Looking Ahead: What Does the Future Hold for Radioligand Therapy in Prostate Cancer?

A roundtable discussion, moderated by Michael Morris, MD, discussed the current landscape of radioligand therapy in prostate cancer, including recent trial highlights presented at ESMO 2023. Dr. Morris was joined by Tanya Dorff, MD; Evan Yu, MD; and Rana McKay, MD.

In the final segment of the roundtable series, the panel shares insights on future advancements in the field, including PSMA-directed Actinium studies and radioligand combination therapy.

Watch more segments in this series.

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Dr. Morris: We don’t have too much time left. I wanted to finish up looking a little bit in the future. The first Actinium studies are open now. There’s an Actinium hK2-directed radioligand therapy. Several PSMA-directed Actinium studies will be launching probably in early 2024. There are already phase 1 Actinium studies that are open and accruing in other countries. How do you see the introduction of the alphas in other than the bone-directed therapy of radium into the tumor-directed realm? What are your expectations, your concerns, and your level of excitement on these? Tanya, why don’t you start us off?

Dr. Dorff: I think they’re very exciting. They’ll have a different efficacy and toxicity profile, so we will need to learn about it. But we’re fortunate to be participating in the hK2 Actinium, and these are definitely active, and not only exploring the new particles, but different targets I think is a fruitful landscape for further investigation.

Dr. Morris: Rana, how about yourself?

Dr. McKay: I completely agree. I think there’s a lot of excitement around alpha emitters, which tend to be more potent, shorter diameter of cell kill. I think the toxicity profile is going to be a little bit different with an alpha particle. It’s not just whether it’s alpha or beta. There’s also small-molecule inhibitor or being linked to a small molecule versus being linked to a monoclonal antibodies. There’s a lot of actually really exciting agents that are in development that I think hopefully will be able to improve upon what has been done already with VISION and PSMAfore.

Dr. Morris: How about yourself, Evan?

Dr. Yu: I’m very enthusiastic about the alpha emitters. Like what Rana said, I think 1 of the things is that alpha will induce double-strand DNA breaks and could induce more potent cell kill. That said, there is a little early experience that’s been done of alpha after beta, and although there’s anti-tumor efficacy, there’s also a lot more xerostomia. That could be a challenge, and that’s where Rana was bringing up the issue with, do you link it to a monoclonal antibody, where it’s going to be a larger molecule, might not penetrate as much in the salivary glands, might not cause as much renal tubular necrosis, but might cause more myelosuppression versus a small molecule that’s going to get more into those areas.

I think that all has to be worked out. Maybe there might be thought of using targeted alpha radiotherapy earlier in disease states since you might run into these problems with xerostomia later on. But there is 1 other potentially limiting factor, I think, especially with Actinium, I think there’s a limited world supply, and I think there’s only 1 production facility, so we have to be mindful, and I think that production facility has to be mindful of who they collaborate with.

Dr. Morris: I think that the field is dealing with that in terms of shifting attention to lead 212, which a generator is about the size of a large suitcase and sits in your own institution. But I think the world acknowledges that the Actinium supply is going to limit what we can study and the number of agents and hopefully the number of patients that could be treated, but I do think that limitation is spurring a lot of innovation and expansion into other radioligands as the payload.

Dr. Yu: I think, fortunately, that supply is right up the street from my office. Everett, Washington.

Dr. Morris: That’s right. I think that the really sweet spot that we look forward to with the alphas is the potential for addressing micrometastatic disease because of the physics of the alpha particle being able to pluck off individual cells at a time. In terms of the antibodies, I just raised the issue of the Scott Tagawa, MD, trial of Actinium-J591, which actually never hit a DLT [dose-limiting toxicity] hematologically. Frequently, what we conceive of in our minds as the limitation of antibodies, we shouldn’t let interfere with actually doing the trials and getting the data, because we can be wrong under those expectations. Indeed, if you look at most trials, we are wrong. Sometimes we’re wrong in the negative way and sometimes we’re wrong in the positive way, and I think that the [Dr.] Tagawa trials have shown that our expectations were actually wrong and it’s less hematologically toxic than anyone would’ve imagined before.

I guess we’ll end with a round robin of what you’re looking forward to in the field of radioligand therapy, whether that’s from a clinical perspective or a study perspective. Rana, what are you looking forward to seeing in the next year or so in the field?

Dr. McKay: I think there’s going to be other radioligands that do the same thing, and I think we’re going to have to figure out how they fit into the picture with SPLASH and I think ECLIPSE study. I think thinking about what are the right combinations, what are the right sequences, I think that’s going to all need to be fleshed out in the design of future studies. It’s exciting.

Dr. Morris: How about you, Evan?

Dr. Yu: Yeah, I think we need to put more effort into understanding mechanisms of resistance to design the next set of studies and agents that we should be going toward next, or rational combinations, etc. I think there’s opportunity to do more biologic exploration or just all the work on that.

Dr. Morris: Tanya?

Dr. Dorff: Yeah, I think combinations are going to be crucial. We know with tumor heterogeneity, which is so predominant in prostate cancer, targeting 1 antigen has its limits. Rational combinations such as with immunotherapy to engage the immune system to maybe access what’s not being accessed by a PSMA-targeted agent, that and other combinations will be really exciting.

Dr. Morris: I should say that there is another registration trial that is fully accrued in terms of Pluvicto, which is PSMAddition. I think that we’d all be interested in seeing in the castration-sensitive space what the potential is, and there, what Rana was saying in terms of do we need so much treatment in that patient population, I think that that will help answer that question.

It sounds to me like there’s a lot of work that everyone’s looking forward to in terms of both the optimization side of the coin and figuring out the resistance side of the coin. Being able to then choose your regimen for an individual patient most likely to benefit from that regimen is really what we have to look forward to. I think there should be a very exciting set of years coming up. There are a lot of really good trials just on the verge of opening in 2024 that will be really exciting, and I think will expand the repertoire for our patients for an active therapy that ultimately, I think, will be to the patients’ benefit, give them new treatment options to live longer and live better, which I think is what we all want for them, and why we all do the work that we do.

With that, I’d like to thank you all for your time for this really interesting discussion on radioligand therapy and thank the audience for your time and for your attention.