The Uromigos Episode 114: Radionuclides Therapy in Prostate Cancer

Chris Sweeney and Silke Gillessen give their opinion of recent data.

Episode Transcript

Tom:
Hey, everybody. This is the second in our post ASCO prostate cancer series, and we’re talking about the vision trial. I’m joined with Silke Gillison and Chris Sweeney, and of course, Brian. Silke and Chris are going to do most of the talking.

Chris, do you want to kick off? So, the study was presented as a plenary session at ASCO. It was a radio nucleotide trial. We’ve had Radium 223 before. Should we talk about the vision trial to start with, and then Silke, I might come and ask you about what it means in the wider radio nucleotide space?

Chris Sweeney:
So, radio nucleotides are with prostate cancer, and it’s not that new because we do, as you pointed out, have radium, which targets where calcium goes, because radium is in the same part of the periodic table and emits some radiation in bony metastases. Survival benefit, there.

So, radio nucleotides are not new to the prostate cancer field, and it is definitely a standard therapy for patients who have bone disease without soft tissue disease or have similarity or two of blood disease. So, lutetium PSMA is patients who have PSMA expressing disease, and the tissue is bound to a protein that identifies and binds to PSMA expressing prostate cancer cells.

There are other cells that express PSMA like the parotid gland and some of the liver, and angiogenic vessels, but it is prostate-specific membrane antigen PSMA. Having said that it is actually folic hydrolase so it’s actually not prostate-specific really at all.

So, this study was in patients who had, had most of their therapy. They’d had either a hormone or docetaxel or not docetaxel-eligible really and could have had docetaxel. And it was lutetium PSMA plus standard of care versus standard of care. And there was a significant improvement in radiographic progression-free survival and overall survival.

I’m just going to pause and say, the first thing I want to say is that there was the Australian study that compared the same drug and pretty much the same patient population but compared it with cabazitaxel. There was a PFS benefit there that the study was randomized phase two and not powerful enough for survival. So even up against a standard of cabazitaxel, a true standard of care, cabazitaxel the drug looked relatively good. They were very specific in the ANZUP study in who got on the study.

They had to be FDG negative, basically appear suddenly PET positive. So, excluding patients who had disease not likely to be targeted and benefit from the radionuclide targeting the PS… If there wasn’t enough PSMA.

Silke Gillison:
Chris, can I jump in for maybe for [crosstalk 00:03:12] Ryan and Tom. That was interesting because I talked to Michael Hoffman and he said he lost 30% about his patients just based on the PSMA PET CT, whereas in the vision trial, the one that we’re talking about now, it was only about 15% of the patients who couldn’t go into the trial based on PSMA characteristic, PET CT characteristics. I think that’s pretty interesting. So, there was already a difference in the selection of patients who were considered …

Brian:
Why would that be, Silke?

Silke Gillison:
Because Michael Hoffman was very strict. He wanted a certain [inaudible 00:03:55] and as Chris already mentioned, he did also the FDG PET to exclude patients who were glucose positive and PSMA negative, and that wasn’t on in division find.

Brian:
Got it.

Chris Sweeney:
And the reason for that… There are two things I think we need to talk about… The PSMA pet as a companion diagnostic, or should it be? And the FDA looked at it and they said, okay, we can’t get everyone to have a PSMA and an FDG PET for this study, so they said, if you had some PSMA PAT positivity and not too much non-discordant PSMA PET negative disease, you can go on. So obviously that’s about that 15% delta between the two studies.

So, there are two things I have issues with that we should talk about. The term standard, I have a huge issue with that. So, the standard of care where basically all the agents in the exclusion criteria, rating cabazitaxel, docetaxel. Most of the patients who got this were either abiraterone and after enzalutamide, or enzalutamide after abiraterone, or maybe they got dexamethasone because they’ve explored all options.

So, it was a minimally active control. And the reason for that is because both arms got this newly active control and you couldn’t get doce or cabazi or radium with the lutetium piece.

