Transcript
mCRPC management unpacked: Imaging, genetic testing, and treatment decisions
“The complexity [of mCRPC] requires multidisciplinary care,” says Neal Shore. When should germline testing be considered? How can PSMA PET imaging be effectively integrated into clinical decision-making? Watch as leading experts explore key challenges in access, workflow inefficiencies, and the evolving role of imaging and genetic testing in mCRPC management. View transcript.
Ken Herrmann, MD, MBA; Nick James, MD, FRCP; Neal Shore, MD, FACS
All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
- Well, hi, everyone. What a great pleasure to be on this programme right now with two dear friends and internationally renowned colleagues, Ken Herrmann and Nick James. We're gonna just sort of briefly touch on the ever-evolving world of metastatic castration-resistant prostate cancer. Let me sort of get right into it. Maybe I'll ask you first, Nick. You know, we have a lot of patients who come to our clinics if they're coming for a consult the first time, saying, "What do I do now that I have mCRPC?" And they can come, you know, depending upon where they're in the world, having progressed just with monotherapy androgen deprivation therapy, or they may have had triplet or doublet therapy, an ARPI with their ADT as well as docetaxel, or just an ARPI and ADT, and likewise, I said, maybe just monotherapy ADT, which we're seeing that evolution. But one of the things I'd like to ask you specifically is when that patient comes in and you don't have any information on whether they've had genetic testing, how do you have that conversation with the patient and what type of testing are you doing?
- Yeah. So, well, I think as you nicely summarised, the options you have in first-line CRPC or subsequent-line CRPC, come to that, are driven by what you've had already. So if you've had an ARPI, in the UK, we're not allowed to switch to another one, so straight away you've removed a whole load of choices. If you've had monotherapy, then you've got, you know, more choices, so, for example, a combination of abiraterone and a PARP inhibitor, for which you don't need testing, you know, based on the PROpel data. But for everybody else, I'm inclined to say you should be offering testing, and if it's all possible, we're going down the tumour testing route. Assuming you can get a hold of the tumour, that is far and away the best way to do it. And we have our own in-house testing facility, so, you know, I can't sort of say we use such-an-such a company's panel. And mostly we're focused on what is in the licence for the various PARP inhibitors in terms of what we test. Although personally I have to say, I'm most interested in whether they're BRCA1 or BRCA2 positive. I think you get the far and away the biggest benefit from those. If they haven't had first-line ARPI, you've also got the very interesting data that just came out from PEACE III around the combination of enzalutamide and radium if they're bone met positive, which I thought was really very impressive. And, you know, we get very hooked into sort of the latest shiny toy and we forget that just because a drug was licenced a decade or more ago doesn't mean it suddenly stopped working because something new has come out. And it has a distinct mechanism of action to PSMA Lutetium, so I don't view it as an either-or as to, you know, one or the other. You know, if they're suitable, try and give them both. So there's a few things like that. There is the rather sort of unsavoury question of funding, you know, different healthcare regimes, and insured and uninsured patients in the UK and elsewhere will have access to different things, so that is a factor in your choice. And then finally, there's things like external beam radiation. So if you've got oligoprogression or oligometastatic disease, you've got things like stereotactic radiation therapy ablation options as well. One of the things I'm very interested in is the idea that if you started off with, say, polymetastatic disease, you've had a good response to your initial hormone therapy, whatever the drugs you were given, and now you've got just one or two sites progressing, yes, they've got progressive disease and in the earlier trials, you do change their systemic therapy. But another way of looking at it is, well, almost all of their disease is still controlled by the original drugs, why not just cook the mets that are progressing? So there, you know, and either with external beam or with radioisotopes or both and leaves them on the base therapy. I mean, this is a whole area for trials that is ongoing of, course. So yeah, we're outside current phase three evidence, but I think this is a really interesting topic. And so finally, of course, the thing I will always discuss is, do we have a trial that we can put you in, because that would always be my preference.
- Yeah, yeah, brilliant as always. Thank you. Yes, clinical trial is a standard of care. All the guidelines recognise that. I love that you brought that up. Just a comment and a question for you, Nick, before I ask Ken to answer the questions that I wanna pose to him. So are you, for your patients, this theoretical patient, clearly your espousing the importance of multidisciplinary treatment, which I think is fantastic, and our audience needs to recognise that. The complexity requires multidisciplinary care. You mentioned somatic or tumor-based testing, so two questions off of that: one, your thoughts on hereditary, or what we sometimes call germline testing, if the somatic is positive or if the somatic is negative. And then the second question is, for these patients who you do the somatic testing on and then they later on progress, as you're saying, they get some additional lesions, oligometastatic in the mCRPC, are you getting serial somatic testing, tissue or liquid?
- So we have relatively restricted access to testing, so we're doing a lot of it in the context of trials and, you know, working where I do with Rosalind Eeles and sort of my colleagues, yeah, a lot of this is just passed over to her and they're all in her studies. But in terms of, you know, obviously, the easiest thing in terms of the testing is to ask people their family histories. If they've got a very strong family history of breast, ovarian, prostate cancer in first, second-degree relatives, then you're definitely gonna want to do a germline test. And, of course, a lot of people don't necessarily know very much about their family history or people may have died, you know, young from heart attacks and therefore are kind of not informative. But I think it is very important to, especially in patients with young-onset bad prostate cancer, that you think about doing somatic and germline. In terms of treatment decision for the patients, I think I view the somatic testing as being the driver here, and there's an evolving role for things like ctDNA. If you're detecting BRCA mutations in your ctDNA but you haven't got tumour or whatever, then that probably trumps, you know, the tissue diagnosis and allows you to go down a PARP inhibitor route of some sort. But clearly, it's also very important for the patient's family that you've explored the germline thing. In the UK, that's done through familial genetics clinics, not through my clinic, and because you've got the whole thing about tracing the family, consent, issues around, you know, how it affects your access to mortgages, all these things, so it's complex once you embark on the germline testing thing. And it's not, for me, a high priority that you do that quickly, but it's something that you do need to address at some point in the patient's care, particularly if they've got a strong family history. But I think the priority is to get the test done that will drive their treatment rather than the sort of broader family counselling thing.
