Upcoming Trials for mHSPC and mCRPC and Next-Generation Sequencing

In the fifth segment of this roundtable series, David Morris, MD, FACS; John Phillips, MD; Jeremy McDuffie, MD; Katy Beckermann, MD, PhD; and Alan Tan, MD, explore the promise of next-generation sequencing, PARP inhibitors, and T-cell engagers for prostate cancer treatment, highlighting their role in precision medicine. The experts share their practical workflows for utilizing tissue and liquid biopsies, examine the evolving landscape of radioligand therapies like lutetium-177 PSMA and radium, and discuss emerging biomarkers and treatment combinations.

Watch the final part of this series: Comparing Alpha and Beta Emitters, and Looking to the Future of Advanced Prostate Cancer Care

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Dr. Morris:
So you mentioned kind of the burgeoning field of partners from radioligand standpoint, and we’ll get back to that a little bit. But in terms of other new therapy combinations coming, I’d like to kind of touch from each of you kind of the things you may be most excited about. But you brought up a great point earlier, which is a lot of the trials are taking treatment naive patients who’ve just been on ADT and are progressing now on their CRPC, but they’ve never been exposed to anything. And now we’re having combination therapies that have been approved with a very different patient population than we hope that we’re seeing in clinic because that means they’ve been undertreated in the hormone sensitive space.

So just if you could touch on that disconnect between what the trials show us and where we are when they get released five years later, but also what are your other options for therapy lines, mechanisms of action that you’re interested in, whether it be parts, whether it be something else that’s potentially coming down the road. Dr. McDuffie?

Dr. McDuffie:

Well, I think you’ve hit Nell on the head with the first one that I’m excited about PARP inhibitors, being able to use the NGS and seeing those BRCA mutations. I’ve got a couple on therapy now that are doing quite well and also seeing some of the studies where they’re used in combination with other drugs. I’m also excited to see what becomes of, not specific drugs, but how we use NGS like AR variants and whatnot to help guide therapy.

I’ll defer to the more professorial part of the panel, the specific active compounds that they’re excited for, but definitely excited to see how NGS helps us make decisions and sequence these therapies that we got a lot of which are now kind of getting into MeToo space, if you will.

Dr. Morris:
So I want to stick with that for a second. So you mentioned NGS testing platforms, tissue, blood, archival tissue, new biopsies. What’s kind of your preference in workflow in the community because often very different than in an academic setting?

Dr. McDuffie:
Tissue, tissue and more tissue is always our preference, but the problem is a lot of times we’re seeing somebody at this point who was originally local disease, received radiation, received surgery, what have you, and is now metastatic to bone, which is not the highest of yield tissue, sometimes difficult to get. We will certainly use liquid-based assays if we can, but certainly the preference is going to be tissue-based NGS.

Dr. Morris:
And are you repeating that? Say somebody had seen you up front, hormone-sensitive disease two or three years ago and you had testing which was negative at the time for the mutations that kind of got mentioned. So you treated them-

Dr. McDuffie:
Correct.

Dr. Morris:
-and now they’ve progressed. Are you re-challenging them? Are you treating them to see if they’ve had some sort of shift in their tumor before you move to the next line of therapy?

Dr. McDuffie:
Typically, yes, unless it’s somebody who I’ve gotten an NGS on and started them on a therapy that they were just kind of primary refractory to. So I’ve had a relatively quick NGS, a recent NGS, I won’t. But if it’s a patient who has done well, reasonably well for some time, and now they’re having a change in clinical status, they’re no longer castrate-sensitive or they’re having progressive disease, certainly will look at repeating NGS, just depending on how difficult it’s to get tissue.

Dr. Morris:
Before we guys get your mechanism of action. Similar sort of testing paradigm in an academic setting?

Dr. Tan:
Yeah, I think so. We might vary amongst ourselves too, but we’re in the area of precision medicine, is it good to know more information? So I like to do upfront dual liquid and tissue. I think it captures the heterogeneity and when cancer progresses and becomes castrate-resistant, cell-free DNA is… The tumor fraction is much higher. So you’re probably going to get much more yield when they become castrate-resistant. So seeing the evolution of the prostate cancer progression as it progresses throughout lines, it is really nice and easy to get with a couple of streck tubes and so that’s a good way to do it without having to do an invasive biopsy. And in fact it’s really difficult to biopsy bone and get something that’s high yield valuable.

Dr. Beckermann:
Maybe the thing I’ll add is that I know, I think also I try to get all the tissue, I typically do it up front and just very first consult and I’ll just highlight, I also, I think we probably all do, but I get germline and somatic mutation testing, so I cover that all up front and then I will get additional tissue. But it typically is kind of after I’ve gone through a lot of the standard regimens, so later lines of therapy I’ll consider re-biopsying. But I wouldn’t say that at every step like going into CRPC or going to Pluvicto or something like that, that I’m always getting.

