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Alicia Morgans: Hi. I'm so excited to be here today with Joaquin Mateo, who is joining me from Vall d'Hebron Institute of Oncology in Barcelona, Spain, to talk about his discussion of PARP inhibitors at the APCCC 2024. Thank you so much for being here with me today.

Joaquin Mateo: No, thank you very much for having me.

Alicia Morgans: Wonderful. Well, let's go through some of the highlights of your talk, and then I'll ask you some questions as you conclude.

Joaquin Mateo: So, one of the sessions at APCCC this year focused on the treatment of metastatic CRPC and, particularly, on the impact of genomic information in our treatment decision process. And my talk was about the role of PARP inhibitors in the treatment of mCRPC patients whose tumors show BRCA1 or BRCA2 gene alterations. And there were other talks about the impact of other HR mutations, but here I'm going to focus on the impact of BRCA1 and BRCA2 alterations in sensitivity to PARP inhibitors and how to best use this drug list.

We know that BRCA1 and BRCA2 mutations are present in around 10% of men with metastatic castration-resistant prostate cancer, sometimes are in the form of germline mutations, and about half of the times are in the form of a somatic mutation, so a mutation that arises in the tumor cells, but in general, we know that this is a subset of the disease with poor prognosis. And several studies by different groups have shown that tumors with BRCA mutations have short responses to hormonal therapies, also to chemotherapy, although the data for chemo is not that clear, but clearly, our patients whose tumors progress much faster than patients without these genomic alterations.

The good news is that in the last few years we have developed PARP inhibitors as a drug class for this subset of prostate cancers, and we now have data from several clinical trials, including two large randomized Phase 3 trials with two different PARP inhibitors, olaparib and rucaparib. We also have data from Phase 2 trials for other PARP inhibitors, such as talazoparib and niraparib as monotherapies, and they all show very similar results suggesting that the level of anti-tumor activity in tumors with BRCA1 and BRCA2 mutations is very high. And both randomized Phase 3 trials were positive, and olaparib and rucaparib are now approved as monotherapies for patients with BRCA1 or BRCA2 mutations mCRPC that has progressed after at least one novel hormonal agent, such as abiraterone and enzalutamide, apalutamide, or darolutamide.

I'm going to focus on BRCA mutations as I was saying, but just so you know actually, olaparib is approved for also tumors with other mutations in the HR pathway, but I'm only going to refer to BRCA1 and BRCA2, because this is the subset of patients with more responses, more frequent responses, and more durable responses have been detected. And as you can see here in the plots, the PFS and overall survival in the BRCA population is quite clear from these randomized Phase 3 trials.

So that's it. Let's say, the easy part of the precision medicine approach to these tumors. But there are questions. There are uncertainties about the specific scenarios where we don't have that much data. And one of them is if there is any difference in terms of activity for patients with BRCA1 versus BRCA2 mutations. And we try to pool them all together for historical reasons, because the preclinical level of evidence is very similar for PARP inhibitors, also the evidence from ovarian and breast cancer.

But the truth is that, in prostate cancer, BRCA1 mutations are really uncommon. It's only like 1% of the patient population, whereas for BRCA2 it's like 8-10%. So really, we talk about BRCA1 and BRCA2, but in fairness, we are mostly referring to BRCA2 mutations. And when you go to the detail, actually, you see some studies, like the TRITON2 or PROfound, that have looked at BRCA1 specifically, and the results have not looked that good as for BRCA2. And it seems that this is not because BRCA1 loss does not sensitize to PARP inhibition, but actually, it seems that in prostate cancer, some BRCA1 mutations do not associate with complete BRCA1 loss in the tumor. So, there may be some cases in which the BRCA1 mutation just happens to be there, is a passenger mutation that is present in the tumor, but it's not the driver of the disease.

So, understanding when the BRCA1 mutation is relevant, and when it's not that relevant, is difficult. We can get part of this information from the genomic report, based on whether there is complete loss of the gene or not in the tumor. But one of the discussions at the APCCC is that it is much needed to fluently communicate with the genomics laboratory to understand the clinical relevance of BRCA1 mutations when they are found in a prostate cancer patient.

