Theranostic therapies expand frontline use in prostate cancer

In this interview, which took place at the 2025 LUGPA Annual Meeting, radiation oncologist J. Travis Mendel, MD, of Rio Grande Urology in El Paso, Texas, discusses the rapid evolution of radioligand and theranostic therapies in urology, particularly in prostate cancer. He notes that this is a transformative era, with nearly 90 theranostic products in early-stage trials and over 500 total studies underway. Initially used for late-stage, treatment-resistant patients, agents such as prostate-specific membrane antigen (PSMA)-targeted therapies are now being studied for earlier use, expanding access to more patients and reshaping clinical practice. Mendel highlights that theranostics—a concept dating back to radioactive iodine treatments decades ago—has now matured into precise, cell-targeted therapy with major implications for radiation oncology.

Discussing the PSMAddition trial (NCT04720157), he emphasizes its importance in moving therapies like lutetium Lu 177 vipivotide tetraxetan (Pluvicto) into first-line settings for metastatic prostate cancer. Similarly, emerging data from the LUNAR trial (NCT05496959) suggest that radioligand therapy combined with stereotactic radiation may someday replace or reduce reliance on traditional hormonal therapy, offering better quality of life for patients.

Looking ahead, Mendel expresses both excitement and caution about next-generation alpha emitters, such as Lead-212 and actinium-based agents. These more potent therapies could better target microscopic disease but raise concerns about toxicity and long-term effects on normal tissues.

Mendel also addresses the logistical challenges of expanding theranostic care, noting the need for purpose-built centers with dedicated imaging and treatment spaces as patient volumes increase.

Finally, he highlights innovative studies like the PSMA-Delayed Castration (DC) trial (NCT05939414), which challenge traditional hormone-based treatment paradigms, and emerging agents for renal cell carcinoma, such as new zirconium-based compounds that could revolutionize diagnosis and therapy. Overall, Mendel said he views the future of theranostics as bright and transformative for urologic oncology.

Urology Times: There have been significant advances in radioligand therapies this year. What are your main takeaways from these recent trials, and where we headed?

Mendel: It's been a very exciting time for the radioligand space. We term this "theranostics." It's a combination of therapy and imaging, all these trials, all these companies. I think there are about 90 products that are in phase 1 or phase 2 trials right now, coming down the pipeline. It's been exciting for urology, because, of course, prostate cancer was the first theranostic agent with PSMA. Typically, the way these things work is they start at the end. For the patients who don't have any other treatment options, they start with this new, novel therapy. What's happening now is they're bringing this more front line, and so that just means that there are going to be more patients who will have access to this more targeted technology that's being developed. PSMA has been great. It's completely revolutionized my practice. It has changed almost everything I do in terms of treatment planning for radiation, and then also therapies that we can offer patients. The theranostics principle has been around forever. Radioactive iodines was, like, back in the 60s or 70s, that's when they started doing this. So it's been decades, but it's just evolved with the times. And so now we're able to actually target specific cells with different radioligands. The future is very bright for this promising technology.

Urology Times: At ESMO, we saw data presented on PSMAddition. What are your main takeaways from this study?

Mendel: I just think it's opening up this therapy to an earlier patient population. It's great. A lot of the things that we're doing, we're just doing them because people did it in the past. For example, hormonal therapy has always been termed the backbone of treatment for prostate cancer, especially metastatic prostate cancer. I think that's going to change in the future, especially with these new trials that are coming down. We have the PSMAddition that's adding Pluvicto to patients with de novo metastatic disease. But there are other trials that are starting to be published. For example, at ASTRO, they presented the LUNAR trial. These are patients who did not receive hormone therapy. They just went on to receive Pluvicto, along with stereotactic radiation, and they had an excellent outcome. I think this is going to be something that people are going to be looking at to replace hormone therapy for those patients who don't want to pursue that treatment option. It's very exciting. I don't like hormone therapy that much. If I was a patient and I had metastatic disease, I would really be looking at other options as well, assuming they're safe.

Urology Times: We're also now seeing emerging data for the alpha emitters like Lead-212 and actinium-based technologies. How might these next-generation radioligands shape the future?

