The Uromigos Episode 104: Plenary Session—177lu-PSMA-617 in Prostate Cancer

A practice-changing phase 3 plenary presentation reinforces that radionucleotides and PSMA-based therapeutics continue to make an impact in metastatic castration-resistant prostate cancer (mCRPC) and are likely to be a big part of the landscape in the future. View the ASCO abstract.

Episode Transcript

Tom:
Welcome everybody, we are joined today by, Mike Morris, from Memorial. Mike I’m going to ask you to introduce yourself in a second, congratulations on your plenary session. You are going to have to be very gentle cause Brian hasn’t had a plenary session yet, and he phoned me before. And he’s a bit touchy about it, to be honest. And so [inaudible 00:00:41] if there are some, if there are some catty questions, just ignore them and move on, just ignore them. [inaudible 00:00:48] Mike.

Mike Morris:
Will do. And thank you for inviting me, Brian and Tom. It’s a pleasure to be with you, as always.

Tom:
Listen, do you want to just talk a little bit about, where you are from or [inaudible 00:01:02] I’m sure you’ll run the prostate group and other bits and pieces, very successful, et cetera. Why was this work selected as a Vasco this year?

Mike Morris:
I think for two reasons, Tom. The first is, it’s a treatment that for drug patient population that just had very, very few treatment possibilities. That is the post-docetaxel, Cabazitaxel, treated patient populations.

So that of course is a new opportunity to prolong life in patients with few opportunities right now. And the second reason, I think is because it’s a new drug class for Prostate cancer. And so that’s significant in and of itself, with real clinical benefit, improving overall survival and RPFS. So, I think those two entrees into the disease are what sets it apart.

Tom:
Could you give, people another trial design, but could you just give us a really two second overview of obviously it is a big round of MySpace three, a bit of an overview of the trial design and some of the strengths, but also importantly, some of the weaknesses of the trial design.

Mike Morris:
Absolutely. So, first of all, a little bit about this drug. It is a small molecule that targets surface protein that’s called Prostate-specific Membrane Antigen or PSMA. PSMA has been around for a long time but has both a diagnostic and a therapeutic target. It’s been well credentialed, and it’s primarily expressed in Prostate cancer across all phases of the disease, as well as most Metastatic sites.

It’s in about 80% of the Prostate cancer population who have Metastatic CRPC. Carrying a payload of Lutetium-177, that’s a beta emitter, so the small molecule hauls that Lutetium around, it’s injected into the blood, circulates around, finds Metastatic disease by virtue of binding to PSMA and then the whole molecule is endocytosed into the prostate cancer cell, where then it is released.

The PSMA recycles to the surface where it can bind to another drug molecule and the radiation that is now internalized kills, that Prostate cancer cell and the Prostate cancer cells that are, around it as sort of a by-stander effect. [crosstalk 00:03:23] Yeah, go ahead.

Brian:
All right, Mike I was going to say, you’ve done a lot of work personally in your group with the Radio nucleotide. So, talk about how Lutetium is chosen, the dosing, how you get the dosing right and that sort of practical configurations.

Mike Morris:
So, you’re absolutely right, this has been a long endeavor for many of us in Prostate cancer been researching Radioligand therapies. And I think the first evidence that there is a systemic, but targeted former Radiation that’s beneficial, and Prostate cancer was probably from the bone seeking radio pharmaceuticals, notably Radium, which was the latest approval in that class.

But unlike the bone seeking radio pharmaceuticals, the tumor directed pharmaceuticals can pretty much kill disease wherever it’s located. It doesn’t have to be in bone, it can be in nodes, soft tissue, et cetera. So, that was a really big advance. The second big advance that led this to be a success was the development by Marty Pomper, primarily at a Hopkins, so the small molecules which get out of the body really quickly, to minimize the amount of circulating radio activity. The radio activity, it is used for this drug, it is a fixed dose of 200 milli curies.

It’s injected once every six weeks, you get a total of a max of six cycles. So, that’s 36 weeks of therapy. That’s what was used in the trial as well. But you essentially got four doses and then if you are responding still at some residual disease, you got another two doses.

It’s pretty easy to administer it to all outpatient therapy, takes about a half an hour of chair time, basically from room in to room out. And so, the trial itself used this regimen of 200 milli curies, given every six weeks for four increasable to six.

The randomization was basically that everybody got a physician’s selected standard of care. In order to be eligible, these patients were considered to be inappropriate candidates for further chemotherapy. They were randomized to two, to one for some non-chemotherapeutic standard of care, to receive Lutetium plus that standard versus the standard alone and the primary endpoints were OS and RPFS.