The second question that we discuss is whether the origin of this mutation, whether it's a germline mutation or a mutation that has appeared de novo in the tumor, is relevant towards a treatment indication. And what I show is these three plots from three different studies, TOPARP, PROfound, and TRITON, with olaparib or rucaparib. And in all of them, the data shows consistently that the PFS or overall survival benefit is consistent, regardless of whether the original mutation comes from germline DNA or has appeared as a tumor mutation de novo. So, in that respect, tumor testing is enough to identify candidates for PARP inhibitor treatments and it is not necessary to confirm if the mutation is germline or not for treatment indication. Of course, determining the germline origin is much needed for genetic counseling and for identifying families who may be at risk of prostate and other cancers. But for treatment indication, it doesn't really matter whether the mutation is germline or somatic.

There is also the question about when to use these drugs. So, we know these drugs are now approved after progression to a hormonal agent, but the trials allow patients before or after taxane chemotherapy. So, we have a mix of data, and we don't have head-to-head trials comparing the sequence of taxane followed by a PARP inhibitor, or a PARP inhibitor followed by taxane. However, we have a subgroup analysis from both randomized Phase 3 trials that suggests there may be more benefit when these drugs are used prior to the taxane. Of course, part of it may be just because the patients are in a better overall condition before having received chemotherapy, but the truth is that at least this supports the use of PARP inhibitors straight after progression to hormonal agents, even if the patient has not yet received taxane-based chemo.

The fourth question that was a bit more controversial is that we also now have randomized trials suggesting that the combination of a hormonal agent and a PARP inhibitor is superior to the hormonal agent alone. And again, I'm just referring to patients with BRCA mutations. These trials enroll much wider populations, but I'm not going to discuss that. If we look at the BRCA-mutated subgroup of patients, they clearly did better when they received both drugs together than if they only received a hormonal agent.

Based on that, one could say, well, we have to give the combination to all the BRCA patients, right? But part of the argument is actually, we just know that giving the PARP inhibitor is better than not giving the PARP inhibitor, but patients may receive it as a combination, or they may actually receive the hormonal agent and the PARP inhibitor later. We don't have robust data to tell us which of the two strategies, combined or one after the other, is better, but based on this evidence, if the patient has not yet received a hormonal agent like an ARPI, it makes sense to consider giving both drugs together. However, something that was much discussed by the panel is that, if the patient has already received one hormonal agent, because we know that there is not that much activity of one novel hormonal agent after another one, there is probably not that much argument for considering the combination in patients who have already progressed on one hormonal agent and may still receive a PARP inhibitor as monotherapy if they have this BRCA mutation.

So, in summary, we discussed the association of BRCA mutations with poor prognosis but with a response to PARP inhibitors. One of the conclusions of the session is that, based on these data, NGS (next-generation sequencing) should be offered to all patients with metastatic CRPC because of the treatment implications, and that we now have evidence for using this drug both as monotherapies or in combination with hormonal agents for patients with BRCA mutations, and probably understanding better when to give them together in combination or alone is something that will need more trials in the year to come. But until then, we can probably start using the combo in those patients that have never received an ARPI drug before.

Alicia Morgans: Thank you so much for that, Joaquin. I mean, that was, I think, really reflective of the conversation and a wonderful summary. I just want to emphasize for the listeners that patients who had germline versus somatic mutations actually seem to respond similarly, and this is something that's so important as we are rolling out genetic testing in our clinics and we're doing this as germline or somatic testing. And, actually, I think, one of the things that was so interesting when we think about the consensus at the APCCC is that there was consensus about certain things, like we should be testing, but when it comes to when and how to test, there might have been less consensus. Can you comment on that a little bit, Joaquin?

Joaquin Mateo: Yes. This is one of the fields that has evolved, right, since the 2022 consensus to now, because I think that there was a general consensus, like almost 90% of the panelists, that patients with metastatic prostate cancer should receive the possibility of genomic testing at some point. Clearly, for those patients who are CRPC, there is a clear indication for the testing, and there was not that much consensus about bringing the test earlier at the metastatic hormone-naive point of the disease evolution. And I think that part of the plan forward for these patients depends on the local resources. I mean, if you are at an institution that has limited access to NGS, clearly you would prioritize those patients with mCRPC, because they are the ones whose treatment may change immediately because of the result, right? But as we get wider access to genomic testing, there is no scientific reason not to test earlier. So, I think the discussion is more about how we organize the healthcare resources.

Alicia Morgans: Absolutely. And I think that's one of the things that the APCCC is so good at addressing because there are people from around the world at that conference, and so, we really are thinking on a global level there.