Mendel: This space is very new, and it's very evident that we do not know that much about it. Everyone talks about the new trials and the agents and things like that, but there are still a lot of things we don't know; specifically, the dosimetry of these agents and exactly how it's affecting the normal tissues, especially in the long term. When you study these patients, these are patients who are only going to live a couple years, so you don't know what the ramifications would be for someone who's going to receive this therapy, and 20 years down the road, what's going to happen to that patient. That's something we're definitely looking very closely at, because we, of course, as physicians, it's do no harm, right? You don't want to be hurting anyone. You want to help them. This is something that's going to be crucial in the future. The actinium agents are supposed to be harder hitting. The alpha agents, the way it works is, the beta is more of an innocent bystander effect. It collects in the cells, it releases the radiation. These particles actually affect the cells neighboring that cell more than the actual cell itself, whereas the actinium agents, or alpha agents, they're kind of harder hitting at shorter distances, and so they'll be affecting the cells that are collecting the agents. And so I think they'll probably have a similar outcomes in terms of efficacy for the patients we're currently treating. But I think they're going to be very good at scavenging cells that are more microscopic disease. The lutetium agents are really good at killing disease that you can see on PET imaging, because it's a nidus and a collection of these cells and so it absorbs those agents. And then, of course, the dose in that in that particular area is high, and so it kills those cells. But I think the actinium will probably be able to kill those cells, but also scavenge the microscopic disease that isn't collected at more than a centimeter, which is usually what you can see on these PET images, and so I think that's going to be fascinating. The question is, is it going to be toxic, and what's that mean to the normal tissues like your kidney and your salivary glands and things like that, when you're giving patients a harder hitting agent? Usually, when that's the case, you're going to see more extreme toxicity. But it remains to be seen, since this is a very novel agent.

Urology Times: From your perspective, what are some of the logistical or administrative barriers to offering radioligand therapy?

Mendel: We actually had a video [at the LUGPA Annual Meeting] on it. We've developed a small-footprint, efficient center with a PET unit, and then 5 therapy rooms and 3 bathrooms. What we were doing before, with Xofigo and then initially with Pluvicto, was we just had 1 room—my personal restroom—and we were just kind of "MacGyvering" it. I think that's what a lot of people are doing currently. But if you fast forward 5 to 10 years, and there are 20 new agents on the market, and you're going to be treating maybe 5 to 20 patients a day, the scenario changes. You can't just do that in 1 room. Pluvicto is easy to give. It's just a syringe; you inject it, and the patient leaves. Things like Lutathera for neuroendocrine cancer - and there are some small cell data coming out for that agent as well - the patients are in the center for up to 6 hours, and so doing that in just 1 room in your clinic is just not going to work. You're going to be treating 1 patient every 6 hours. And so I think people are starting to think outside the box and develop these theranostic centers, where you have the imaging right there. You have uptake and cool-down rooms, therapy rooms, your pharmacy, your hot lab, and things like that. It's really opened up the clinical research aspect of things as well, because there are many trials. The last time I saw, there were 500+ trials that are in this space currently.

Urology Times: In the prostate cancer space, what emerging agents or ongoing trials excite you the most?

Mendel: We're participating in the DC trial—delayed castration. I'm very excited about these trials, where they're kind of being very provocative and challenging the mantra that we've been living with for the past 100 years with castration and hormonal manipulation and things like that. These trials are really causing us to take a step back and think, is this really what we're going to continue doing into the future, or should we try something different? And so I'm very excited about that trial. The LUNAR trial is a very similar phase 2 trial that was presented, and it's a very similar capacity. I do a lot of intact prostate radiation therapy, and some of these patients will receive hormonal therapy, just because that's how it's always been. For decades, we just do that, because that's what we did, and now we're having these other agents that might replace it and actually give the patients a better quality of life post treatment.

Urology Times: Is there anything you would like to add?

Mendel: The future is bright in this field. It's been fascinating to see a lot of these agents. Urology in general, has been very lucky, where they've been able to utilize this new technology in the clinics. In particular, there's a new zirconium agent for renal cell carcinoma coming down the pipeline, which I think is going to be revolutionary for treating our patients with renal cell cancer. Right now, just like prostate cancer was 2 or 3 years ago, all we have are CT and bone scans for those patients. Now, we're going to have an imaging agent that's able to, with 90% accuracy, diagnose these patients, and then also a therapy agent that goes along with it, hopefully in the future. These kinds of things are going to be revolutionary for urology.