Tom:
What’s the commonest control arm?

Mike Morris:
So, let’s talk about that control arm for a minute. Clearly in a combination strategy, you have to have safety data on the combination, right? So, we don’t have safety data on the radio pharmaceuticals, plus Docetaxel or Cabazitaxel or Pembro or many other drugs.

So those combinable regimens for which we do not have safety data were excluded, but on the other hand, these patients were all post androgen receptor pathway inhibitors and post one to two, regimens of chemotherapy, and their clinicians needed to say that they weren’t chemotherapy candidates.

I think that had received the primary prolonging therapies, perhaps with the exception of Radium 223, in terms of, whether they were denied something by verge of having a non-chemotherapeutic standard of care. And if you look at the number of patients who got chemotherapy after the protocol, it was only about 20%.

It is not like that the control arm was denying them some magic bullet here that would give them a [crosstalk 00:07:10] significant life.

Brian:
So, what did they get?

Mike Morris:
The primary things that they got were other hormonal therapies. If they originally qualified by getting Abby, they got Ensa and vice versa. They got Glucocorticoids, they got palliative radiation therapy, the usual supportive measures that we do for this very, very late patient population.

Tom:
And Mike, with this control arm, with the uncertainty around it, what was the dropout rate in that control arm?

Mike Morris:
So, when the trial first opened, there was a significant problem in regard to the dropout rates. About 50% of the patients dropped out at randomization before any treatment went assigned to the control arm. So, this wasn’t a control arm intolerance or on acceptance issue, this was that the patients wanted to get Lutetium and their investigators were allowing them to be randomized without having even started a standard of care.

And before any treatment, those patients dropped out. This was a physician and an investigator issue more so; I would say than it was a patient issue. So, with re-education and with a lot of hooking up nuclear medicine physicians with medical oncologists to better manage the control arm in this advanced patient population, that dropout rate significantly dropped.

From initially 56%, before that cessation of accrual of re-education, reinforcing of the intent of the study to 16% in the control arm. I think that was probably a training issue and a collaboration issue. And an understanding that the trial has to involve multiple disciplines, it’s nuclear medicine, as well as medical oncology, because these patients have really advanced disease, and it involves systemic treatments that were beyond Lutetium and in order to participate the [crosstalk 00:09:13] trial on that standard care.

Tom:
So, from a global perspective, where did the trial enroll and did this dropout rate result in imbalances in the baseline characteristics?

Mike Morris:
This was a European as well as a U.S study. I haven’t looked at where most of those imbalances occurred. I certainly know from the U.S sites that there are a fair amount of those imbalances were here in the United States.

On the other hand, when you look at the post-protocol follow-up of these patients, very few of these patients received Lutetium by going to Europe in order to, where it is accessible, and very few of these patients also received post protocol Radium. So, I really do think this was an investigator issue more than anything else. And by addressing the investigators, the dropout rate went from 56 to 16%.

Brian:
So, Mike talk about the high-level results and if they exceeded your expectations or based on what you designed the study around.

Mike Morris:
Sure. So, there were two primary endpoints. One was OS cutting to the chase. The hazard ratio was 0.62 for OS. So, in other words, a 38% reduction in the risk of death in this late population, the standard of care arm lived less than a year at, at a median at 11 months.

And this, the addition of Lutetium increased their survival by an additional four months to a median of 15 months. So that four-month prolongation in OS is pretty typical for almost all con recent FDA approvals in advanced patients.

So, that’s not pricing. I think the relative benefit with a hazard ratio of 0.6 is quite good. If you think of what the improvement in the risk of death for, let’s say chemotherapy, right? That’s a 20 to 30% improvement in OS. So, this was a 40% improvement, basically, right?

If you look, look at RPFS, which of course is a measure of what’s happening in terms of disease control while on treatment, as opposed to OS which is on treatment and off treatment, or post-treatment. The median improvement in RPFS or time to radiographic progression or death was 60% with a hazard ratio of 0.4.

And the median improvement in the improvement in the median RPFS was five months. That is from 3.4 to 8.7 months with the addition of Lutetium to the Standard of care.

Brian:
Was there any evidence that you set these targets wherever PSMA has expressed, it’s not bone specific, like radium, any evidence of a differential effect among organs.

