Barriers to the Use of Radioligands and Navigating Patients Through Multi-Disciplinary Care

In a roundtable moderated by Tanya Dorff, MD, of City of Hope, panelists Michael Morris, MD, of Memorial Sloan Kettering Cancer Center; Benjamin Garmezy, MD, of Sarah Cannon Research Institute; and Yu-Wei Chen, MD, MS, of the University of California, San Diego discuss new treatments and therapy considerations in the field of castration-resistant prostate cancer.

In the fourth part of this series, the panelists discuss barriers to the use of radium-223 and other radioligands, including navigation through multi-disciplinary care.

Watch the final segment of this series: Discussing Novel Radiopharmaceuticals in Development for CRPC

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Dr. Dorff:
Are there barriers to use of radium-223, I think one of you alluded to it, and other radioligands? Do you find that there’s a challenge in getting patients navigated through that multidisciplinary care?

Dr. Chen:
Yeah, so I think thanks for bringing up radium-223. I think nowadays people come to the clinic and many of them actually ask about lutetium, and it’s not surprisingly, and even in localized disease, have experience with patient come asking for lutetium. I’m really curious about what is the best sequencing strategies we are going to apply the PEACE-3 data nowadays? Are we going to do followed by lutetium or are we going to use that before lutetium? I think this is still an unanswered questions, and we still need data to get treatment sequencing here.

Dr. Dorff:
Yeah, I think sequencing is challenging. There are data from the RALU study showing that you can give lutetium after radium, but how about from your perspective?

Dr. Garmezy:
Yeah, I’ll say two things on that comment. So one on the RALU study, I just want to put a little bit of hesitancy out there. It’s this early-phase study, but is it safe to give while you’re collecting data on that study? What we don’t really know is the three-year safety events when we’re using radioligand monotherapy as well as radioligand back on radioligand. So I do think some of the conversation we had earlier about cytopenias and things like that, we just need to keep in mind that we really need to think about long-term safety when it comes to some of the use of these drugs, which is a little bit different than perhaps some of the other drugs we give in prostate cancer.

Then the second thing is the access concerns. I mean, most oncology practices now have radiation oncologists that can be authorized users to give these drugs, but smaller clinics don’t necessarily have radiation oncology. So it takes sending a patient from your practice to another practice in order to get access to that drug. So I think that is potentially a small barrier here that’s going to be real in both the urology community that is providing early prostate cancer therapy as well as in the medical oncology community that don’t have radiation oncologists on site.

Then the final piece of that is there are some cost-benefit analysis concerns as we start to move more towards some of these governmental programs that have some of these drugs under a little bit more scrutiny than other drugs. I think we’ll see how the political landscape unfolds over that. But for now I think it’s more of a, do you have it in your practice or not? And then if you don’t, is it exciting enough to refer out to? Because patients aren’t necessarily demanding it the way they’re demanding lutetium.

Dr. Morris:
Two thoughts just to sort of complement what was just said. First, in terms of the sequencing, we need to remember that all radiopharmaceuticals are not equal. Radium has a much more favorable hematologic profile than lutetium does and a completely different target. It’s hydroxyapatite and not the tumor. So it’s much gentler on the marrow than lutetium is. So I wouldn’t see that, for example, an alpha PSMA-directed therapy, be it a small molecule or even more relevant for the hem-tox potential, an antibody is comparable to sequencing with an alpha that’s a bone-seeking radiopharmaceutical followed by lutetium for both of those circumstances. So I think that the data needs to be collected, but sequencing is not class-specific, it’s drug-specific, target-specific within a drug and then the size of the targeting molecule and the payload. It’s going to be complicated, and we’re going to have to work our way through it.

In terms of the practice patterns, it’s incredibly rewarding and professionally enriching to develop those relationships with nuclear medicine and work together on these drugs, both in terms of development and taking care of the patients. We have a lot to learn. Every day I learn from those folks and to not engage in those relationships is truly reprehensible and not to release the patients because you are not in a position to have those relationships is also truly reprehensible. So A, we all need to learn how to develop those relationships, play with each other in the sandbox and recognize that patient care is that much more rewarding for everybody if we can do that. For those who live in communities where those relationships just cannot be made, then you have to release the patient to-

Dr. Garmezy:
Absolutely.

Dr. Morris:
Somewhere. That’s just not ethical not to do that.

Dr. Dorff:
But I think we are not releasing them. It’s still so important that we see them-

Dr. Morris:
Yep. Right.

Dr. Dorff:
Just as we would between chemotherapy cycles and provide input as to whether we think it’s beneficial, whether we should delay a dose, those types of things.