Dr. Morris:
And I think there is some testing fatigue for patients. The liquid test obviously very convenient. You mentioned just a few tubes and it gives you an answer, but it does require some tumor to be floating inside. So minimal PSA changes probably not going to yield valuable results.

Dr. Tan:
High-volume will get you some heterogeneity there.

Dr. Morris:
Dr. Beckermann, any interest, PARP inhibitors mentioned. Anything else that you think is, besides other lines of therapy moving earlier, what is it you’re kind of most excited for or looking for?

Dr. Beckermann:
Yeah, I want us to be excited about a lot of things because I think to the point that we are using triplets now so early, it feels like our tool bucket has actually almost shrunk. So while we’re getting longer on frontline treatment to CRPC and better overall survival, unfortunately we still have a lot of patients who progress. And so then essentially your second line option is do they have a BRCA2 and 1 mutation that you can go for PARP or are you going to Pluvicto?

I think my most exciting, but probably still not quite there yet, a mechanism of action is these kind of bites and looking at T-cell engagers, I think there’s a lot of side effects and things that we need to work through and being done in a lot of very specialized centers. So probably not quite there yet, but I think exciting data has been coming out over the last year, so hopeful for that.

Dr. Tan:
Okay. Yeah, I would echo those sentiments. So ARV-766 is AR degrader that’s currently being studied. I think Novartis has it now, but that’s something that’s signing order, including it into one of our cooperative groups’ trials.

But the bites, the T-cell engagers, that’s probably the most exciting thing for me because we’ve long thought of prostate cancer to be immune, non-responsive, a cold tumor and only the patients with Lynch syndrome or high macrosightlight instability can get benefit from PD-1 inhibitors, but that’s not the case. We have these T-cell engagers xaluritamig or AMG 509 targets, STEAP1. And if you look at these waterfall plots in these really heavily pre-treated patients, really impressive as the side effects. I think we can get through them, their cytokine release syndrome. They may be scary for us. We’re not malignant hematologists, but they’ve seen it for many years now. So they’ll teach us.

Dr. Morris:
I’m glad you would say that. They may be scary for you. Imagine what they would be for a community urologist, even those that do a lot of prostate cancer management. So you mentioned some of the AR mutations in terms of radioligand therapy. Are there any particular markers other than currently we use PSMA PET as a biomarker for therapy, is there anything that you utilize, whether it’s SUVs from the scan, what are you looking at before you’re trying to select whether radioligands are kind of the next step for somebody?

Dr. Phillips:
Yeah, so I think in the upfront decision-making on is Pluvicto or lutetium the right choice versus a second line cabazitaxel looking at the intensity of the uptake on the PSMA scan, which we measure is like an SUV.

And so if you have diffuse metastatic disease, lots of lesions, high PSA, but then you get the PSMA and it’s cold, that’s not the right person for lutetium.

And then when we’re treating patients, I think there’s motion to use and inspect inter-fraction analysis to make a decision on do we need to continue the lutetium, should we discontinue early? And so I think there’s going to be integration of SPECT into future trials to make decisions about when to stop, when to potentially do stereotactic radiation to a non-responding lesion. So I think we’re just scratching at the surface of not just saying like, “Oh, you’re on this therapy for six months.” We’re going to say like, “Oh, we’re going to assess it maybe every two rounds with imaging and then make a decision about are all lesions responding or to some lesions need additional therapies.” Now that hasn’t come out… That’s not integrated in any of the trials yet, but when we talk at our national groups, that’s sort of the direction that we’re heading on a lot of these RLTs.

Dr. Morris:
So I guess along the lines of we now have two approved in the US. Are there patients that you would push one way or the other? If I’m the community urologist saying, “I think this patient has run out of other options, they don’t want chemo, I’m sending them to you. I mean, maybe they got a whiff of chemo before and that’s why they don’t want second line chemo, but I’m sending them to you and all things are on the table.” Are there things that would push you one way or the other between the radioligand therapies we have available?

Dr. Phillips:
I think right now the big differentiator a lot of times is have they had chemotherapy up front in order to be eligible for Pluvicto because the cost associated with it is so high, getting approval is sometimes very challenging.

I think that if we did a PSMA PET scan and we saw a lot of non-AVID lesions that would push me more towards radium. And then I think moving radium up the chain, we still haven’t, I at least don’t have a solid heuristic in my head. I have a solid heuristic in my head for like, “Oh, they’ve had taxane but a BRCA mutant, so let’s put them on a PARP inhibitor before we do Pluvicto.” I don’t think we quite have that yet for integration of radium upstream, but generally I think the patients that we’re making the decision…

Pluvicto is so complicated to get approved right now because of the high cost that a lot of times we’re really narrowly defining who can go onto Pluvicto up front by the trial criteria. That may change if the FDA approves it up front of taxanes, but we’re all sort of uncertain as to whether or not that’s going to be approved.