BRCA1/2 and Beyond - Molecular Diagnostic Testing and Treatments with PARP Inhibitors for mCRPC - Joaquin Mateo

November 23, 2020

In May 2020, the United States Food and Drug Administration approved olaparib for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC), who have progressed following prior treatment with enzalutamide or abiraterone.

Efficacy was investigated in the PROfound study, a prospective, multicentre, randomized, open-label, Phase III trial testing the efficacy and safety of olaparib versus enzalutamide or abiraterone in patients with mCRPC who have progressed on prior treatment with NHA treatments (abiraterone or enzalutamide) and have a qualifying tumor mutation in BRCA1/2, ATM or one of 12 other genes involved in the HRR pathway.

A statistically significant improvement was demonstrated for olaparib compared to the investigator’s choice in Cohort A (patients with mutations in either BRCA1, BRCA2, or ATM ) for radiological progression-free survival, overall survival, and objective response rate.

In this conversation Alicia Morgans, MD, MPH, and Joaquin Mateo, MD, Ph.D. discuss the practice-changing data we have learned from the PROfound study, which solidifies the importance of precision oncology for our patients. They discuss what this data suggests for those patients beyond BRCA1/2 and the critical need to prioritize enrolling them in clinical trials. Clinical trials for this patient population beyond the PROfound study could exploit other DDR defects in prostate cancer, leading to additional optimal treatment options

Clinical Trial Information: NCT02987543


Joaquin Mateo, MD, Ph.D., Vall d’Hebron Institute of Oncology (VHIO), Barcelona.   Joaquin joined the Vall d´Hebron Institute of Oncology in November 2017 as Principal Investigator of its newly established Prostate Cancer Translational Research Group to lead research aimed at translating prostate cancer genotypes into phenotypes and a clinically-relevant classification of the disease. He and his team will also seek to build a precision medicine core for prostate cancer patients. 

After completing his medical training in Oncology at the Catalan Institute of Oncology (ICO, Barcelona), he completed postgraduate studies in clinical trial design, with a particular focus on early-phase clinical trials with companion biomarker development.  He joined the Drug Development Unit at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research (London) in 2011 for a two-year fellowship under the mentorship of Johann de Bono and Stan Kaye, working in first-in-man clinical trials of several PARP inhibitors and compounds targeting the PI3K-AKT-mTOR pathway. From 2013, he progressively focused his work towards the design and development of clinical trials for castration-resistant prostate cancer (CRPC).

Alicia Morgans, MD, MPH, Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today a friend and colleague, Joaquin Mateo, who is a physician-scientist and medical oncologist, and the team leader for the Prostate Cancer Translational Research Group at the Vall d'Hebron Institute of Oncology in Barcelona, Spain. Thank you so much for being here with me today, Dr. Mateo.

Joaquin Mateo: Hello. It's a pleasure to be here.

Alicia Morgans: Wonderful. So I wanted to talk with you a little bit about the updated results that we have heard from ESMO and now the New England Journal from the PROfound trial, looking at patients with DNA repair defect alterations. And think about that data as well as the real-world application and use of that data as olaparib has now been approved actually in many countries, including Spain last week. Which is fantastic to have access for our patients with metastatic CRPC.

Why don't we start by just reviewing the data? Can you tell us a little bit about the updated survival data from PROfound and just review the study schematic overall, of course, first, as you start? Thank you.

Joaquin Mateo: Sure. It was actually great to have the chance to update the results to the broader community. Just to recap, so PROfound is the registration trial of olaparib. It's a Phase III randomized trial where patients with DNA repair mutations, so they were prospectively selected based on tumor sequencing testing. They were randomized to receive either olaparib or a second hormonal agent.

All patients would have had prior abiraterone or enzalutamide and they would be randomized to get another hormonal agent versus olaparib. And the primary endpoint was actually whether olaparib improves radiographic progression-free survival in what was called cohort A, so those patients with mutations in either BRCA1, BRCA2, or ATM, because they are the commonest. What else? We had another cohort, cohort B, that was an exploratory cohort, where if we found a patient with mutations in other DNA repair genes, for which there was maybe not that much data out there already, they were also treated, but they were not part of the primary endpoint analysis.

And a secondary endpoint we look at overall survival. That is what we reported in their recent paper at ESMO. So the results show that in cohort A, patients with BRCA1, BRCA2, or ATM mutations, olaparib results, not only in an improvement of radiographic progression-free survival, but also an improved overall survival for that population.

However, it is true that when you go to the granularity of the data and you go gene per gene, looking at the different subsets and with all the caveats that the trial was really designed to account for the population as a whole, it showed that patients with mutations in BRCA2 that accounted for over a third of the overall trial population, just because it's the most common gene alk in this pathway in prostate cancer, were the ones that were driving the benefit the most, were the ones getting a hazard ratio for overall survival of round 0.59, I believe it was. Whereas when you look at ATM individually, there was not such a clear difference. Despite we know that some patients respond and we have seen it in several Phase II trials, the difference was not there. We're looking at these patients as a sole cohort.