Silke Gillison:
Question? Can I say something? So, so all the patients had one taxane as an inclusion? So, I think docetaxel is not the big issue here. It’s really [crosstalk 00:05:20] or radium, because I think from that standpoint, it was kind of clean because everyone had at least one taxane, or one [crosstalk 00:05:28]

Chris Sweeney:
Yeah, for sure. But the radium and cabazitaxel may not have been given. They were good standards of care which the patients didn’t get.

Silke Gillison:
Right. Exactly.

Brian:
So, expand on that further. So, in the radium, as I remember, it was the same sort of standard of care as the control [inaudible 00:05:50]

Chris Sweeney:
We didn’t. Absolutely. So.

Brian:
I know the drugs didn’t exist but…

Chris Sweeney:
Exactly. So, but let’s call it. I just say, I think the term standard of care is a misnomer because they’re not agents I would have chosen if I was trying to compare it with another patient.

Brian:
I guess the real question is, does it matter? Does it diminish your opinion of activity of the drug or how you use it?

Chris Sweeney:
No. The answer—the drug works, and that the drug was designed from a company that was trying to show the drug works to get it approved. Let’s actually call it what it is. It’s not a standard of care. It was designed to show activity. The other thing is we know the drug works, it’s just doing a study to show it works.

The number of patients in the dropout speaks to the fact, and another bugbear of mine, is there was so much press around lutetium PSMA because all the reports were emphasizing, overemphasizing, the extreme responders. Then they would go and see the nuclear imbed people, and they had such a huge dropout because there was such a true believing in the data.

So, in the … was told it was going to work, but people didn’t want to go on the study, and they dropped out. They had to fix it out.

So, it speaks to the background of what went into this lutetium PSMA is another chess piece on the chess board. It’s great. Let’s put it in context. It didn’t cure patients. It’s a good therapy, like all the other therapies. It just didn’t replace anything. It’s another chess piece on the chess board. We just need to put it in context.

Brian:
Got it.

Silke Gillison:
Yeah. But I would also say to be, to be fair, I think, yes standard of care, I guess that’s not the right expression, but you also saw that even after the study in the so-called standard of care arm, you saw that only about, I forgot, 18 or 20% of the patients received chemotherapy, so maybe some of them are not eligible for chemotherapy and they were eligible for the PSMA PET and lutetium …

Chris Sweeney:
For sure. Absolutely. And these were patients who were chemo fit when they went on the… Were trial fit to go on. Absolutely. Call it what it is though. [crosstalk 00:07:59]

Tom:
I guess from a global perspective, some countries may or may not have access to second-line cabazitaxel and …

Chris Sweeney:
I think nearly everyone has cabazitaxel, but not everyone’s chemo fit. [crosstalk 00:08:12] Radium is a bit of a mixed story as to its availability.

Tom:
We’re going to come for him in a second… I guess Brian and I have done lots of sunitinib trials. In fact, I think the last one’s closed now, but only relatively recently. I think what we tend to do under those circumstances is we compare all the trials that used an imperfect control arm almost against each other, which allows us to make indirect comparisons of axi pembro, cada nivo. [crosstalk 00:08:37] So I think I’d go back and say there’s some activity and in context. The question I’ve got. Yeah. Sorry.

Silke Gillison:
Sorry. I just wanted to say I think that’s very interesting because I looked at that for a publication right now, and it’s really interesting if you look at PROfound and [inaudible 00:09:00] and this lutetium PSMA vision trial now. So, I think the benefit is really very similar and also, actually they ones in the control arms are really very similar.

So, I think this is kind of reassuring that probably really gets the benefit of all of these drugs, and that we have now a new drug that will be approved hopefully soon. So, I think I’m pretty positive, and I totally agree with Chris that standard of care is probably not the right expression, but I think it doesn’t take away from the activity, and also the tolerability of the drug.

Chris Sweeney:
And absolutely, and don’t forget the Australian study did compare with cabazitaxel and there was evidence there. Can we turn the conversation to, should the PSMA PET be a companion diagnostic?

