Joaquin Mateo: Thank you for having me.
Neeraj Agarwal: And Joaquin, there's so much I can talk about you before we start the main topic of conversation today, which is genomics and genomic testing in patients with prostate cancer. I do really like to give you the shout-out for doing the first biomarker-based trial in prostate cancer, the TOPARP-A, which started the whole journey of PARP inhibitors in prostate cancer. We just saw the fantastic talk by Dr. Maha Hussain, who got the Lifetime Achievement Award at the PCF Annual Retreat this year, and she started her talk pretty much with the trial you did, along with Dr. Shahneen Sandhu and Dr. Johann de Bono. So congratulations for all those accomplishments over the last decade, doesn't even look like it has been a decade.
So let's start with, first of all, your take on genomics of prostate cancer, where do you think we are today, how we are going to move forward, and then we will end up with testing. So your take on genomics and how it is driving treatment of prostate cancer, maybe the top two or three takes.
Joaquin Mateo: Yeah. I think that what you mentioned about the history of the last 10 years and the work that we have done together on the field of PARP inhibitors in prostate cancer, beyond bringing a new drug to the clinic, I think that even more important than that is that we demonstrated the concept that genomics can help making individual patient decisions and helping patients at that individual basis. And so, I think that beyond bringing this one family of drugs, it's about the concept, that we can treat patients better if we use the information that we can get from genomic testing.
I think that there are mainly three areas that we can use genomics for in everyday clinical practice. Of course, there is the discovery research part, but in clinical decision-making, first is indicating a treatment, and we have the example of PARP inhibitors for patients that have certain mutations in the BRCA family of genes. But also, there is the example of immune checkpoint inhibitors. We know these drugs don't usually work for patients with prostate cancer, but we know there is a small subset of patients that we can identify through genomic testing where this drug can help. That's point one. Point two is identifying those individuals that may carry inherited mutations that also imply higher risk of cancers for their relatives.
These two indications of genomic testing are already happening in clinical practice. There is room for improvement, we need to do better in terms of access and harmonizing interpretation. But these are very straightforward implementations of genomic testing that are now happening that were not part of the standard of care 10 years ago.
Neeraj Agarwal: So treatment selection with PARP inhibitors, for example, for patients with HRR mutations, immunotherapy, pembrolizumab, can induce really long-term remissions in many of these patients, so TMB-high, MSI-high status. And you brought up a fantastic point, many of these patients have germline mutations which can affect their daughters and sisters and sons.
Joaquin Mateo: And it is true that there are other ways to identify these hereditary mutations through germline testing. But the advent of tumor testing to a wider population has also increased the number of patients in whom we identify these hereditary mutations, people who before would not qualify for hereditary germline testing based on the old criteria, so I think this is something that also has changed our mind.
And then, there is a third application, that is still not in clinical practice, that is identifying those diseases that are going to have an aggressive course. So there is very robust data, that depending on the mutations that you have in your genome and the tumor genome, there are tumors that are going to be more aggressive than others. And we have very robust area for P53 mutations, PTEN mutations, RB1 mutations, you published very nice papers on SPOP mutations and a subset of patients may do better. We still don't know how to use that information for making individual patient decisions, and I think that's going to be the next step. So we need to advance in pairing mutations to treatments, but also in pairing mutational profiles to the long-term trajectory decisions in the disease of individual patients.
Neeraj Agarwal: Absolutely. The great very nice paper by Elena Castro and David Olmos showing patients with HRR mutations have much more aggressive course of disease in metastatic hormone-sensitive prostate cancer. And we just saw, in the CAPItello trial, patients who had PTEN loss, although it was diagnosed based on IHC, but I have no reason to believe if they have PTEN loss on NGS testing, will have a very aggressive course. And what do you see about that disconnect in the PSA progression and radiographic progression based on PTEN deficiency?
Joaquin Mateo: Yeah. We have just seen the data, it probably merits a bit more of thought about it. I think that we know that there is a disconnection between PSA progression and radiographic progression, particularly in those cases that are a bit less aggressive, so it's strange what we are seeing in this trial. I think that PTEN immunochemistry is a very good, relatively cheap marker, but it is also true that we know that PTEN status sometimes is heterogeneous within a tumor, and those tumors with genomic loss of PTEN are the ones have a bona fide complete PTEN loss. So probably the disconnection between the IHC and genomic results, that, by the way, we've already seen before in the IPATential150 trial with another AKT inhibitor, mean that we have some patients with bona fide complete loss of PTEN, and then some others that partially lost PTEN or lost PTEN in some of the tumors by other mechanics that are not genomic, and probably those, the clinical effect of those drugs is also slightly diluted.