Alicia Morgans: Which is so important and so interesting. And when we see this survival benefit in this population, it's encouraging to think that we're not just prolonging radiographic progression-free survival, of course. The drug actually was approved prior to this updated survival data, but really now I think solidifies the importance of this option for our patients. Can you talk a little bit about when you think about using treatments like olaparib for your patients with metastatic CRPC, of course, noting that sometimes label nuances can be different from country to country, but let's tackle first the idea of pre- or post-taxane. What are your thoughts? What does the data suggest in terms of the use in those settings?

Joaquin Mateo: I think that's a critical question. The pre- or post-taxane. I think that first in a more general view, of course, I would think in prescribing a PARP inhibitor to a patient, if I have a patient who has progressed already to a hormonal agent at least because every single trial in this space so far, that has reported has been in a population of patients who have received that have progressed to abiraterone and enzalutamide. It is true that the trial that has led to the approval of rucaparib the TRITON2 trial that is a single-arm response rate based Phase II trial only allowed patients post-docetaxel hence the approval of rucaparib after chemo whereas PROfound, we accepted patients regardless of prior exposure to chemo, and that's the defense of the label. Not because we have seen a difference really among these populations, it's just how the trials were designed. 

I think that PARP inhibitors, by being the first biomarker selective therapy approved in prostate cancer, I'm going to need from us to change the way we understand these sequential lines of therapy. We have not proven that using a PARP inhibitor is better than using chemotherapy, really. What we have proven is that using a PARP inhibitor is a suitable additional option for these patients. And of course, now, it will need another wave of trials to position it as first or second-line therapy in the prostate cancer space. But I think it's the same situation as we have had for years. How do you select if a patient gets docetaxel versus enzalutamide first? It comes to individual patient characteristics and a discussion with the physicians. We know that the olaparib and also rucaparib in some labels and in some countries will be an option, for some patients with prostate cancer based on the genomic profile and whether we will place it before or after in the line of therapy until we have more trials, it will probably be based on patient comorbidities, patient preferences, and also the experience of the physicians I think.

Alicia Morgans: Absolutely. Well, I think it was interesting to see some of the exploratory data gene by gene in the PROfound trial. Now, just to be very clear, this is all exploratory. There were so few patients with some of these alterations that it really doesn't make any sense to draw final conclusions because you really didn't have the power to do that. But when we did look at certain mutations, there's been a lot of talk about their outcomes, including mutations like ATM, PALB2, even CDK12, which has had a lot of buzz around it CHEK2, of course. What are your thoughts from a mutation by mutation basis in terms of use of these agents?

Joaquin Mateo: I think that the data for PROfound, as you said, was not intended to be definitive in the gene analysis, but it's true that it goes in line to what we have seen in the several Phase II trials, not only for olaparib, the TOPARP trial, but also in rucaparib with the TRITON trial and even the preliminary data that is being presented from the talazoparib and olaparib trials seems to point in the same direction that patients with BRCA2 mutations have very high response rate, very durable responses, probably for patients with BRCA1 mutations is going to be something similar, but these mutations are just so rare in prostate cancer, that it's going to be very difficult to draw conclusions as a group. And then we have two caveats here, right? One is those patients with mutations in ATM, and I'm going to leave CDK12 apart because one of the things that happened is that by the time we started PROfound, we didn't really have any data on CDK12 like from TOPARP, for example, in the first trial.

So we really didn't know what to expect, but it is true that in ATM, we had seen responses before. And in PROfound, we did see some responses. It seems that particularly... And this is an exploratory analysis, patients who got olaparib with ATM mutations in the very latest stage seem to be deriving some benefit actually, but it is still not clear who are the patients? How do we identify the patients with ATM mutations that are going to benefit? This is not about ATM yes or no. It's about okay, if only some of these patients are benefiting, how do we identify them? And right now let's accept that we don't really have the tools to identify who they will be.

Then coming back to your pre- or post-chemo question. Okay. If I have a patient with a BRCA2 mutation and I have the option of chemo or a second hormonal agent or olaparib, probably I will put the chemo on the olaparib at least in the same level of preference, right? Maybe in patients with mutations in ATM or other genes for which there is less evidence. Personally, I may be prioritizing the chemo if that's an option and keep the olaparib as an option for later on, if the patient has no further therapeutic options.

I think there are completely different scenarios where you mentioned about PALB2. And there may be other genes such as RAD51C and RAD51D. We have seen patients with exquisite responses to PARP inhibitors in this population, and it's not only in prostate cancer. There is now data coming from ovarian and breast cancer studies showing a similar thing.

