HRR Mutation Testing in mPC
Transcript: Unlocking the HRR pathway
David Olmos, 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, and welcome to Expert exchanges: HRR in metastatic prostate cancer. Today, we're going to talk about unlocking the HRR pathway and why it matters in metastatic castration-resistant prostate cancer. I'm so excited to have here with me today, Dr David Olmos, who is joining me from Spain, where he has been defining the field, actually, for the last many years. Thank you so much for being here with me today, David. - [David] Thank you very much, Alicia, you are really kind. I think that has been the war of many of us working together and collaborating through the Atlantic. - [Alicia] Well, thank you, and certainly we've appreciated all the work that you and your team have done to bring this forward, as an issue that's so important for prostate cancer. So let's just set the stage. This is the first episode of many in this series, and I think it would be helpful if we all thought about how your understanding of the HRR pathway has informed the way you think about disease progression and treatment resistance in metastatic castration-resistant prostate cancer.
What's the way... How do you think about this? - [David] Okay, I think that we have to start from the beginning, in that for many years, we were looking to understand the heterogeneity of the clinical behaviour of patients that become to metastatic CRPC in so many ways, and they respond so differently to drugs. I think that the advances of the genomic analysis, particularly with the revolution next-generation sequencing, has allowed us to dig in the tumour. So much more profoundly, and this has allowed us to identify different pathways that are frequently altered that can be druggable for the future, but might have also prognostic predictive implications. And HRR pathways, one of them, we knew for many years ago that BRCA were connected beyond breast cancer to prostate cancer. As many others describe how important was BRCA germline alterations for prostate cancer from diagnosis. But more recently, especially mCRPC, we have been expanding this work to understand mutations, also that happening in the tumour that are not inherited, that are acquired in the oncogenesis or through progression, as well as other alteration of genes that collaborate in the end repair, especially in homologous recombination repair, how they impact in the evolution. Nowadays, we know that many patients and maybe another factors that respond for short times that they present with aggressive characteristics might present some of these alterations.
And that has allowed us to identify patients for trials with drug LipE PARP. - [Alicia] Absolutely, you know, I think it's been your team too that has defined, as you said, the way that we can think through the prognosis of people with HRR mutations who have prostate cancer. And I know you've done that in the localised disease setting and more recently with the CAPTURE study that looked at BRCA mutations in patients with metastatic castrate-sensitive prostate cancer and mCRPC, and tried to understand the prognosis of these patients. Can you tell us a little bit about the CAPTURE study and what you found in that study, particularly in terms of the survival outcomes of patients? - [David] Yes, one of the needs that we saw when the advances of next-generation sequencing were applied to the patients that we have a lot of information about alteration of genes that might even reveal or give possibility to develop certain drugs on drugged patient on trials. But what's happening with the patients with normal treatment, how we should treat them beyond a targeted drug, if we don't have access, if we don't have a trial. And that was the motive that we started to capture, is to understand how patient with HRR alterations behave with different treatments, with different sequences. And that we saw is we confirm in some way that as we expected, somatic break alterations and other HRR alterations behave aggressively. That was something inspected, but not confirmed. And we have confirmed that now in metastatic CRPC and metastatic hormone-sensitive prostate cancer, and especially BRCA. In fact, I think that one of the most interesting findings from CAPTURE in metastatic hormone-sensitive prostate cancer is that if you have a BRCA mutation, doesn't matter that you have low volume of metastasis or you have four or five metastasis, BRCA always behave aggressively. And when we are speaking about the escalating... The treatment of some patients, we identify BRCA, these data are pointing at that, we have to maximise the treatment of this patient because they are always going to behave aggressively. - [Alicia] I think that's so important. And one of the things that would make that possible, of course, is that we test for these alterations, whether it's BRCA or the other HRR mutations. And I wonder, how do you think about the timing of HRR testing for patients who have metastatic disease? How does that influence the way that patients may have an opportunity to overcome potentially a BRCA mutation or other HRR mutation that inherently puts them at risk for a prognosis?
- [David] I think that one of the limitations sometimes with this is that it's difficult to implement in our daily practise, is only informing about prognosis, because we have so many prognosis factors. But here it's going beyond prognostic. We have drugs, but also it's important to understand how these patients progress and how we had to manage standard treatments and when to treat. Because these patients... There are two very important observations, okay? We know that sometimes when patient progress by PSA takes time to progress radiologically, and we can... Depending on how the patient is clinically, we can maintain a treatment or not. In BRCA patients, the PSA progression, the biochemical progression, happen almost at the same time the radiographic clinical progression. So we have to monitor this patient more closely and be a little bit more aggressive in treatment decisions. And the second thing, because the trials that has shown nowadays that the incorporation of PARP is improving outcomes of these patients in mCRPC, but also AMPLITUDE trial has showed that improved outcome in metastatic hormone-sensitive prostate cancer. I think that it's important that we test this as soon as possible. If possible, from the diagnosis of metastasis. If not, as soon as they become mCRPC. And here, we might confirm a difficult choice because if we don't have a good biopsy and we use a plasma sample, we might confront with a false negative result if there are not enough tumour burden. And this is an issue that probably will be discussed by other that have a lot of expertise in plasma, but plasma analysis is conditioned by the quantity of disease that I have that translate in more tumour circulating DNA, and I need a minimum quantity of tumour circulating DNA to detect some of the most frequent alterations in HRR. - [Alicia] Well, along those lines, let's kind of dig into that a little bit. So plasma testing is going to be for our somatic testing using ctDNA. And certainly, if we happen to have a prostatectomy specimen, we might go back to that. But germline testing is also important. And as you mentioned, there are treatments that we can give to patients who have HRR mutations or BRCA mutations even potentially, at some point in the near future, in the metastatic castrate-sensitive setting based on some new findings from the AMPLITUDE trial. As we're thinking about implementing this testing, though, we do have to think about how we do it and when we do it, implementation of these strategies can be challenging. Are you prioritising germline or somatic?