Now, one of the things I'd love to hear as I'm considering going to the clinic tomorrow and you are going tomorrow or maybe next week, how do you think about the reports? These can be really complicated. You were talking about passenger mutations, particularly with BRCA1, and sometimes we'll get a report that says, oh, 1% of the alterations in this sample have a BRCA1 mutation, and maybe it's even a pathogenic BRCA1 mutation, but it's 1% or 0.1% or just a small fraction of those mutations that are identified in that report versus a larger percentage. How do you actually think about that? How do you interpret that? Because we are increasingly getting reports that are trying to give us the breakdown of the proportion of cells and the proportion of DNA that may have these alterations, and it can be very challenging when you're in clinical practice to really break that down and understand what does this mean for my patient.

Joaquin Mateo: Yes. The genomic reports are indeed complex. And not only are they complex per se, but also when we are in the clinic, we may get reports from different laboratories, in-house laboratories, external providers, patients may come with the report done by a third-party lab that we are not even used to. And this is getting very tricky. And I guess there is some risk of misinterpreting the genomic reports because we, practicing physicians, may not be experts in reading genomics data.

What we are trying to work on, and as we from ESMO, are working on a consensus document about how to report genomics data that hopefully will come soon, is that we are really recommending that the laboratories include part of the report that is the technical description of all the findings, but then there is a clinical context interpretation that will need the physician's input there. Of course, the report is never going to tell you, 'give this treatment,' because the treatment is not indicated just based on a mutation. It's based on the overall patient condition. But I think that we need genomic reports to include the technical details, but also, the potential clinical relevance using standardized terminologies and making them very clear to the physician. Right?

But as we work on it, what I would say is, the same as you would do for a CT report, right, CT scan, or MRI report. If you are not sure about how to interpret, you would go to the radiologist, if the radiologist is in your institution, or try to contact whoever has reviewed that scan to discuss it, right? So that would be the same. I think that when you're working within an in-house laboratory, that's easier because you can call the person in the lab. But even with external providers, there are normally ways to communicate with them and get help in interpreting. And I think that, particularly for BRCA1 mutations, it's important because not all BRCA1 mutations may be equally relevant for indicating PARP inhibitors.

Alicia Morgans: That's such a valuable piece of advice, when in doubt, reach out. I think that's really, really important and empowering hopefully for the clinicians who are listening today.

So, as you think about the studies that need to happen, certainly we don't know everything, and actually, with each study, we ask more questions. What studies need to be done? What questions do we need to answer next?

Joaquin Mateo: Well, I think that's something that was discussed in the panel is that we don't really have the right studies to decide between using PARP inhibitors and NHAs together or in sequence in BRCA-mutated patients. Okay? I'm focusing on this population.

But we also agreed that there are areas where the data might be much more needed. So in patients that are first-line CRPC who have never received an ARPI, probably we can design the ideal trial, but it's unlikely that it's going to change much what we're doing now. I think that one of the important areas where we need more data is in those patients who have received an ARPI in the hormone-naive setting, whether the data for the combination therapy still is relevant at the time of CRPC, because all the combination trials were run between 2017 and 2020, where the use of new hormonal agents in the hormone-naive setting was not that widespread, so not many patients had been exposed to this drug. So I think that that's an area where we really need the studies. Studies comparing to the NHA alone, but also studies comparing to the PARP inhibitor as monotherapy, because that would be the standard for these patients, and probably also comparing to taxane, right? That's one.

And I think that the other area that we discussed where we anticipate that data is going to be needed is that if these drugs, PARP inhibitors in combination, are now being tested in hormone-naive, where we anticipate three to four years of treatment, and that's good news. Right? That means that patients are responding for long periods of time. There are concerns about long-term toxicity. So, I think that I would like to see trials testing different smarter approaches of using these drugs maybe intermittently, maybe as an induction therapy that can be re-challenged later, but I think that, as these drugs are moved to earlier stages of the disease with longer treatment periods, we are going to need trials testing different schedules of drug administration, rather than just treating until progression.

Alicia Morgans: Absolutely. Well, thank you so much for lending your expertise. This was extremely useful today. And congratulations on your talk at APCCC 2024. I look forward to talking to you after the next conference in 2026. Thank you so much.

Joaquin Mateo: Thank you very much.