HRR Mutation Testing in mPC
Transcript: Real-world therapy sequencing in mPC
Gunhild von Amsberg, MD, and Alicia Morgans, MD, MPH
Interview recorded November 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.
- [Host] Hi, and welcome to another of our expert exchanges and HRR mutations in metastatic prostate cancer. Today I'm so excited to speak with Dr Gunhild von Amsberg about sequencing therapies in the real world and talking to her about what she would do. Thank you so much for being here with me today, Gunhild.
- [Gunhild] Thank you so much for having me.
- [Host] Well, wonderful. Well, you know, I think we should really just dive right in. This is a complicated discussion when, even when you're not thinking about HRR mutations, but they certainly add some flavor and some options to the list of opportunities that we have as we sequence treatments for advanced in metastatic prostate cancer. Let's just start at the beginning. How do you interpret HRR test results in the context of these decisions around sequencing agents, especially when you're thinking about the different mutations you might see, the way the cancer may be progressing in a particular patient and what therapies that patient may have had in the past.
- [Gunhild] So first of all, currently we do have only approvals around the globe for the mCRPC settings. So this is where we normally start to test our patients. If it's not germline testing, I think around the globe, germline testing is possible even earlier. But for HRR testing in general, this is more or less in the metastatic castration or system setting. So if we do testing, we need to know what we are testing. Are we going for somatic testing? Are we going for germline testing? Are we tissue testing or are we performing liquid biopsies? And there are huge differences around the world, what is covered and what is reimbursed and what is available. So normally, our gold standard in Europe is still somatic testing from tissue and germline testing at the very beginning of the first diagnosis. So what we would do if a patient enters the mCRPC setting is see if the patient already had a germline testing, if anything is already known. And if not, we would try to cover as many HRR genes as available. And of course, BRCA1 and 2 should be included within the set and preferable as CDK12 and PALB2 as well. And this is because BRCA1 and 2 has the best evidence for the sensitivity to PARP inhibitors and there is some well-known sensitivity from PALB2, as well as from CDK12, while the other ones are more or less sensitive depending on what we are looking at.
- [Host] I think that makes a lot of sense. And similar to your practice, I think I also do germline testing in metastatic disease, even in advanced, locally advanced prostate cancer, high risk localized prostate cancer, we can do germline testing in the US. And so often, we'll hopefully have that information even as we get to the point of metastatic CRPC. But somatic testing is something that we may need to do at that time. And as you said, you know, this is going to vary around the world, but is absolutely helpful as we are thinking about all of the options for the next treatment in the sequence. And so I wonder what role, as you think about these options, you've mentioned a couple of these mutations as being perhaps more sensitive or better, more evidence at least of sensitivity. Does that mutation type play a big role in the way that you make decisions around treatment sequencing in advanced disease? And are there some that you would say, "Well, I'll prioritize a PARP inhibitor, perhaps a PARP inhibitor and an AR pathway inhibitor combination," or others where you may say, "I'm going to use a less targeted treatment strategy even though this is one of those genes that might show up in an HRR testing." Yeah.
- [Gunhild] I think that's a very important question because if we look at those panels and if there are less information regarding the genes, our decision may be different. I mean, the best evidence, and we've already pointed this out, is regarding the BRCA1 and 2 alterations, especially BRCA2, and especially if both genes are affected, meaning that we have a very high allele burden here. Here we have on the one hand a very high sensitivity to PARPis, and we have seen the best results within the PARPi ARPI combinations, and on the other hand, we know that those patients really face a dismal prognosis and show very, very disappointing results to other available standard treatments including chemotherapy with taxanes or the other ARPI options. Those would be patients I would definitely treat in this way. And then as already pointed out, PALB2 and CDK12 show promising activity while, for example, ATM and CHEK2 are less sensitive to PARPis and those are not approved, for example, for PARP inhibitor monotherapy in Europe.
- [Host] Yeah, I think those all make sense. I take a similar approach in my clinic. You know, one thing though that comes up and the answer varies around the world, even within our own practices within a single institution, I think, is the idea of whether we should retest with a newer test, whether it's maybe a ctDNA test when we had prior tissue-based testing or even just repeating ctDNA liquid biopsy for patients who have progression. And as we're thinking about sequencing, of course, they may have had prior tests, not just prior treatments. Is that something that you would ever consider and what factors go into the decision around considering retesting for HRR in these patients?
- [Gunhild] This is a very hot discussion in Germany as well. So I think point one, if we did have only germline testing before, we know that not all the alterations are covered because, for example, BRCA1 and 2, only 50% of the patients are captured with germline testing. The other ones are acquired alterations. So we will only detect them with somatic testing. So that would be my first point. If only germline testing has been performed, we need a somatic testing. The next point we need to be clear about is how was the quality of the testing that has been performed? So was this an old sample where we may have made missed some of the results was the ctDNA, maybe with a low tumor burden. Those are factors that may actually impact the result negatively. So if I knew that I have had an old test or an old sample for the testing, I would redo it, especially if it would influence my decision how to choose the next treatment line. And of course, if the patient progresses very rapidly, subclonal alterations may be of interest as well. And also, we know that HRR alterations are a rather early event. I think we would retest those patients anyway for other acquired alterations, and then I would include HRR alterations again.
