HRR Mutation Testing in mPC
Transcript: What’s new in HRR testing?
Joaquin Mateo, MD, PhD, and Alicia Morgans, MD, MPH
Interview recorded September 2025. 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.
Alicia: Hi everyone and welcome to the "Expert exchanges in HRR in metastatic prostate cancer." I'm so excited to talk on this podcast about what's new in HRR testing. And joining me today is Joaquin Mateo. Thank you so much for being here with me today. Joaquin: Thank you, Alicia, for inviting me for this discussion. Alicia: Always a pleasure. So let's dive right in. I think, you know, some of the things that have been coming through the congresses in the last few years have really been focusing on HRR testing, and I just wonder from your perspective, how have the updates at congresses like ASCO GU or EAU or ESMO really influenced your perspective on HRR testing in metastatic castration-resistant prostate cancer? -: Well, I think that every year, we have more and more data of how relevant this is for patient care. It's been a few years now since many, many studies demonstrated that this testing impacts patient management in the latest stage disease. We also knew already that this testing can impact hereditary cancer risk assessment.
And some of the data that we are seeing at recent congress is that it may impact patient care even earlier than we thought. So we are seeing now trials testing PARP inhibitors at earlier stages of the disease, such as metastatic hormone-naive prostate cancer, and there was a larger study presented by Gert Attard at ASCO this year, and that, if confirmed, will evolve moving also the testing earlier so we can identify who are the patients who should receive these therapies. Alicia: I agree. And there have been some really exciting blockbuster type presentations at some of these meetings. Other than that trial, I think you're talking about the AMPLITUDE trial, were there other studies that really stood out when it comes to either the use of the data from testing or HRR testing as you think about your practise? -: I think the other piece of data that we have seen recently that is very important is that beyond a treatment indication, HRR testing also helps identifying patients with prostate cancer that have a distinct clinical trajectory. We have seen data from several groups, including liquid biopsy studies from the lab of Alex Wyatt and Kim Chi, but also more recently a large study from my colleagues David Olmos and Elena Castro, showing that those tumours that have mutations in HRR genes have a more aggressive course than the others. So beyond the indication of one treatment, this testing also points us towards patients who may need a closer follow up and who are at higher risk of progressing to standard therapies. -: Yeah, I think that the implications in terms of prognosis are so meaningful when it comes to sitting down with a patient.
And so I completely agree. And then, of course, as you mentioned, the implications for their family, which is also of critical importance when patients are newly diagnosed. The guidelines have really tried to incorporate different strategies and different thought processes around the utilisation of HRR testing into the guidelines and give us suggestions on timing and type of testing and which patients. Have there been any changes in the latest guidelines that really have had the biggest impact on how you work through HRR testing in your practise? -: Yes, I mean, changes in the guidelines depend on new data emerging, but also in when is the guideline updated, right? So sometimes we think that there are discrepancies between guidelines that are just the result that one guideline may have been updated a year ago versus two year ago, and there was new data in between. I think that what we have seen, for example, is that the ESMO guidelines are currently recommended testing for BRCA1 and BRCA2 at minimum, whereas, for example, NCCN guidelines already recommend a wider panel of genes to be included in the testing, but this is probably the result of the label and the reimbursement access framework for different PARP inhibitors in Europe versus other parts of the world, not necessarily because the data is different. So I think that clinical guidelines are about the evidence, but also about the pragmatic evidence for implementing something. -: Yeah, I think that's one of the things that I find most interesting about this, that the same studies, the same reports lead to different guidelines in different countries.
And, of course, the reason for that is that there are different labels for these drugs in different countries. You know, as you're thinking about the guidelines, the labels and your opportunity to use PARP inhibitors, either in clinical practise or in clinical trials, if you don't necessarily in your location have access in all the places that you'd like to have access to these PARP inhibitors, can you think of a patient case where these changes, these updates have really affected or influenced your testing strategy or your treatment strategy for that patient? -: Well, definitely because before, you would only indicate this testing when there was a strong family history of cancer in a patient. And we know now that yes, family history is important, of course, for assessing certain risk, but definitely that should not guide our testing. And I always remember one of the first patient that we treated with PARP inhibitors in clinical trials a few years ago, who was a 77-year-old man, he was actually a physician with no family history whatsoever of prostate or breast cancer, neither of ovarian cancer. You know, newly diagnosed at age 75. So you would not expect that patient to be carrying BRCA mutations. And he actually was carrying a germline BRCT mutations and had a fantastic response to a PARP inhibitor for over a year. And that really, you know, changed something in my mind when thinking about this testing is that we should not be looking at family history of the disease and we should offer the testing to all patients with metastatic disease. Having said so, for example, the European guidelines right now recommend testing in the CRPC space.