Mike Morris:
We don’t have the breakdown data yet, to actually look at a lot of things in relationship to what you’re touching on here. Is there a relationship between PSMA expression and response? Remember all of these patients had to be eligible by getting a PSMA scan, so we could see what the targeting was in various organs and see how that target impacted overall survival, so that whole analysis still has to occur.

I would say that it’s important to recognize that with PSMA screening study, only 13% of the patients were actually excluded from participation in the trial for PSMA negative disease. That’s quite a different approach than the previous PSMA-based Theranostics studies, for example, the Mike Hoffman’s therapy study.

The Australian approach has been to carefully select using a combination of PSMA and FDG imaging for patients most likely to respond. And I think this study shows you can be a lot looser with your entry criteria, to the extent that you’re actually only excluding just over 10% of the population at 13% while benefiting the majority of these patients. This trial was a lot more liberal in terms of its acceptance. Yeah, go ahead.

Tom:
What shows there were subgroups that benefit, and what are the biomarker development plans around this?

Mike Morris:
So, to take the forest plot issue up first, it did not show that there were really any pre stratified subsets of patients that surprisingly either responded extraordinarily well or extraordinarily poorly. There were a few items on the forest plots, especially in terms of racial breakdowns of patients, where we get into just a handful of patients in which the forest plot did cross 1, but basically all anticipated subgroups that were the Strat factors for the trial looked like they benefited from therapy.

In terms of biomarkers and most important biomarker, I think both in terms of a therapeutic approach and the utilization of social resources approach, is this relationship between imaging and therapy. So doing PSMA, pet scans and everyone who qualifies for this type of therapy is a major investment on society’s part.

We need to understand better if we can use those scans to their best effect, to really identify the treatment, that the population will benefit. And also, with Echo Pause, you need to see whether those scans are actually contributing significantly into, patient selection, before they receive the therapy, especially as this therapy moves earlier in the disease spectrum.

Brian:
Mike, what about toxicity? What did you see in terms of toxicity?

Mike Morris:
So, the major thing that we are concerned about with all PSMA radioactive radioligand therapy is Xerostomia because these molecules do insinuate themselves into both the lacrimal and the salivary glands. And in the past Xerostomia has been an issue. So, in this trial Xerostomia occurred in 39% of the patients that was all grade tox, no high-grade Xerostomia was seen.

There’s also in around 40% of the population, nausea and vomiting, all grade that’s controllable with premeds about 1.5% of the patients had high grade nausea and vomiting. And again, that’s an infusion related issue, not a long-term toxicity and then there’s marrow suppression.

So, in terms of high grade tox 13% of the patient population had anemia and then 8% had high grade Thrombocytopenia. And again, no new signal here, all of these issues are present with radioligand therapy. And I would say that, if you look at how many patients actually couldn’t complete treatment as a result of toxicity or some minority of patients, and most of these patients received all the full six doses that were intended.

Tom:
Mike talked about durability. So, one of the issues I guess, will be that you are treating patients towards the end of their lives in its current setting.

Mike Morris:
Yeah.

Tom:
And by shifting median survival by four months is a massive step. But for many people, their ambition will probably greater than that. Was there any evidence of long-term durability? And is there an issue of re-challenge with the same drug if patients were the first time?

Mike Morris:
Good question. So, I think that the re-challenge question will need to come from a separate trial, where we approach that question with long term safety data with further administration, but certainly don’t know that the FDA will approach this. Like it did with radium, you have safety data on six doses. And so, six doses is what you’ll get in terms of long-term duration of effect.

Of course, this is a patient population that is prostate cancer, with most prostate cancer trials, the median really underrepresents the true experience of the majority of patients because the median actually just describing the middle patient. And the reality is in that prostate cancer, you get long term responders to almost any therapy and then some group of responders that either don’t respond or respond very, very briefly.

Certainly, Mike Hoffman had shown that in his studies. And so even in these very advanced populations, you do get patients who really respond [crosstalk 00:18:03].

Tom:
What are the characteristics of those patients?

Mike Morris:
Certainly, we would love to know that wouldn’t we? That’s the biomarker question. Can we pre-identify those patients ahead of time? Is that a question of just their disease, biology and genomics, for example, we all speculate that the DNA repair deficient patient population would be particularly responsive to this type of therapy, or is that an issue of dosimetry?