- [Host] Yeah, that makes a lot of sense. And it's interesting, there have been some registries, there's a real world registry of the promise registry that did look at retesting among patients who were just getting this in standard of care, real world practices. And there was some low rate of picking up additional abnormalities, especially in test two and three. I'm not sure for those patients who were tested seven or eight times even in that registry, I don't know that there was a lot of added benefit, but it was really interesting to see that we can pick up some additional mutations that can be targeted and hopefully harness to help the patient if we do consider repeat testing, though real considerations also need to be made around, is this covered? Can the patient afford it? Is this something that's going to be available to that individual? So it's a complex discussion and debate as you said. There are other studies, of course, I mentioned PROMISE, but there are studies that are emerging that are registry real world studies, and there are clinical trials that led to the approval of the single agent and combination agents of PARP inhibitors and AR pathway inhibitors. How do you think about using that real world information and integrating it into your treatment decisions? Do you do that? Do you really focus only on trial data? What do you think about these different sources?
- [Gunhild] I think of course the trial data are the ones that give us the best evidence because the patients are very selected. But on the other hand, we need the real world data to see if we have some kind of selection bias within the trials because within the trials, normally we have very experienced centers who may already have some kind of idea who may turn out to be positive or not. And so I think the real world data are very important to interpret the results from the phase 3 trials. And I think therefore, we do need those real world data just to find out what you just mentioned. If somebody turns out to be positive at a later stage, we need to learn which HRR genes are really worth to look at because all the three trials covered kind of different panel of HRR genes from the three trials that led to approval in the first line setting of mCRPC. And I think therefore, it's really worth to have those real world data as well.
- [Host] Yeah. And you know, especially when it comes to sequencing, I think I'm hopeful that real world data might give us some better understanding, though it's difficult to test every sequence. We don't, there's no way that a clinical trial, prospective clinical trial can test every sequence. I do have another question about sequencing though, just based on some of the head-to-head comparisons that we did see, and there was a study that reported a couple of years ago, the TRITON trial that looked into, it was a randomization of rucaparib versus a subset of the control arm in the first line mCRPC setting that received chemotherapy. And it was really interesting, as I think about that data, the only randomized comparison of a PARP inhibitor versus a chemotherapy. As I am thinking about sequence, and I wonder, can you share your thoughts on that kind of a comparison? Was that meaningful to you? And of course, we should probably mention what it showed which one was better.
- [Gunhild] Yeah. So I think it was a very important trial because it taught us, even though rucaparib is not available in Europe, the PARPi is more efficient set than the taxane, right? We knew from the profound trial that the PARP inhibitor as immunotherapy is more efficient than a second ARPI, but that was not surprising in this context. But with the TRITON trial, we had the evidence that the PARPi is more efficient than docetaxel in BRCA1 and 2 altered patients. So that was a very relevant information and influences our choice if we do know that there is a BRCA1 or 2 alteration in the patient, because then you definitely should prefer the PARP inhibitor either as immunotherapy or as a combination approach.
- [Host] Yeah, I think it was quite powerful. So it sounds like you felt similarly. And certainly, informs our sequencing. You know, if patients have these alterations in that trial, it was really patients with BRCA1/BRCA2, and there was a subset also with ATM, which we've already said is not one that seems to have an excellent response to a PARP inhibitor. But with BRCA1 and BRCA2, I favor the PARP when considering sequencing over chemotherapy if I have access to that drug and if the patient can tolerate it. Now, I wonder, we have these combination therapies. I also just wanna hear, this is another, this is a clinical trial, but not one of the registration trials that was done as an investigator-initiated trial that, called the BRCAAway trial that tried to understand, again, sequencing by looking at whether in patients with these HRR mutations, particularly BRCA1, BRCA2, we should be doing a PARP inhibitor followed by an AR pathway inhibitor or AR pathway inhibitor followed by a PARP inhibitor or whether we might benefit patients by giving them the combination. I wonder if you have any thoughts on that because that's another trial that sort of informs my thinking about sequencing.
- [Gunhild] Yes, absolutely. You're completely right. So what the trial did actually was looking at the combination of Abi-Ola or the sequence of both drugs and compare progression-free survival for the patients with either BRCA1/2, or ATM alteration. And what we've learned from this trial that was actually run under Hussain's observation was that patients that actually received the combination did better even though the other patients did receive one drug after the other and the other way around. So the combination really seems to add efficacy. And I think, and I'm a believer in the BRCAness effect, meaning that the inhibition of the androgen receptor signal transduction pathway does affect the HRR genes and their functional activity intracellularity. So it adds efficacy in this setting.