I think, Alicia that the NCCN and ASCO guidelines recommend testing for any patient with metastatic disease. That's quite of a different patient population in terms of the number of patients we see, right? But I think that's gonna change as the data in this earlier space is consolidated. I think we're gonna be moving the testing earlier. -: Yeah, and to that point, and you alluded to this, I follow the NCCN guidelines usually in my practise. I have the luxury of doing that. The NCCN is in the United States, where I practise. And so many of our payers and our institutions and the people that make decisions around our ability to do this testing do follow the same guidelines, but with the differences in guidelines sometimes are more restricted. You know, as I think about consensus guidelines that are, of course, based on the data, but also at some level based on what's possible in a region, and then also, I am sure based on practises that influence that, I really often look to the APCCC as an organisation that tries to bring together consensus, recognising differences in the way that we apply this data, even in high resourced countries versus those with fewer resources or poorer resource accessibility. And I wonder what guidelines, what body of evidence for HRR testing do you look to in your practise, and how do you think through all of the different options? Joaquin: Yeah, so first of all, I agree with you that the discussion we had at the last APCCC panel meeting, it was a year and a half ago, was really interesting. And I think that we came with a strong consensus and wording for recommending the testing. And I hope that in a few months when we meet again in Lugano, there will be an opportunity to update these recommendations. In my practise, I work in Europe, so we follow the ESMO guidelines.
Having said so, I would like to make a point, like sometimes we discuss about the genes we have included in the panel that may be different from one guideline to another. But I mean, I don't know if that's the case for you, but I don't choose which genes do I want to test in my patient. I have access to certain tests, to certain panels and that's what I can offer my patients, right? So I also want to put this discrepancies in context because at the end of the day, we test patients based on what we have available. Alicia: That's such an interesting point because certainly the NCCN makes a point in calling out which genes should be tested, and we discuss at different meetings, you know, we have to make sure that we include these genes, these mutations in the panels that we're using. And I remember many years ago, actually when some of your first data came out, the TOPARP data that you worked on with Johann de Bono, and you had such a beautiful presentation and such elegantly characterised data. And I went through and made sure that the test I was using had all of the genes that you had included in your initial design so that I could make sure that I was getting that for my patients. But these days, these panels are actually quite expansive in most cases. And I do make sure that my key player genes are on those panels, but we have little influence, no influence I guess I would say, on whether a particular panel is going to include something. How do you think through that? I mean, are you still going through and checking to make sure that your panel includes those genes of interest or are most of the panels that we have access to these days, most of the tests that we can access pretty inclusive of things that matter for people with prostate cancer?
Well, I do worry about the panel that we use. It's important to discuss that, but it's something that we have to discuss with our institutions or with our, you know, reimbursement frameworks, but not necessarily at the individual patient level. So I think that's not something we need to worry every day in clinic for every individual patient, but it's more on a strategic decision that we need to discuss with our institutions and hospitals of which tests that we're using. It is true that most of the available panels out there already include a significant number of genes, also for pragmatic reasons. There are many centres that just centralise testing in one facility there in-house or with an external partner, and they just have one or two panels that they use for patients with different types of cancer. So I think there are very few centres that are using prostate cancer-specific panels. So probably when you offer testing to a patient, very commonly you will end up with much more information than you need. The important thing is that we are aware of which is the important one and that we can interpret it. So I take the point in the guidelines as the minimum we need to ensure that our patients are tested for, but I don't think it's the critical point when it comes to offer testing if my tests or the tests they have access to includes a few more genes. Alicia: Yeah, that is such a great point. It definitely speaks to, I think the evolution of our integration of these panels, both germline and somatic testing into our clinical practise. It is now not just standard, it is imperative. And so I think that, as you said, your institutions, our institutions are really making it something that we have access to and making it a priority. And where that's not possible, it's important for us to advocate. So I wonder, are there innovations though in HRR testing and the methodology in the way that we integrated this into care that you find most promising, that you are most celebrating and excited about in your practise? Joaquin: Yes, I think that on one hand, every day we see that laboratories are capable of delivering high-quality testing with lesser amounts of DNA, you know, with lesser amount of tissue. And these are normally things that don't come up in the big papers, but these are the advances in laboratories every day that make a difference to increase the number of patients who can access testing. I think that something that is also very important is the improvement that we are seeing in the quality of liquid biopsy testing, because this is an important alternative to tissue testing that has positioned as a very strong way forward for testing patients if they don't have available material or if the material that was acquired from that patient is another institution. There is also the point of liquid biopsy testing to look at new mutations that emerge over testing.