Tom:
We can do that.

Chris Sweeney:
So, I’m going to propose, you could go Mary-Ellen Taplin’s approach. Don’t worry about it because most patients who went in, where they get on and most patients will probably get a benefit. Maybe the treatment effect would go down, maybe not like the 0.6, more like 0.75, in non-selected manner, or would you actually get, if you had a much better, and developed it as a companion diagnostic, had the right cut point for the right amount of disease would the treatment effect be higher?

So, I’m going to ask, do you think we should develop a better cut point… Define the best cut point with PSMA PET to work at, to maximize efficacy and minimize futility?

So, I have to say, the only patients that I’m really concerned about are all the patients with the liver metastasis, because there are liver metastases that have a high [inaudible 00:10:52] in the PSMA PET CT, and they seem to respond pretty well. And then you have these liver metastases that are negative in the PSMA PET scan or low PSMA. So, for these patients, I personally, would prefer to give chemotherapy. So, I have to say I am specifically concerned about the liver meds to be honest.

Tom:
Let me tell you, I think Chris. So, I think that …

Chris Sweeney:
Come tell me what you think.

Tom:
So, I think by widening the net and ignoring the biomarker is a mistake in broad terms in cancer medicine.

Brian:
We agree.

Tom:
And so, I think, and it’s not always, I think drug development has not always focused on biomarkers correctly, but if you’ve gone down this route and then you ignore it, because the data is pretty good, and you broaden that net in an uncertain population I just think that’s the wrong direction in which we should go in. So, I would just [crosstalk 00:11:48]

Silke Gillison:
I would maybe try to challenge that even if that’s difficult, if you said that, but it’s a PSMA PET CT, right? So, there is some data from your, or they know, that maybe the PSMA excretion really, if you look in tissue, would be higher. So, there is a question. It’s not a biomarker where you looked in the tissue like most of your biomarkers, or in DNA and whatever, but it’s just a bit ruder, right? It’s maybe not as …

Brian:
You can just do a small study in 30 patients who are PSMA PET negative of the agent. Right? And just see if you have any activity, right? That’ll tell you.

Chris Sweeney:
That’s. Yeah, but actually let’s go… I’m going to put my conspiracy hat on. Conspiracy theory hat on. So, these decisions are made …

Tom:
I’m keen to avoid that if possible.

Chris Sweeney:
So that you’re interested to hear, aren’t you? So, these decisions are made by people who are in the business unit, the medical team saying, okay, what’s our market share if we go with a PSMA-specific group versus a little bit more of a looser criteria.

Then there’s the conversation with the FDA. What’s the overall patient benefit? So, there are many factors that go into these decisions, but I’m with you, Tom. I would like a bit of a purist to actually define the most top point.

Tom:
Yeah, let me try and take that differently, Silke. It sounds like you think you’ve all got completely the wrong biomarker, and therefore I agree completely. If you’ve got completely the wrong bio marker, let’s start again and find the right biomarker. [crosstalk 00:13:25]

Silke Gillison:
It seemed to work in all the trials so it’s not the wrong biomarker. We just don’t know. It’s a little bit like the story from breast cancer, right? So, the low estrogen receptor, does that really mean that someone doesn’t respond to hormone [crosstalk 00:13:46]

Brian:
It’s an imperfect biomarker. That’s what they all are.

Silke Gillison:
If it’s imperfect, it’s not the wrong one, but it may be not perfect because you have …

Tom:
So, let’s pursue it and get it right then. Let’s pursue it and get it right. [crosstalk 00:13:51]

Chris Sweeney:
Tom, what did I say at the very beginning? Define the best cut point.

Tom:
And I support that approach.

Speaker 5:
Can we lock this day down? Tom and Chris agreed?

Brian:
Are there are studies going on, looking at that, looking at different cut points, looking at negative patients. I mean that’s the way …

Tom:
No. I don’t think… I’m not aware of that, Brian. What is actually happening is a whole host of new agents, a whole bunch of new radio-like meds had been developed with different antibodies to target, and different actinium and thorium and the other ones, so there’s going to be a whole wave of these.