- Yeah, no, thank you. Testing is important. Understanding when to test, why to test, how to test, super, super important. We'll have other educational modules on that through Medthority. But Ken, so two questions for you. Broad, open-ended but incredibly important because much like radiation, oncology is now finding ubiquity in attacking lesions, both in sensitive and resistant disease, not to mention the primary. We've now have this amazing world of nuclear medicine radiology where PSMA PET-based testing is changing so much of what we've seen compared to what we describe as conventional imaging testing. And then the second part to the question is, when we have that information, maybe touch upon for our resistant patients the role for radioligand therapy. Nick already commented about the use of radium-223 based upon the PEACE III. Great study by the EORTC and Silke Gillessen and Bertrand Tombal.
- So, excellent question. So first of all, PSMA PET, obviously, is still quite new. We have shown in a lot of studies bringing actually this compound to approval that it's more accurate than conventional imaging, both for primary staging as well as for biochemical recurrence. However, and I think this is what the question leads to, is in many of the trials and of many what we have learned in the last 10, 15 years, we use conventional imaging. And now the big question is, how does it really change when you use actually a different imaging modality? And to be honest, this was never part of the clinical trials which led to the approval of PSMA PET. The interesting thing, and I'm gonna highlight this, is that we actually do have now so-called real-world data, a big registry, the PROMISE registry, and there are now more than 8,000 patients published. And, but for me, the key message of these data was that actually PSMA PET, at the different stages of disease, it doesn't matter if it's primary staging, if hormone-sensitive disease, or metastatic castration-resistant prostate cancer, in each of these cases, a PSMA PET is highly prognostic. So patients who have a lot of PSMA tumour volume, a lot of disease manifestation have a significant inferior prognosis compared to patients who have much less disease. I think this is a very good information. I'm kind of dodging a little bit your question, obviously saying, how do we now integrate PSMA PET? How does it replace conventional imaging? How do we do PSMA PET for assessing treatment response? And the truth is, I don't have an answer there. I think PCWG4 is going to propose for the first time how to define progression on PSMA PET, but this is more eminence-based and evidence based and we now have to wait another few years. I hope that we don't have to wait for 10 years to really validate perspectively these proposed criteria to see if this is a good way to use it. The second question is much easier. So how do we use PSMA PET in case of resistance? And I think, first of all, I think for this decision, HRR testing also plays a role, at least in Germany. We need to make sure that patients, and we highly encouraged actually, that patients are tested, so because in case if they have a mutation, they should get a PARP inhibitor first. In case they don't have a mutation, we select patients based on PSMA PET imaging to make sure that we really confirm the expression of the tumour. And then right now we use, I think, very basic criteria. The so-called vision criteria really define that we have at least one lesion, which is actually higher than the liver. But I think also in the future we are going to refine this. We are going to use more sophisticated parameters, and I'm a big fan and believer in the PSMA total tumour volume. This will really help us identify patients who have a high likelihood to benefit from a PSMA-reliant therapy, and it will also help us to monitor actually the success of this therapy.
- Can I ask a question actually on that? So for our CRPC, PSMA decision, we are just doing a PSMA PET scan. And we're not doing any other imaging, we're just using the CT component to assess whether there's significant PSMA-negative disease and that we may supplement that by doing some additional, say, liver imaging if we think we need to. But if we're happy there's no liver mets, we kind of don't bother. But some trials have gone, you know, dual PET imaging, FDG, and so on. The other thing we're exploring at the moment is whole body MRI as an alternate way of looking at it. So, and also there's the data from TheraP, I think it was, where it suggested if you were strongly FDG positive and PSMA a bit patchy, you were better off going down the chemo route rather than the radioligand route. So there's quite a lot of complexity into how you integrate, a, the different imaging and b, the different treatment options, obviously contingent on what you've had previously.
- Very valid points. So, first of all, I mean, we perform PSMA PET/CT including contrast-enhanced diagnostic CT, which means when you think about conventional imaging, it's actually CT or bone scan, so a significant important part of conventional imaging is always implemented. But you're absolutely right. I mean, whole-body MRI is super good. Unfortunately, it's not vitally available, and there are also very few sites where it's good, for example, at the site where you are working, how to interpret it. The second point is also true that the FDG PET is providing a lot of complementary, potentially complementary information. I have to say we perform FDG PET in every patient here. I do differentiate myself a little bit from my good friend Michael Hofman because I think it's good to have it, but it's not mandatory to have it. And we actually looked in our own data, seeing how much do we change the decision based on the additional information provided in FDG PET in comparison to using the contrast-enhanced CT, and it was a total of 3% of patients. If you really change the decision at 3% of patients, it might become not really cost-efficient to do this. However, it's more accurate. There's no question about it. I fully agree it's more accurate, and I also agree that we need to understand better which patients benefit and do not benefit PSMA-reliant therapy. And I think, again, coming back to the PSMA total tumour volume is actually maybe something which might help us to do this even without needing FDG PET, but very good points we need to learn.
- Well, gentlemen, that was fantastic. So much covered in the short period of time and so many more topics that we could have talked about. And I know we will, and other of our colleagues who are really dedicated to the field will be having conversations on specific challenges both in mCRPC and mCSPC. So thank you very much.
Ken Herrmann, MD, MBA; Nick James, MD, FRCP; Neal Shore, MD, FACS
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