Charles Ryan: Hello from PCF 2019. It's a pleasure to be talking to Joaquin Mateo, who is a Principal Investigator and Translational Scientist at the Vall d'Hebron hospital in Barcelona.

Joaquin Mateo: Yeah.

Charles Ryan: You've been involved in really the many pivotal studies that are reporting and ongoing with PARP inhibitors in prostate cancer. First of all, congratulations on that work.

Joaquin Mateo: Thank you.

Charles Ryan: Second of all, tell us what you think .. How PARP inhibitors are going to be integrated into the standard of care for prostate cancer.

Joaquin Mateo: I think the most important piece of information over the last few years is the fact that it's now clear that genomic stratification of advanced prostate cancer matters. And that we cannot treat all patients through the same route, but we have to understand the differences between their tumors. And PARP inhibitors are an example, maybe the first example we have on how only certain genomic backgrounds would benefit from this treatment. And for me that's the most important thing.

Charles Ryan: That's a really important point. I think it's no longer acceptable for a clinician to not do genomic sequencing when they're faced with a patient with metastatic castration-resistant prostate cancer.

Joaquin Mateo: Agree.

Charles Ryan: Because there's such a potential upside opportunity for them. Let's talk about some of the individual studies. The most important one I would say is PROfound because it's a Phase III and it just reported demonstrating a radiographic progression-free survival advantage for patients with BRCA1 and BRCA2 treated with olaparib compared to physician's choice. Tell us what you think is the most important aspect of that study that a clinician should integrate into his or her clinical daily life.

Joaquin Mateo: So in PROfound we included patients that had a mutation in one of 15 genes in the DNA repair pathway. Although it is true that a big majority of them had the mutation in two or three genes mostly. I think that the take-home message is that when patients have progressed to hormonal agents, if they have these mutations, they would benefit most from getting a specific treatment tailored to their mutations rather than continuing with another hormonal therapy. We presented the high-level results at ESMO and it was positive in terms of an increase rPFS, there is a clear trend towards an improved overall survival. Although it is still early, it was not mature enough, but even with only 38% of events and with a big proportion of patients going through crossover, still we saw a difference in survival. But it's true that we still need to dig more into the data to understand the differences between patients who had one or another mutation within this group.

Charles Ryan: Right.

Joaquin Mateo: That we pool as DNA repair defective prostate cancer but actually may mean different things.

Charles Ryan: I think that's a key point, which is we can't just put them all in the same pool-

Joaquin Mateo: Correct.

Charles Ryan: ... And say DNA repair is one entity. We clearly have some mutations that don't appear to be benefiting all that much from the PARP inhibitors. And ATM comes to mind because that's the, I think, third most prevalent mutation. And what are your thoughts on where ATM will go?

Joaquin Mateo: Well, we've been working on ATM for a few years now.

Charles Ryan: Yeah.

Joaquin Mateo: And first of all, we have to admit it's very challenging. We wish it was simple but it was not. There are some patients who clearly benefit, with ATM mutation that benefit, and that has been seen in different PARP inhibitors trials. But there is a big chunk of patients with ATM mutations that seem not to respond. And I think that rather than just dropping it as a group, therefore, has to be an understanding what's the difference between those that did respond. Because there are some patients that would benefit and we need to improve the way we identify those patients. Maybe genomics is not enough and we have to integrate other tests, a more complex biomarker-

Charles Ryan: Yeah.

Joaquin Mateo: ... To know who are these patients and why are they different to the others.

Charles Ryan: Yeah. Are you surprised as PROfound matures and TOPARP-B reports that the response proportion in certainly in BRCA2 to PARP inhibitors is only around 50%?

Joaquin Mateo: Well, I think that 50% in the latest statistics in terms of radiographic response-

Charles Ryan: Right.

Joaquin Mateo: ... Is quite a high achievement.

Charles Ryan: Right.

Joaquin Mateo: And if you compare it to the pivotal trials of drugs that are now approved and part of standard of care is actually quite high. There is this impression that precision medicine means that you will just get it right for every single patient, right?

Charles Ryan: Right.

Joaquin Mateo: And everyone is going to respond. And unfortunately, again, it's not that simple. I think that I really loved Eleni Efstathiou's discussion at ESMO, she made the right point. This is not perfect, but it's a significant improvement-

Charles Ryan: Yeah.

Joaquin Mateo: ... And it's bringing a whole new concept of genomics-

Charles Ryan: Right.

Joaquin Mateo: ... For prostate cancer.

Charles Ryan: No, I agree. I'm optimistic. But I think it's interesting that you can discover a patient has a BRCA2 alteration that's pathogenic and you initiate PARP inhibitor treatment with all kinds of optimism and it doesn't always work. And, I guess that brings to the fore, you know, why would that not work? Right?