It is true that for HRR mutations, until now, we don't really have evidence that that's a critical thing. But we have started to implement liquid biopsy testing in our institution for HRR testing as an alternative when tissue is not available. And clearly in terms of the technology of liquid biopsy testing, the sensitivity to detect these mutations, the sensitivity to detect deletions of the genes that are also relevant, particularly for BRCA2, and testing a deletion in a gene was quite challenging 10 years ago with liquid biopsy for, you know, technological details that probably we're not gonna discuss now. But I think that the change in the quality of liquid biopsies from 10 years ago to now is amazing. And now it has become a real alternative for clinical use. -: I couldn't agree more. I remember really kind of reeling against or pushing back against the use of liquid biopsy, especially when the technology was new and tissue testing has been the gold standard and I certainly didn't want to miss something that could be clinically meaningful to my patient.
But at present, I utilise a moderate to high amount of liquid biopsies in my daily practise for many logistical reasons, including not having access to the primary biopsy specimen or prostatectomy specimen, as well as, you know, that specimen perhaps being 10 years old or being older, such that it's either difficult to access or may not be of high quality. So I think that this is very, very important from a logistical perspective and it's wonderful that the technology has improved. One of the other things that I really wanted to talk about from a practical standpoint though is how you and your multidisciplinary team are really adapting to the integration of this type of testing into your practises. And I wonder if you have any thoughts around the workflow and what works best for your team when it comes to HRR testing testing? Joaquin: Yeah, and that's a very important point. I think that same as we would not order an MRI scan and assume that whatever is in the piece of paper, it's what is there to know and never go back. You want to discuss with your radiologist the result of an MRI scan. You want to discuss the no answers of a finding. It's the same for genomic testing, for HRR testing. First of all, a multidisciplinary team is important to set up efficient pathways at institution level. So the pathologists have to be engaged so they can have a say in which samples are optimal for testing. Like when we are discussing about liquid biopsies, well, many times the tissue biopsy may not be good enough. So we need the pathologies involved in this discussion. So they give us feedback and may actually suggest a liquid biopsy testing if they see the biopsy and it's not good enough.
Clearly, in a world where we are treating prostate cancer patients in a multidisciplinary manner, this multidisciplinary team also has to be at the forefront of the decision of testing because I do believe that testing is gonna be moved to the point of diagnosis at some point, and it will be part of the initial assessment of the patient as a whole rather than something you do later on ad hoc, right? So here in multidisciplinary team it's important. And then once you get the results, again, having fluent communications between all the stakeholders involved is very important. Sometimes these genomic results are not easy to understand, and it is very important that you have a point of contacting the laboratory to clarify questions. And in our case, for example, every time you received an email with a genomic report result, there is the possibility of replying to a certain email address with your question, and then you either get a response from the laboratory or the case will be added to the next molecular tumour board and you will get notified when your case is gonna be discussed, right? And then also, let me get back to the point of hereditary risk assessment, hereditary cancer risk assessment. When we do HRR testing, there is a possibility that we identify a mutation of potential germline origin. So it is important that our hereditary cancer teams are involved in the framework of testing, so they can probably identify those patients who may merit genetic counselling and further testing for confirming hereditary risk.
Alicia: I love that. I'm wondering how I can incorporate this general email box so that I can email with questions about the genetic test results directly to the molecular tumour board and to the team. I think that's such a wonderful part of your workflow that is really so clinically impactful and also educates everybody on that multidisciplinary team along the way because these things change quickly. And as you think about the way that our data, the way that testing approaches change and evolve in the next few years, what are you looking forward to? What gaps can we fill as we try to make things even better than they are today? Joaquin: So earlier in this conversation, we discussed about prognostic value. I mean, we don't really know how to act upon prognostic biomarkers yet, and this is why the testing of HRR genes is right now the only bit of the genomic testing that has a clear clinical implication. But I am confident that as we develop newer drugs in the prostate cancer arena, but also as we become wiser in using the drugs that we already have, particularly in the metastatic hormone-naive space where we have so many options and our tools, to guide individual patient decisions are limited, we are gonna find the relevance for other gene testing beyond HRR testing. And when that happens is when we will need to move this testing to the diagnosis and put it together with radiology finding, with histology finding to make a risk assessment, a holistic risk assessment of the patient and the case. I think that's gonna be a big change. And I don't think it's that long until that happens. -: I couldn't agree with you more on that and I really do look forward to the day when we do risk stratification in prostate cancer by T staging, N staging, M staging, and then some molecular pathologic component that comes in and helps us really understand where that patient sits in terms of the risk of disease, the risk of the aspects of treatment, the opportunities there as well. I sincerely thank you for your time today, Joaquin. It's been such a pleasure and always exciting to talk to you about HRR and anything related to advanced prostate cancer. Thank you. Joaquin: Thank you, Alicia.
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