How are you doing this in your clinic or how would you like to do it in your clinic, recognising that it can be difficult country by country? We have challenges around, you know, testing with reimbursement, and laws for the country, and counselling, perhaps, that may be required. So how would you do it ideally, and what is that ideal state that we could have, maybe germline and/or somatic testing to try to understand those treatment options? - [David] So in a ideal world, with all the resources available and no limitations of my health insurance on my national health system, I think that we should do both, because both are giving information and our approach in our research project has been always using both, because both help to understand the results. However, that we do in daily practise depend a lot what is covered, is not covered. If we do germline, that is a possibility. We might be announcing only a half or a third depend on the genetic background of our population. I have a population with frequent funding mutations, like as Ashkenazi Jews like the Icelandic mutation, et cetera. I might just do BRCA in germline and detecting the majority of patient, but I don't have like happen in Spain that we don't have funding mutation. We can have mutation in all across the BRCA gene and there are no one that is more common than other. It's only a third of all the alterations. And there, we are going to be missing if we only do germline. But it's the only thing that I have access, I will do at least germline. I think that the alternative approach is use somatic, being aware that sometimes somatic might lose a small percentage of germline alterations, but will detect most of the germline alteration, as well as the somatic. And here is very important with tests. I have access when I do it, if I have a good sample and many other questions, but at least try to do somatic. If you don't have somatic, do germline. - [Alicia] Yes, it does get complicated. And thank you for breaking down the expected rates that we might have with these two different approaches in terms of finding these alterations. You know, you made reference to this, but I wanna call it out a little bit. You mentioned that in the CAPTURE study, it was the BRCA mutation that really was overriding all of the other prognostic factors, so can you dig into that just a little bit and make sure that everyone understands? So this would be more prognostically relevant than maybe visceral metastasis, or more prognostically relevant than high volume or low volume, or de novo versus recurrent status in your CAPTURE dataset?
- [David] Okay, so we already saw that in metastatic CRPC, BRCA was most important than other prognostic factors like localization of the metastasis. For example, from the data on mCRPC, we can see that having BRCA is worse than having visceral metastasis, no? What we learned more recently in metastatic castration-sensitive prostate cancer in the second CAPTURE study is that... Is more important than volume and other risk factors. In fact, BRCA patients with high risk are worse than patients with no BRCA alterations, high risk or high volume. Definitely, you can use both definition, BRCA is worse. The more striking results was when you look to the low volume, a population that sometimes we are speaking about the escalating treatment or using approaches like oligometastatic definitions to treat also with radiotherapy, and reduce and maybe the hormone therapy. The patients that have BRCA, the survival, the RPFS and the overall survival was more similar to the patient with high volume BRCA than to any other group, suggesting that you have BRCA, doesn't come metastasis, other risk factors come after BRCA, and we have to maximise treatment. In fact, when usually the time from biochemical progression to radiography for clinical progression in patients with low volume disease or low risk are usually more than a year. For BRCA was happening within three months. So it's a really aggressive disease, pointing out that probably that we have to change our approach just based in volume if we have certain conditions. And maybe it's the same... And we don't know, it might be something to learn for other alterations beyond HRR, like p53, or retinol, or RB. - [Alicia] That's just such a critical point, so I appreciate you really being very clear with that. And I wonder, you know, if we're doing this testing and these patients are progressing within just a few months, we're already in the setting of metastatic castration-resistant prostate cancer. You know, there are multiple studies, in this particular setting of mCRPC that have informed our ability to choose treatments, I wonder if you can share how the profound trial, which has been out for a few years now, helped to shape your thoughts around using PARP inhibitors in patients with mCRPC who have these HRR mutations, perhaps particularly, those with BRCA mutations or ATM alterations. - [David] Yeah, I must say that I'm a little bit biassed. I was part of the PROfound study development, as part of the studying committee. And I am a firm believer of the role of PARPs from very early on. For BRCA patients, for me was very clear. Even that was not a pre-established analysis endpoint it was a post-hoc analysis that we should give PARP as soon as possible. Because we knew from periphery, from early data, that patients, even when they respond to taxanes, they respond as short leave. And for PARP... With PARP, we saw that there were strong signals of benefit. So I have been very supportive or giving PARP as soon as possible.