Joaquin Mateo: Correct. And also why does it stop working eventually? Maybe after six, nine, 12 months. We have some patients that benefit for two or three years.

Charles Ryan: Right.

Joaquin Mateo: But many progress after six to nine months. So we need to understand how to treat these patients when they progress to these therapies. Some of them are going to become what we call DNA repair proficient again, and then probably we need to go through a completely different route. But there are some that may still present the same defect after the progression and we need to understand if then other drugs in the same pathway may be helpful for these patients.

Charles Ryan: Right.

Joaquin Mateo: But this is all new still. It's a lot of work to go.

Charles Ryan: So there's sort of three potential outcomes? A patient can go on a PARP inhibitor and not respond. Patient can go on a PARP inhibitor, respond and develop acquired resistance with or without proficiency in DNA repair, maybe from a reversion mutation.

Joaquin Mateo: Correct.

Charles Ryan: And then you're saying there's a third path, which is they develop progressive disease but they continue to harbor a tumor with a DNA repair defect.

Joaquin Mateo: We haven't seen so yet in prostate cancer, but that's the data in ovarian and breast cancer. We can anticipate that we're going to see a similar proportion of patients. But these are the studies that we can only do now that we have treated so many patients. This is something that we still... We cannot assign numbers to each of the groups yet. But I think this is going to be one of the priorities in the next few years in the field.

Charles Ryan: One of the things that's really interesting is if we go back and we look at Colin Pritchard's data and the Robinson cell paper for example, where we had a really nice kind of atlas of what's the genomic alteration in... Landscape in prostate cancer. We see that many patients with BRCA2 alterations will have other alterations as well.

Joaquin Mateo: Correct.

Charles Ryan: Right? TP53, PTEN, those types of things. And others will not. We don't have any data now to suggest whether any other, if you will, commingling genomic alterations, impact outcome on PARP inhibitors. And I'm curious as to why we don't have that data. And I think that that's where the answer may be. And what are your thoughts on that?

Joaquin Mateo: Well, I mean, in the past there have been trials looking at the impact of PARP inhibitor based on, for example, PTEN loss or the presence of [inaudible 00:06:40] arrangement based on very strong preclinical data suggesting that those alterations matter. When it was translated to the more complex patient environment rather than a cell line, it didn't seem to matter that much.

Charles Ryan: I see.

Joaquin Mateo: But that doesn't mean that actually these other alterations when they occur on the presence of a DNA repair defect may modulate the overall sensitivity of the patients. So until now we haven't focused on single biomarkers. You do have a mutation in BRCA, yes or no? You do have a mutation in ATM, yes or no? But I think the next step is going into more complex biomarker development. And how a same event in the presence of other events may have a different meaning.

Charles Ryan: Right, right. And that's going to take more patients-

Joaquin Mateo: Correct.

Charles Ryan: ... And higher numbers to make statistical associations, which will be difficult. But one of the challenges, as I see it, is we are now developing PARP inhibitors in the post-docetaxel setting, a heavily pretreated setting. We have studies in the pre-docetaxel CRPC setting. And some are advocating that we should even consider not giving hormonal therapy if we discover a patient has a BRCA2 alteration, maybe they're going to be so sensitive to PARP inhibition that we shouldn't put them through all the other treatments. And I just wonder as the disease evolves under treatment, whether that will alter in a positive or negative way the sensitivity to the PARP inhibitors? Right? So, what are your thoughts on where we are and sort of the treatment spectrum or the clinical states of the patient?

Joaquin Mateo: I would envision that if we move PARP inhibitors earlier, the magnitude of effect may be bigger because these patients would have less burden of bone disease. That is what primarily relates to the hematological toxicity. Okay?

Charles Ryan: Okay.

Joaquin Mateo: Having said so, we still need to understand if the DNA repair defect is present from the very beginning of the disease or is something that emerges over time.

Charles Ryan: Correct.

Joaquin Mateo: The data we have so far seems to suggest that is there from the beginning. And that would also support that the drug can be given earlier. Whether it can be replacing eventually hormone therapy? Well, I know there are trials looking into that. I'm not sure. What we know so far is that the proportion of patients with DNA repair defects that develop AR alterations or that have a high AR signaling seems to be very similar to patients without DNA repair alteration. So, to me, these are still AR driven tumors that on the top of that have an additional pathway alter. But I don't think these patients would not have the typically AR driven prostate cancer. Hence I'm not sure we would be able to replace androgen targeting therapy, but I know that there is people looking in that.

Charles Ryan: It would be interesting to see what those studies show.

Joaquin Mateo: Yeah, correct. Yes.

Charles Ryan: So congratulations on all this work. You are really one of the leaders showing us the way on how these drugs are going to work in the clinic. And there's a high demand for more knowledge on this. And congratulations, and thank you for sitting down with me today.

Joaquin Mateo: Thank you very much.

Charles Ryan: Always a pleasure.