That is how much radiation gets into the tumor and that correlates with the duration of response or is that there’s some other feature such as distribution of disease, for example, is that a virtue of having primarily bony disease versus bone and liver disease versus liver disease alone, all these questions you going to have to get teased apart over the next several years. So, we can best optimize the marriage here of patient population with treatment. [crosstalk 00:18:54]

Tom:
And Mike, the moment we don’t know if, for example, the DDR or the Olaparib treated population is doing particularly best or worse, that was, or wasn’t in the forest plot.

Mike Morris:
That was not in the forest plot. This trial, its inception was [Preap 00:19:09] and [cap 00:19:09] approval.

Brian:
And Mike, I have one sort of big picture question with some sub parts left. I’d sure. Just like to note, I haven’t asked a single caddy question during this [inaudible 00:19:17].

Mike Morris:
No, not at all in fact.

Brian:
Thank you.

Tom:
We, chatted about it beforehand. Like very so [crosstalk 00:19:24], sort of the obvious, where’s it going from here? Where does it fit in? And there’s sort of maybe two sub parts to that. One is, is other standard of care therapy needed or can it be standalone?

Brian:
And then the second part is you mentioned radium before, which is an alpha admitting radio nucleotide. Is there any reason that you can or should use those in combination or is that they are just really distinct and separate?

Mike Morris:
So, for that latter question, the role that radium will play in the future, I think is something that we’re going to have to sort of see where it fits into the armamentarium and how it’s going to be used. Having a tumor directed radioligand therapy that makes PSA go down and that makes scans clear is a pretty reaffirming thing to both patients and to clinicians and radium doesn’t really have those features, plus a radioligand therapy that can go to nodal disease, circulating disease and soft tissue disease, also offers advantages.

So, I do see radium having probably a more significant Lutetium PSMA, having a more significant role, both in terms of patient and clinician satisfaction and as well overall biologic advantages that radium doesn’t have. So, I do see it displacing radium to some degree and leaving a question of where radium will stand.

Radium certainly has an excellent safety profile, and there’s no reason why these can’t be sequenced where a patient could get radium up front or radium following. And I think that that is a really good question as to sort of what’s going to be the safety of that.

Brian:
And standard of care needed. I mean, it was sort of a trial design issue, but.

Mike Morris:
So, think about how we have deployed radium and also what standard of care means. Right? So, because the [EMCA 00:21:12] trial also was standard of care plus or minus radium, and that’s been interpreted really quite loosely. So sometimes patient’s standard of care is just opiates, palliative, RT, and glucocorticoids, right?

Which is basically supportive care for symptomatology. Sometimes standard of care could be other therapeutics that you have in your armamentarium. And the standard of care on this trial was much the same. It was the best management of the medical Oncologist for the patient’s own individual situation.

So, I think that the same degree of latitude will apply after we hope the FDA approves this, which allows the doctor to be the best doctor that he or she can be in order to treat the patient. What you decide standard of care should be, will really be an entirely up to them as long as it stays within a safely combinable regimen. That’s the key.

Tom:
Mike radium, wasn’t taken up in the same way as perhaps [aberration 00:22:15] or other agents in this setting.

Mike Morris:
Yeah.

Tom:
The data set’s different. It’s a different approach, but in broad terms, there are many parallels. Why is this going to have a similar impact or was it going to be larger? And if, why would that be the case?

Mike Morris:
I don’t think that this is the same as radium from a patient or clinician adoption standpoint. Remember that one of the reasons that we had such a high dropout rate initially is because there really is a huge amount of patient enthusiasm for this, patients want to see their scans improve. If not clear, patients want to see that their PSA goes to no measurable amount clinicians do as well.

I’m not separating those interests, they do dovetail. And so, I think you’re already seeing a lot of patients who can’t afford it already going to Germany, going to Australia to get treated. They’re voting with their feet on this, even preapproval, right? They’re establishing a market need for this already. So, I think there’ll be widespread adoption.

Tom:
Let’s assume it gets FDA approved. Where does this fit into your treatment paradigm? Just talk about, let’s say we’ve got a typical patient with metastatic prostate cancer. Just talk about where this fits in. What are you giving first line? When is this incorporated into the pathway? Assuming you have unlimited resource and it’s approved.

Mike Morris:
If you look at most patients who are newly diagnosed with prostate cancer, now they’re going to get ADT and an RSI or docetaxel. So, they’re, going to come into metastatic disease. Having already been exposed to if not refractory to those agents for most of my patients, they are getting either a [za 00:24:04] or APA as opposed to dosing. And so, when they come into metastatic CRPC, then they’re going to get docetaxel.

