Limitations of Lutetium-177-PSMA & Addressing Treatment Challenges

This interview is part five of a roundtable led by Dr. Daniel George, Professor of Medicine, and Surgery in the Duke Cancer Institute, featuring Dr. Oliver Sartor, Medical Director of the Tulane Cancer Center; Dr. Preston C. Sprenkle, urologic surgeon and a urologic oncologist at Yale University; and Dr. Rana McKay, GU medical oncologist at the University of California-San Diego.

Dr. Sartor and Dr. McKay discussed some limitations (and advantages) of lutetium-177-PSMA. The treatment, according to Dr. Sartor, induces positive responses in lymph node metastasis but is less effective at treating large liver lesions and lesions with less PSMA uptake.

Dr. Daniel George:

This is now looking at beyond PSMA. Now let’s think about potentially some of the mechanisms of resistance that might be underlying some of the variations in response that we might see to treatment with lutetium-177-PSMA.

Oliver, why don’t I start with you first? What are some of the limitations of Lutetium-177 PSMA? Because as this rolls out into the community, we’re going to treat patients and we’re going to see some responders, but there are going to be some non-responders and some limited responses in patients. And that’s just a fact of any therapy, as you stated earlier.

Give me your overview thoughts on what might be driving some of the refractory biology and nature in these patients, and what might we be thinking and looking for in patients who are at risk for non-responsiveness?

Dr. Oliver Sartor:

Yeah, great question. We’re still working through this, of course. It’s all still pretty new. One thing is, I’ve created in my own mind what I call a hierarchy of badness. At the bad end of the bad are the liver mets, typically large liver mets. And I can pretty much say across the board, large liver mets are bad news. But we just didn’t see a lot of good activity in large liver mets. On the other hand, for lymph nodes we saw some really dramatic responses. Some lymph nodes that were quite large could shrink all the way back down to normal.

If you actually look at the CR/PR rate; remember these are highly refractory patients, the CRs were about 9%, PRs are about 42%. So CR/PR, by RECIST criteria was actually over 50%. It was about 51%. I think it’s extraordinarily high. If you compare that to things like Abiraterone or Cabazitaxel in this refractory patient population, it’s down below 20%. So it’s a big response rate, but a lot of those are lymph nodes.

One of the other things we talked about a little bit earlier was the heterogeneity of the patients. Well, yes, the patients are heterogeneous, but also even the lesions within a patient have heterogeneity as well. Some lesions have a lot of PSMA uptake, and some don’t. And you can actually sort of go lesion by lesion and sort of predict the response. These high PSMA uptake lesions are the ones that are going to respond pretty well. And the ones that are lower are typically not going to do so well. And then I’m going to venture off into different lands.

We didn’t really evaluate things like FDG PET in the VISION trial. But the Australians have shown us that FDG uptake is poor prognosis and they quoted the TheraP trial, which had both Cabazitaxel and the PSMA Lutetium in it. It doesn’t matter what you’re being treated with. You got a lot of FDG uptake? That’s a bad sign. Those are very aggressive tumors. And then as we speculate more, talk about the underlying genomics, what about P-53 mutations? What about B mutations? What about things like prior treatment or DNA damaging agents like platinum? There’s so much to explore here.

I’ll simply say today there is a hierarchy and the liver lesions are the ones that seem to be the most difficult. And the ones that have a lot of PSMA uptake seem to respond best and perhaps that’s intuitively obvious, but that’s sort of where I am now in my own understanding.

Dr. George:

Good, great advice. Great insights on this and Rena, what, what are your thoughts on this?

Dr. Rana McKay:

I would agree. I think it also comes back to the molecular underpinnings of what’s happening as tumors evolve during the CRPC course under the various selective pressures of treatment and thinking about lineage plasticity with the emergence of sort of a neuroendocrine phenotype that we’re beginning to see in like 15 to 20% of patients with advanced disease.

You would hypothesize that those patients are probably not going to respond to therapy and probably have tumors that express little PSMA. There’s also this emergence of what’s been coined sort of this double hit of neuroendocrine negative, AR negative molecular phenotype with prostate cancer and suspect that those patients may not necessarily be responsive.

I think thinking about strategies to overcome resistance, it’s strategies, where, how can we actually induce PSMA expression potentially? Thinking of combining it with another agent where you can actually modulate the PSMA expression and what’s the best timing? Especially as, we’re going to talk about this a little bit later, but as we move into the hormone sensitive setting where people are getting ADT. Where things are treated, where you may be modulating down PSMA expression, how does that modulation affect response and resistance?

So I think there’s a lot to learn in the genomics for both PSMA avid, PSMA non-avid, and FDG avid and actually looking at the molecular signatures of each of those three imaging clinical phenotypes would be really cool.

Dr. George:

Really cool. Absolutely. There’s one other factor for us to consider in this, and that is sort of volume of disease. Size of tumors and volume of disease. Because we see this time and again that the higher volume tumors are harder to treat. And this is radiation therapy at the end of the day. We would anticipate that these larger volume, higher, bigger volume sized individual lesions would be harder to treat than some of the smaller lesions. Any data from that Oliver from the VISION side, you’re aware of?

Dr. Sartor:

I can’t recall data from VISION, but then I agree with you. And I think it’s related to the heterogeneity, the molecular heterogeneity. As these tumors expand, there’s just more possibilities that they’ll not reflect the original lineage. We talk about truncal aberrations and then the branches and then the leaves. And as you expand that tumor size, you’re talking about the opportunity for tumors to be derived further away from their truncal origin, if you will.

I like the way Rena talked about it in the plasticity. We’re using this incredible selective pressures when we’re applying things like ADT, Abiraterone, Enzalutamide, taxanes. And remember these patients were exposed to all those previously. Just imagine how the tumor begins in the body, when it may have been initially found in the prostate and what it ends up when we’re actually treating with PSMA Lutetium and all the therapies that exert that selective pressure and the mutations that arise and the resistance patterns that arise.

I mean, I’m pretty amazed that it turned out to be a positive trial in these patients who were so heavily pretreated. Because this is not your grandfather’s prostate cancer. This is like a whole new prostate cancer. Rena mentioned importantly, about these different patterns, these neuroendocrine patients that are emerging, but we used to see those kind of once in a blue moon. Now I see them all the time.

I think what we’re doing is we’re treating that traditional adenocarcinoma, that traditional AR dependency. We’re wiping out those cells. But the cells that emerge later, oh boy, those are the tough ones. We’ve got our work cut out of us in order to show further improvements. It’s not just going to be hitting AR harder. Now we got to understand new pathways, new resistance patterns, and apply new technologies to be able to overcome that resistance. So it’s a challenge today.

Dr. George:

Absolutely. A lot to learn. And I do feel like we’re still at the beginning stages of this journey and VISION was really just the first step. I think there’ll be a lot more. And that really leads us to our last section, which is, I think the current landscape of treatments with PSMA. And we’ll talk about that next.

Watch part six of the roundtable segment to learn about additional PSMA-targeting agents currently being assessed.

In additional segments, the panel discusses an overview of lutetium-177-PSMA and the VISION study, PSMA PET scans, palliative benefits of lutetium-177-PSMA, and if lutetium-177 is perfect.