.2, the median PSMA tumor volume was 212 mLs. And when we look at the metastases on PSMA PET, we see 63% nodal metastases, 73% bone and 7% visceral metastases.

This is the treatment summary for the trial. So we're going to focus on the far right column, which is the combination of the phase 1 and phase 2 portions of the study. 70% of patients received all six cycles of terbium-161. The median range of cycles received was six. Total radioactivity in gigabecquerels median was 38. Looking at the number of patients that had dose delay due to adverse events was only 10%. So 90% of these patients did not have any delay due to AEs. And we go down to the bottom part of this table looking at patients that permanently discontinued terbium-161, only 30% of patients and we see that overall, ultimately during the follow-up period, 23 patients died. 67% of patients remained on follow-up and 10% on treatment.

In terms of adverse events, on the left is treatment-related adverse events. On the right is serious AEs, we'll walk through these. And so at the bottom we see any adverse event, 43% grade 1, 47% grade 2, and 7% grade 3. Some of the more common ones, which you would expect very similar to lutetium-177 safety profile. Lymphocyte count decrease 27% grade 1, 33% grade 2. Anemia 53% grade 1, 13% grade 2. Fatigue 40% grade 1, 3% grade 2. And importantly dry mouth 70%. But all of these grade 1 adverse events.

The serious adverse events, these are broken down by patients. So there was one myocardial infarction 192 days after cycle 1, one patient had a skin infection, one patient had a late fever, two patients had pain, wound complications, two patients and kidney infections, two patients. The rest of these were all grade 3 adverse events, of course the myocardial infarction leading to mortality was a grade 5 adverse event not related to treatment.

This is the waterfall plot of best PSA response. PSA reduction greater than 50% in light blue and PSA reduction less than 50% in this orange color to the left. And this tallied up for a PSA 50 response rate of 70% in these patients and a PSA 90 response rate of 40% for these patients. This is the spider plot looking at PSA change from baseline and the take-home from this figure is that you can see here in the bottom left majority of these patients had an early and relatively deep PSA response within about 24 to 32 weeks. Among 12 patients that had measurable disease based on RECIST v1.1. The objective responses were partial response in 50%, stable disease in 17% and progressive disease in 36% of the patients.

This is the swimmers plot looking at each patient. You can see on the left 1 through 30, the events listed here, there was 47% of patients that had PSA progression, 40% of patients eventually had radiographic progression and as I mentioned previously, 23% of patients over the course of follow-up eventually died.

This is the survival outcomes with the median follow-up of just under one year. PSA progression-free survival, median 9.0 months, radiographic progression-free survival median of 11.1 months and progression-free survival median of 8.2 months. This is an interesting figure. So this is a three time point quantitative SPECT at cycle 1. There's some interesting take-home points here based on the design of terbium-161. This is the baseline gallium-68 PSMA PET on the left. You can see normal organ uptake as well as the metastatic deposits. When we move to the middle part of this figure, this is a SPECT at 4 hours, at 24 hours and at 96 hours. And we see that terbium-161 retention in the metastasis continues but it washes out of the normal organs over time, where at 96 hours, the majority of this terbium is just in the sites of metastatic deposits.

This is a pretty neat overlay of both the metastatic uptake as well as the normal organ uptake. And so the pink is the metastatic disease deposits. And then this scale based on gray is the normal organ uptake and we can see here most commonly in the kidneys.

Again, this is looking at the absorbed dose for normal organs at cycle 1. I mentioned, the kidneys lit up the most. This is the highest absorbed dose for kidneys at a median of 2.28 gray. We also see a median of 0.9 gray for parotid glands, submandibular glands 0.94, and relatively low uptake in the liver and the spleen. And generally this is within the published ranges of uptake for either lutetium-177 I&T or lutetium-177 PSMA-617.

So by way of discussion, the VIOLET trial is the first reported trial using terbium-161 in any cancer type. So this is not just for prostate, this is any cancer type. It had a favorable safety profile, a few grade 3-4 treatment-related adverse events, no dose reductions and no treatment discontinuations for toxicity. And this is important because despite additional radiation from Auger and conversion electrons. What's interesting is the highest radioactivity level of 7.4 gigabecquerels for terbium-161 is equivalent to nearly 10 gigabecquerels of lutetium-177.

There are several important considerations though. So if we look at this, the current infrastructure logistics and procedures used for lutetium either PSMA-617 or I&T radioligand therapy, these can be transferred to the use of, and so this likely supports the generalizability as terbium-161 moves forward. Also, importantly, identical radioprotective measures currently used for lutetium-177 PSMA-617 or lutetium-177 PSMA-I&T can also be followed for terbium-161. And finally terbium-161 with high radionuclide purity can be produced in nuclear reactors with similar methods to lutetium-177 production. So all three of these considerations lead to the take-home point that if you are set up for radioligand therapy with lutetium-177, the conversion to terbium-161 should be reasonably straightforward.

There are also several registered clinical trials using terbium-161 ongoing in mCRPC. There's a PROGNOSTICS trial, which is a Swiss single-center phase 1A/B study investigating terbium-161 SibuDAB as well as the REALITY German registry, which is assessing various radionuclide therapies. So we continue to look forward to these outcomes in the setting of VIOLET recently being published. So take-home messages. terbium-161 PSMA-I&T had an encouraging safety profile at the maximum administered dose of 7.4 gigabecquerels in patients with progressive metastatic CRPC. What's interesting as well, because this is so well tolerated, there's an additional cohort assessing 9.5 gigabecquerels that's currently recruiting. And so finally, this data from VIOLET provides a platform for further clinical evaluation of terbium-161 PSMA-I&T in patients with mCRPC and in earlier disease leveraging the superior treatment of micrometastatic disease.

We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club of the recently published VIOLET trial.