So, this agent would be typically the one that might follow that. I do think that the DDR population is a special one because they do have drugs that are specifically approved for them for, so for them it will probably be ADT and a RSI followed by a PARP inhibitor, followed by Doci, followed by R RLT.

Brian:
Am I given that many men with advanced prostate cancer don’t want chemotherapy? And I recognize this would be off-label. And outside of your data set, would you give it prior to chemotherapy? Is that reasonable or unreasonable?

Mike Morris:
There is a study that’s now actively accruing looking at lutetium PSMA in the pre chemotherapy population.

Brian:
Yeah.

Mike Morris:
I think that trial will accrue quickly and will have those data, you know, relatively quickly in order to answer that question, but until I certainly see a role for it, but there’s no data around it until that trial is completed. And my practice in terms of standards of care is to practice where the data are and otherwise put the patients on studies.

So that’s an international trial. There is an opportunity to put those patients on pre chemo within the context of a clinical trial. And that’s where they should go.

Brian:
[crosstalk 00:25:28] Brought to me, are there other trials, you mentioned the pre chemo trial, what other trials are going on?

Mike Morris:
So, there’s a collaboration between Novartis, NRG, and Alliance for clinical trials in Oncology of a study that will be led in the US by Scott Tagawa and Oliver Sabra. And that study is looking at newly diagnosed men with metastatic disease. It’s a randomization between ADT and the, an RSI of choice of the physician plus or minus lutetium with a primary endpoint of RPFs.

Tom:
Wow.

Mike Morris:
So that’s moving this treatment into the castration sensitive population, which is a whole new real step in the earlier direction on the disease spectrum.

Brian:
Awesome.

Tom:
Mike, so what are the other radio nucleotides that are being developed, and what do they look like and how are they being tested?

Mike Morris:
Absolutely. So, there are other lutetium-based radio nucleotide. So, there is certainly an effort with antibodies still looking at J591 with both lutetium, as well as actinium, there are small molecules that are being explored with actinium as well.

There are new targets such as HK two, which is similar to PSA, but it’s membrane bound with an actinium payload that is in now it’s dose finding study. And then there’s the thorium anti, which is a PSMA targeted antibody with an alpha pay load study that is in its dose finding as well. And that’s just the single agent studies.

They’re also a host of combination studies that are in early phases being developed as regimens right now. So, it’s really quite an active field. There are a lot of new treatment possibilities, not just for earlier patient populations, but new combinations, new targets, new payloads that have different properties in terms of potential side effects versus benefit relationship. So, there’s a lot of work going on and a lot of hope for patients here.

Tom:
My last question there isn’t, what can other tumor types learn from this? We haven’t utilized widely in other tumor groups. We’re developing antibody, drug conjugates, obviously, and there are other bits and pieces we’re spending perhaps more time on immune therapy than you are in prostate cancer for lots of different reasons. What can the wider field learn from this?

Mike Morris:
A few things? So, one thing would be that you know, the approach works for some of the major solid tumors right now you do have Luda there, that’s FDA approved for GI neuroendocrine tumors, but such relatively small patient population compared to something like prostate cancer.

You could adopt this, you could adapt this technology for breast, colorectal, lung, et cetera. And indeed, those efforts are in their nascency. But and I think that logistically everybody’s going to have to expand their capacity in nuclear medicine or radiation oncology in order to accommodate these large solid tumors from just a logistic standpoint.

And then finally, in terms of how oncologists, radiation, oncologists to nuclear medicine, physicians collaborate in taking care of these patients, we will show in prostate that it’s feasible to do so that the other diseases can see that, it’s feasible and make those adaptations as well and how they practice in a more multidisciplinary manner. Any last question for you, Brian?

Brian:
No, I think this is great, Mike, thanks for your time. Really appreciate it.

Tom:
One, one last question from me, any advice for Brian on how to get his plenary session.

Brian:
Mike’s trying to help me for 20 years.

Mike Morris:
Brian’s doing pretty well. I think even without that. So, I think that you’ve advanced the field of kidney cancer to such a degree that the plenary just doesn’t matter [crosstalk 00:29:28] plenary [crosstalk 00:29:28] memory plenary.

Brian:
OK. Listen, you’ve been very gracious today and you’ve been, you’ve been a great friend to both Brian and myself, and we’re very proud and honored that you were able to join us today. Congratulations. It’s a huge deal. I agree. I think it’s terrific data.

Mike Morris:
Thanks so much. Thanks for having me, and here’s to seeing each other live next year.

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