Which one’s going to be better? I don’t know, but there’s a whole host being developed in different situations that can be worked on.

Silke Gillison:
Brian, we could go in, if there is interest, division studies are there and you could go and look at who has a high [inaudible 00:14:44] versus low whatever cut-off you are using, 20 or whatever. So, the data would be there. Right? That’s the question. [crosstalk 00:14:53] I think that would be a great idea.

Brian:
The patients who were below wouldn’t have made it down, right? The patients wouldn’t have …

Silke Gillison:
Yeah, exactly.

Chris Sweeney:
And so, I, I’m just going to say we, as investigators have to push for this, and if we’re on steering committees, we actually have to be a little bit more vocal on these things. This whole, which patients should get a PARP inhibitor, and the developers have elaborated they’ve got this slew of potential mutations that may benefit, but it’s really driven by mostly by BRCA1 and BRCA2, and all the other is, if at best, iffy data.

Tom:
That sounds like a podcast for a different day Chris.

Chris Sweeney:
It is. But I’m calling out the topic that we, as the investigators, need to actually push for more rigorous biomarker development.

Brian:
Yeah, I agree. We agree. So, I don’t know if we’re going to move onto radium, but I guess the question at the end of the day is, assume it’s approved. Assume you can get PSMA PETS whenever and wherever you want. How are you going to use this chess piece? Chris, you can start. How and when, I guess, is really the question. When in the course of CRPC?

Chris Sweeney:
I think my goal is to get as many therapies in as possible. Get the chemo fit, get the docetaxel, and the cabazitaxel in its own stage. If they’ve got a BRCA mutation worker, get the profile again, see if they’re a PARP inhibitor candidate. I actually probably would use it prior. It depends on what the label comes out as, but I’m hopeful. It’s a little bit broad and we could use it …

Brian:
Yeah. Assume it’s [crosstalk 00:16:20] then you can use it wherever you want.

Chris Sweeney:
I would probably use it before chemotherapy in patients who has cleared PSMA PET positivity. A profile is less an activity as good, if not better, if you got the right cut point.

Brian:
Yeah. Yeah. Silke? How about you?

Silke Gillison:
So, I have to say we had it available as expanded access, and before that we could send patients to Germany. I have to do the same thing. We did it after one novel and a docent agent, one chemo at least. That’s how it was done here. And then most patients said before they do a second chemo, they want to do that PSMA PET for lutetium. And I guess that’s a reasonable approach, except again, in maybe some patients who have a hyper scan, they were excluded in the division trial.

I think this is very important because then otherwise you get probably a lot of myelotoxicity. And that’s what other nuclear medicine people would say. And again, as I said, the patients were delivered meds that don’t have really low PSMA expression, so there I would be careful.

Chris Sweeney:
And just to also be very clear, I have not seen anything to suggest that patients cannot tolerate cabazitaxel because of potential bone marrow toxicity after they’ve had any of the radionuclide.

Tom:
What’s the future of radium 223 Chris?

Chris Sweeney:
Sorry?

Tom:
What’s the future of radium 223?

Chris Sweeney:
I reckon radium 223 is challenged by the fact that PSA doesn’t go down in most patients, and they may actually have some soft tissue progression on therapy and it’s really hard to keep the patient on after the six doses, where there is the benefit if the PSA is going up. So, you grit your teeth. You grip it and rip it actually.

Brian:
So, you think it’ll be replaced largely then?

Chris Sweeney:
I think so, because it’s just easier and less stress because everyone wants to see the PSA go down.

Brian:
Yeah.

Chris Sweeney:
And the Lutetium PSMA does that.

Tom:
I think we’re going to call it. Sweet. Any more questions, Brian?

Brian:
No, it was a good discussion. Good discussion.

Tom:
Thank you both very much. Indeed. Going to see you all soon.