Neeraj Agarwal: So to summarize, testing for these mutations, P53, PTEN, RB1 loss, SPOP, HRR mutations, may or may not alter the treatment we are going to give to them, but they definitely are already helping in our clinics with patient counseling, prognostication, and how often we should monitor them.
Joaquin Mateo: Yeah. I think that we as a field need to build more data on how to use that information for decision-making, but that will only even increase more the value of genomic testing. I think that implementation of genomic testing in the clinic is completely justified by the treatment selection with PARP inhibitors and immune checkpoint inhibitors and by finding hereditary mutations. But I think that there is still much more that we can get out of it if we find how to use the information also for making, for example, intensification treatment decisions. But for that, we still need to generate more data.
Neeraj Agarwal: So Joaquin, you just talked about the implications on treatment, implications on families, implications on prognosis, prognostication, counseling, monitoring, why these tests are not happening?
Joaquin Mateo: That's a very good question, and I think that here, we all have to assume part of the fault. We've been developing these technologies and generating data for the last 10, 15 years, but we need to invest in making it happen to every single patient in routine clinical practice. And I think that we have, again, focused a lot in generating the data and in the technology, but we also need to invest in the implementation science part of it, so what are the barriers that probably are different from one community to another that limit the access to testing. Because sometimes, we say, "Oh, it's cost," but it's not necessarily cost, sometimes it's just getting access to the expertise to interpret. Many of our colleagues who are not familiarized with this kind of data may feel some rejection towards implementing those in the clinic if they don't feel comfortable in interpreting the data.
So I think that beyond continuing pushing research, there is still work to be done in helping our colleagues to feel comfortable with this kind of data, in helping patients being aware that this data is important and that this kind of testing is important, and then also working together with regulators and payers so they understand that this is a critical part of the patient journey. It's not an add-on thing that we request because we have the technology, it's something that will help us to treat patients better, and has to be considered in the same way of a CT scan or a pathologist looking at the histology for scoring the Gleason score. This is information that helps us understand what's the best way forward for each individual patient.
Neeraj Agarwal: So I like the way you just said, it is just not add-on testing, it is a critical part of our patients' testing and treatment, and we can no longer afford to not do germline and genetic testing in our patients with advanced prostate cancer. And this is pretty much endorsed by every guideline, ASCO guidelines, ESMO guidelines, NCC and AUA, you just name it, and everybody is endorsing them to be done in our patients with advanced prostate cancer, I would say even locally advanced prostate cancer.
Joaquin Mateo: Yes, you're right. Actually, I think that part of the reason why it's not happening in a universal manner for our patients is because until now, the indications that we had for PARP inhibitors were in very late-stage disease, thus meaning there was no pressure to test very early. And then, there is always the risk that you lose the momentum, and maybe if the doctor is not completely engaged, may not activate the testing later on.
I think that with the data that we have seen from your trials in first-line CRPC, but also in the data we've seen from Gerhardt Attard and others in the hormone-naive prostate cancer-
Neeraj Agarwal: AMPLITUDE trial.
Joaquin Mateo: AMPLITUDE trial, it's now fully justified to test patients at the diagnosis of metastatic prostate cancer, which we know that for many patients is the moment of diagnosis, we know that many patients with metastatic prostate cancer are diagnosed already with metastatic disease. I think that bringing testing earlier to the first diagnosis is a grand opportunity for harmonizing testing, because then we can implement it as part of the standard routine process.
Neeraj Agarwal: Like we do CT scans.
Joaquin Mateo: Correct, we do CT scans, we score Gleason grade on the biopsy. So if that becomes part of the initial evaluation of a patient with metastatic prostate cancer, I think it will be much easier for our healthcare systems to harmonize the implementation of testing.
Neeraj Agarwal: Fantastic comments as usual, Joaquin. Final message from you, test every single patient with metastatic prostate cancer, or even locally advanced prostate cancer, because such a high risk of developing metastatic disease, with germline testing and tumor genetic testing, to improve their treatments, improve the outcomes of their family members, and help with prognostication and counseling of these patients, and potentially monitoring of disease down the line.
Joaquin Mateo: Yeah, totally. I'm a complete believer that the more we understand the disease of a patient, the better we are positioned to make the right decisions for every single patient.
Neeraj Agarwal: Fantastic. As usual, all the words of wisdom for us and for our audience worldwide. Thank you for joining us today.
Joaquin Mateo: Thank you very much.