Some results that were confirmed later by TRITON, that is probably better for BRCA to give PARP than give a taxane. ATM is a little bit more complex, and I think that we don't fully understand yet ATM, it's the same having biallelic or a monoallelic alteration, because it's very common to find ATM mutations in just one allele that might not activate the pathway and might not be directly linked to the aggressiveness. So we need to do more work on that. But if I don't have a better option of treatment, if a patient... I am keen to give PARP inhibitors to patients with ATM mutations if I don't have any other better option. - [Alicia] I think that's a great message to these different alterations, these different mutations can have different implications in terms of our treatment decision-making with BRCA being the mutation type that we aim at most importantly, and some of the others, particularly ATM, may have a less robust response, and this can be important for clinical decision-making. When you are doing things like testing, in routine practise, I wonder if you can share how you might have overcome some of those practical challenges that you face, and we alluded to this a little bit before. But a goal of this series is to help people understand why they should think about testing and how they can actually implement that practically in their practises. So how have you been able to successfully do that in your practise? - [David] I mean, we are very lucky on that because we have access to a lot of reserve resources. And that means that we have our own project usually supported by grants to sequence patients. We have also the support from running many clinical trials that give access to the training. We have also an excellent thing of familiar cancer and cancer genetics, Selena Castro is one of the leading physicians on that part in our centre. We have been able to test more patients probably than many others in our country. But we are always looking to ways that we can maintain that, and sometimes that mean referring the patient to a colleague that have access or having always looking to other alternatives that they they can access. The important message I think is that we have to test these patients.
If we don't have a good test and we think the patient might have an alteration, try to test again with a better test. That is an important message. Because sometimes we might have the local test that is not ideal, that is not detecting, for example, BRCA lesions. Maybe the hospital on the other side of the city has a trial and have access to a really good test. So send your patient for testing because I think that is really key that is detected and the patient is treating accordingly with the benefit that we have nowadays. And we have also been working a lot improving how we test the patients at a technical level, because that's an important issue, is something that has provide success in many diseases, but probably the majority of the test that we have in our hospitals has been developed, thinking in breast cancer, in lung cancer, in colorectal cancer, but not in prostate. And we have multiple issues with prostate cancer samples that make a little bit more difficult to sequence and detect things. - [Alicia] Would you mind going into that a little bit? And also, how this may be different because we're trying to work as medical oncologist, you and I, with urologists who are, you know, a very specific surgical subspecialty that is now getting acquainted with this type of testing, but hasn't necessarily been as focused on this before. So what are our unique challenges, and how do we best use the multidisciplinary team to accomplish this gargantuan task of making sure that we test all of these patients? - [David] I think that the most important message, especially, for our colleagues urologists that are from the beginning involving the diagnosis of the disease, is that even when the patient in metastatic, they have to try to get the most quantity of material possible, the better biopsies that is possible, that this biopsies has to be taken with care and process rapidly in the pathology departments, because now, it's mandatory that we have this... That we can sequence these samples. And the traditional problem is that we have very little tissue, very little tumour cellularity, and this is a real challenge when we try to detect alterations in tumour cells using techniques like next-generation sequencing. So improving the quantity of material and the presentation of the biopsy is essential. We had to do the most effort even when the patient is metastatic, to attain the maximum of tissue as possible. And then I think that is very important that we start thinking about and learning a little bit about what is able to detect the test that I perform on the test or what is not able, like we know that for sentinel lesions, we need a PET scan of an MRI and not CT scan.
So for detecting BRCA or ATM, we need certain tests and no other that is not able to detect that alteration. We have to learn as physicians ordering that test, which is the test that they should prescribe. And there are many that can do that. So we don't have to be focusing one option or the other, it's just that the option that we choose is several... Is able to detect what I need to detect in prostate cancer. - [Alicia] Great, so for the last minute or so, if you could just share with us what are your thoughts in terms of how we can make HRR testing the most actionable and clinically relevant thing in our everyday practise? Just a high level bullet, what is your message in terms of making that the most effective thing that we're able to do for our patients in clinic? - [David] I think that one of the things that might help us is that we do that in a organised manner. Because many times, all my experience is that many colleagues are trying to do that and they have to do everything by themselves and that is tiresome when you have busy clinics, to do everything, to look to the biopsy, to recover that, to do the paperwork, whichever. This has to be implemented structurally within the normal diagnostic pathways of our hospitals. I think that the way of thinking has to be, this has to come from the diagnosis, especially the patient's metastatic, and has extra effort that they have to do during the 15 or 20 minutes that I have to see my patient. It has to... I think that has to be reactive, initiated from the time that a sample arrive to the pathology department in a metastatic patient. That moment is where diagnosis has to be activated, is the key for success. - [Alicia] I think that's a great message.
Be structured, be systematic, involve all of us, including the pathologists in making sure that this happens, as well as the urologists, and certainly, the medical oncologist who need to support some of the treatment decision-making that we now have the opportunity to make. So thank you so much for sharing your insights, David, it was truly a pleasure to talk to you. - [David] Thank you very much, Alicia, has been a pleasure.
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