Dr. Morris:
Sure. It just depends on what role you take. If I’m going to send a patient to radiation oncology for their primary therapy, I think of them as the captain of the ship. I’m there as an oarsman and with enough comfort level between the two disciplines, I can certainly relinquish the captaincy of that ship to nuclear medicine provided that nuclear medicine has the skills and takes ownership of a lot of those issues for the advanced patient. That’s up to you to do that education. If you want that collaboration, you have to invest in the relationship. My patients while they’re on lutetium, I do see myself now as an oarsman as opposed to necessarily the captain or we co-captain.

Dr. Dorff:
Yeah, that’s an interesting perspective. It’s so complicated, the sequencing and to throw another layer of complication in, there are combination trials now with radiopharmaceuticals. I think UCSD has taken the lead on one. Any combinations that you predict might be most interesting, whether it’s with immune checkpoint inhibitors or PARP inhibitors or something else?

Dr. Chen:
Yeah, I saw a poster presentation at ASCO combining the radioligand therapy, actinium, as a one dose. I think this study was led by the Cornell group. It was one priming dose of actinium, and the rationale behind that is trying to increase the neoantigen and then followed by using the pembrolizumab immune checkpoint inhibitors in traditionally within the prostate cancer doesn’t really work. But I think that data, we see PSA response in their presentation, which is very novel idea and mechanism and rationale.

Dr. Dorff:
Yeah, and we have seen PRINCE using lutetium followed by immune checkpoint inhibitor as well, so there’s definitely interest. I think unfortunately the Phase 2 kind of trial designs just can’t really answer the question unless maybe we saw some tremendous signal.

Dr. Garmezy:
I’m cautious about trying to go down the anti-PD-1 path with any combination partner in prostate given all of the failures in drug development. But it’s possible, and that’s why you got to do these studies and look for signals. I think in combination, when I think about how do we intensify patients to give a long runway where they’re feeling good, it’s in the hormone-sensitive setting. That’s the concept behind either SBRT to oligometastatic disease or docetaxel in high-volume disease to debulk the primary. So if you have less cells that can become resistant to hormonal therapy, then in theory you can hypothesize that that patient’s going to have a longer runway in that hormone-sensitive phase, which is kind of what we’ve seen.

How do we bring radioligands up where one, we may have less overall marrow issues in the future because there’s less disease that’s bringing radiation into the marrow, so it might be more effective there. We have a great study out of the Australian group giving two cycles and docetaxel looks very promising. Now whether or not that’s the right amount of drug or whether or not you need docetaxel, whether or not you can just get away with an ARPI, I think that’s interesting. I personally think using it early when there’s enough disease that it can be active but not too much disease to keep patients off of chemo perhaps and in the hormone-sensitive phase for longer, I think that’s probably where I’m most excited.

Dr. Dorff:
So more excited to move it early versus a novel combination. Interesting.

Dr. Morris:
I think the most impressive combination data that I’ve seen is Louise Emmett’s combination of enzalutamide and lutetium 177, because first of all, there’s such a compelling rationale for metastatic CRPC with down-regulated AR signaling and up-regulated PSMA. She has actually shown that with the serial PET scans that she did.

Second, the data themselves look really good. And third, she did an adaptive dosing schedule, which I think is really a future treatment paradigm. That study encompasses a lot of things that I like to see in combination studies, which is a biologically sound hypothesis, data that actually supports that hypothesis, and innovative dosing around the combination that perhaps wasn’t done in monotherapy studies that are registration trials and sort of a keep it simple precept.

For early disease, and I think we have to recognize now with both SPLASH and with PSMAfore, I have some concerns. We have now two Phase 3 trials, which we’ve moved earlier than VISION, which have not yielded a survival advantage. In large part there are a number of reasons that may account for that. One is our own designs. They had crossovers. Two, they are beta emitters and perhaps then we should look to alphas as we move earlier. Three, the eligibility criteria perhaps are not enriching as much as we should be for success to get an OS advantage. We’ll see what PSMA addition has to yield, but it also has a crossover, similar eligibility and also is using lutetium.

I might venture to say that before we go really early, we need to get some things sorted out to get the stage set for seeing an overall survival advantage. That may mean no crossovers, better enrichment and moving to alphas to really expect early therapy to yield a survival advantage. I would like to see that actually happen. There’s some prep work and thinking work that I think needs to be done in order to further leverage what is really active therapy to yield a survival advantage in earlier disease populations.

Dr. Dorff:
Yeah, there’s so much we don’t know.

Dr. Morris:
There’s a lot there.

Dr. Dorff:
Right? Dosing is an issue we just keep coming back to with these radiopharmaceuticals.