- [Host] Yeah. Well, thank you for talking that through. And hopefully, where we are and where we practice, we're able to access that if that is the right choice for our patient. Now, here's another question. When you're thinking about interpreting these HRR testing reports, do you have any tips for clinicians to navigate those findings and to translate them into treatment discussions around sequencing or just in general, how do you approach that with patients and help them to understand what your recommendations may be?
- [Gunhild] So I think that first of all, we need to clarify for ourselves, are we looking at a somatic or a germline alteration? Because if it's a germline alteration, does not only affect the patient, but also the family. And this brings the patient and the family sometimes in a very emotional situation. So this is something we should keep in mind. And if we then try to translate our knowledge into terms the patient can understand, we should really always keep the goals of the patient in mind. And you have done such an enormous amount of research on shared decision making. So I think this is something we should aim at in the setting as well. So trying to make the patient understand the mechanism of action behind the drugs we're offering, trying to make him understand how the drugs are working intracellularly and why the side effects normally come along with those drugs and how we can deal with them makes the decision for the patient much easier because then he feels himself empowered to go this way of treatment.
- [Host] Yeah, that's great. I think an informed and engaged patient is always going to be a better partner in making these decisions together because it can be overwhelming, but breaking it down and explaining, as you said, the mechanism of the drug, the sort of generalities around what are we looking at, what does this mean, and how can this particular approach really help you with this particular cancer, I think, is a great way to do it as you said. Now, here's a complicated question though. What happens when these reports are more complex? When you have multiple genomic alterations present, it's not always that we find just one thing. How do you think about that and prioritize them? Do you have some mutations that might be sort of taking precedence over others and how do you think about that?
- [Gunhild] Very important question because sometimes, those lists are very impressive with all the alterations we can find. So first of all, if we look at a report, we look if there is enough tissue. So is this a reliable report? Are there enough malignant cells that have been looked at? And with the next step, I would like to identify the pathogenic or likely pathogenic alterations just to rule out the variants of unknowns significance or the benign alterations that are not impactful for my treatment decision. And then a third step, I would look at alterations where I think they are drivers either because of the allelic frequency or because of their pathogenic impact. One very well taken example as we already discussed, the BRCA alterations that do actually not only influence life expectancy of the patients and the sensitivity to standard therapies, but also give us a very well proven option to treat the patients. So if I see a BRCA1 or 2 alteration that is pathogenic or lightly pathogenic, and is detected in a significant frequency that would most likely influence my treatment decision for the first line. And other alterations may influence my treatment decision depending on the allelic frequency and on the, well, so to say the data that are available either from the prostate cancer or for prostate cancer itself or from other tumor entities. Sometimes we detect something that is well known in another tumor and where we do have level one evidence for another entity and that we may be able to transfer to the prostate cancer patient and the situation as well.
- [Host] That's very, very helpful. And I appreciate that you brought in not just the mutations themselves, but also these allele frequencies. And thinking about, and sometimes even talking to molecular tumor board teams can be helpful. What is driving this cancer or what is driving the majority of the clones? And I think this is a really important consideration as we try to work through some of the complicated reports that we do see. When patients do have these mutations, we already talked a little bit about this, but I wonder if you just have, as we wrap up, some advice for clinicians who are getting the germline testing and patients do have maybe a germline genetic alteration that has implications not just for them, for their cancer, for their treatment options, but also for their families. Do you have any guidance for clinicians who are trying to communicate that
- [Gunhild] Well, I think the most important point to look at is what options are available in the specific countries because normally, especially for BRCA1 and 2, there are extensive programs that help families that are affected, especially the female members of the family for screening, for dealing with the potential diseases for children that are growing up. So if there is a network that can help out and information from this network, this calms down the whole situation. But what I think would be my first point is get a genetic counselor in the team just to make sure the information for all the members of the family are available and are sufficient to help them go through this challenging time.
- [Host] Yeah, thank you. And I know that's not necessarily specifically associated with sequencing and how we choose the next therapy, but absolutely comes up as we are trying to make a plan for this patient over time. Sometimes it's important also to ensure that we are helping him and his family think through their future and how they can potentially get involved in some of these programs, as you mentioned. Well, I think that was a wonderful conversation. I so appreciate you going through the complexities of considering sequencing when it comes to these HRR mutations, the testing, the treatments available. Thank you so much for your time and your expertise today. - [Gunhild] Thank you so much.
Developed by EPG Health. This content has been developed independently of the sponsor, Pfizer, which has had no editorial input into the content. EPG Health received funding from the sponsor to help provide healthcare professional members with access to the highest quality medical and scientific information, education and associated relevant content. This content is intended for healthcare professionals only.
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