The problem we have here is that these mutations are so rare that we will never be able to conduct properly powered trials for these populations. So here we have two options. One is to pull them as a group. And clearly, that has caveats because you're going to be pulling things that are different. So how do we polish and how do we refine this pulling of different genes? And the other... And this is one of the research aims that my group works on is how do we define other biomarkers that tell you that these tumors are very similar to the BRCA ones hence supporting the approval. But it is true that for example, in Europe, we just received news of a more restricted approval for olaparib limited to BRC1 and BRC2. The discussion may be about ATM. But actually, my question is also what happens with the patients with PALB2 mutations or RAD51 mutations? How are we going to get these drugs approved for them if we cannot really prove the benefit with a standard clinical trial approach?

Alicia Morgans: Yeah. And that's what's so difficult. Exactly as you said, you will never be able to power a trial with those specific alterations. And so when you see patients with those alterations and you don't have access to olaparib, for example, what do you do? Do you have an alternate approach? Do you use a platinum? Do you do routine standard taxane chemotherapy? Are there other approaches that you've been using clinically? Recognizing of course, as you said, we don't actually have perfect data to tell us one is the better option over the other, particularly in these very more rare mutations.

Joaquin Mateo: Well, I would say that for those patients beyond BRCA1 and BRCA2, first of all, we are really trying to prioritize enrolling those patients in clinical trials so we can actually generate the data. But outside the clinical trial setting, again, the data on PARP inhibitors does not mean that other treatments will not work. This is not about PARP inhibitors versus chemo. This is PARP inhibitor as an additional option. So these patients still have the option of chemotherapy, of hormonal agents of radium-223. The disease is limited to the bone. So these are still options that probably work equally well in these patients. If not, you mentioned platinum as an option. I mean, you know well that platinum is not part of the standard therapeutic armamentarium of prostate cancer, but we know from ovarian cancer, that there is a signal there that patients who respond to PARP will respond well to platinum.

And when they become resistant to one, they may become resistant to the other. There is not a hundred percent match, but there is a [inaudible 00:11:48]. And there are some reports suggesting that patients with BRCA2 mutations and prostate cancer respond very well to platinum. Beyond BRCA we have isolated case reports. We don't have that much evidence. But it is true that in the past, clinical trials have been exploring platinum or platinum combinations in prostate cancer without the biomarker selection component. And there were some patients who'd respond. So I think that it would make sense to consider that as an option for some of the patients if the standard options are no longer available. But I would say that as a community, we have to prioritize that any of those patients that get enough of these treatments are getting the treatment in a frame that allows us to collect data prospectively through observational registries or post-marketing studies so we can actually learn from these cases and in one or two years time, we can sit again and discuss properly with data, which is the right way for those patients.

Alicia Morgans: I think that's a wonderfully balanced response and so helpful to everyone who is trying to make those decisions. What I think is important and what I want to reflect back is that you said, of course, that these studies of PARP inhibitors and PROfound in particular was not a study that tried to determine whether olaparib was going to be better than chemotherapy or better than radium, or better than anything that was not actually designed into that trial, which was second AR targeted agent and patients who had already progressed on one.

So it really is incumbent on all of us to continue to understand how these different standard of care therapies are going to react in patients both before or after their PARP inhibitor treatment when they have these DNA repair alterations. And so we really do need to continue to perform these trials and to identify those patients who have these less common alterations, so we can get them into these trials and others to understand how to best approach their cancers as well.

So thank you so much for reviewing all of this. Congratulations on the phenomenal work within the PROfound trial, congratulations on helping us understand a new therapy for men with CRPC that does have a survival benefit. And that's so important to us as we try to take care of these patients. And congratulations, of course, on your ongoing work and all that you've done with the TOPARP studies and future work. I really appreciate it. Any last words or final messages for the listeners?

Joaquin Mateo: Well, I think that the trials will bring an additional therapeutic option, but it's also bringing a change on the way we manage those patients with advanced prostate cancer by introducing the component of genomic stratification. I hope it's not only going to bring an additional therapeutic option, but it's going to be an accelerator for the development of other therapeutic strategies and it also will cause, I know, some struggles at the beginning until we find the optimal way to perform the testing, we are going to have to change some of the pathways that we have in our centers. We don't have to struggle with how to interpret sometimes the data if we don't understand it well. But I think that this is an investment now, a learning process that hopefully will result in better and more precise patient care in the near future.

Alicia Morgans: Fantastic. What a wonderful note to end on. Thank you so much for your time and your expertise, Dr. Mateo. I do hope to see you in person again someday soon. Take care of yourself and keep up the good work.

Joaquin Mateo: Hopefully I'm also looking forward to it. Take care. Bye.