Understanding BRCA Mutations: The Pivotal Impact of the CAPTURE Study - David Olmos

June 22, 2023

In a conversation between Alicia Morgans and David Olmos, they discussed the exciting findings from Olmos' presentation focusing on prostate cancer patients with BRCA mutations. Dr. Olmos highlighted that BRCA1 and BRCA2 mutation patients, regardless of germline or somatic origin, generally have worse outcomes compared to other patients. The CAPTURE study he spearheaded, which involved multiple cohorts, helped to shed light on these findings. His study further revealed that these poor outcomes can potentially be improved by incorporating PARP inhibitors into standard therapies. Despite the promising implications, Dr. Olmos noted challenges related to the availability and accessibility of combined treatment with PARP inhibitors, such as abiraterone plus olaparib, in various regions, including Europe. As a final message, Dr. Olmos stressed the importance of testing for BRCA1 and BRCA2 alterations to provide precise patient care and potentially improve outcomes.


David Olmos, MD, PhD, Medical Oncologist, Centro Nacional de Investigaciones Oncológicas

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here with Dr. David Olmos, who is at Hospital 12 de Octubre in Madrid. Thank you so much for being here with me today.

David Olmos: Thank you very much, Alicia, for having me here today. Oh,

Alicia Morgans: Wonderful. So, David, I'm so excited to talk to you about your presentation at ASCO 2023, really exciting information about patients with BRCA mutations. Can you tell me a little bit about this?

David Olmos: I think that the key message from the present, our study presentation today was that, BRCA1, BRCA2 patients define if the origin of their mutation was in the germline or somatic, have very poor outcomes compared with other patients. And we can change these outcomes in light of the recent results of phase three trials by adding PARP inhibitors to standard therapies.

Alicia Morgans: Very important. And now tell me a little bit about how you got to that conclusion. How did you put it together, I think you, you said several cohorts in this study, in this analysis to give us this information.

David Olmos: Yeah, so because we knew before a lot about the role of germline BRCA2 mutations in prostate cancer and we have seen how people have just assumed that somatic alterations in BRCA2 and other HR gene were the same, that germline BRCA2 and this was not demonstrated. So to test this question and also how to better manage with the standard therapies beyond PARP inhibitors, these patients, we built the CAPTURE study. The CAPTURE study has three cohorts here. We have presented just the initial result of the first cohort that was focused on metastatic castration-resistant prostate cancer. And this was built from patients enrolled in five different prospective cohorts from our PRoCuRe biomarkers study network. We elected only the patients that were prospectively enrolled before starting first line for mCRPC. And we have a sample of RNA for germline line barring analysis as well as a formalin-fixed paraffin embed tumor sample, which according to the central pathology review was amenable for molecular analysis. And we ran in parallel, germline and somatic sequencing of the samples establish both, the pathogenic of single nuclei variants indels and very importantly to differentiate on homozygous and heterozygous losses in BRCA1, BRCA2, ATM and other genes related to homologous recombination repair.

Alicia Morgans: Very interesting. And now you specifically mentioned ATM, which at least as we think about some of the therapeutic trials looking at PARP inhibitors like Olaparib or Rucaparib in these populations, they don't necessarily always seem to have such robust responses and you included them I think, which is so important for our information. Did you see differences between ATM patients, and the BRCA patients or any other alterations? Though of course I acknowledge you only really presented the BRCA, so maybe you're not actually ready with that data yet.

David Olmos: Yeah, we are not ready yet for that. Alicia, we, we stratify analysis according to BRCA and the plan was if we found a difference between BRCA and BRCA, was to compare BRCA with other HRR Non-BRCA as secondary analysis and we found also difference. Now we are working for future presentations to analyze, which is the ATM role. The problem is that we compare ATM role ATM with no at tm and in this patient we include BRCAa. We might not see a difference and we are working how to better understand separating BRCA where we have established clearly a difference from ATM, but we are not presenting this data yet as we need to have more robust results.

Alicia Morgans: Well, certainly you have our appetites wetted to see this data come in the future. We're very excited for this. When you did look at the BRCA population, you mentioned they had poor outcomes. Was this something that you could remedy by treating them with PARP inhibitors, really targeting that alteration to try to harness that weakness of the cells?

David Olmos: So Alicia, we exactly saw is that when we compare BRCA1, two analyze together with non BRCA and with HRR, this patient has worse radiography, progression-free survival, worse progression-free survival too. So adding the effect of first and second line and over overall survival. And this was an accumulative effect that we saw how increased as we have more treatments, this effects were not attributed to having worse prognostic factors at baseline or to have a less treatment exposure. In fact, they have more SEC active treatments than non BRCA patient that were progressing less and have more long term responders to first line. So in conclusion that we saw is that infinitely on the gen line and somatic status allelic or monoallelic, when we analyze together BRCA1 and BRCA2, they are always worse with arsis and with vaccines. But we know that adding just a PARP to an IC from the phase three trials, we can revert these poor outcomes.

Alicia Morgans: Wonderful. And you'll have to tell me, I know that there are places in Europe where now in first line mCRPC using the combination of abiraterone and olaparib is actually approved and is potentially available for patients. This is unique I think as we in the United States do not have that luxury. But I wonder is this a combination that you have considered using in your clinic at this point in time? Is this available for you as you're making these choices for patients with first line mCRPC?

David Olmos: So it is a complicated situation. It's true that EMA, the regulatory authority in Europe has approved the combination of abiraterone plus olaparib for all commerce and also has approved niraparib plus abiratone for BRCA one and two. But the fact is that the reimbursement is not there yet, especially in Europe that we have our practice is usually based in national health service funding. So we are not having the opportunity to give this combination to many patients. But if have the chance, of course I will treat a patient with BRCA2 alteration with a combination of an ARSI plus and PARP inhibitor independently of the PARP inhibitor that I can

Alicia Morgans: Wonderful to sort of just have that context. Thank you. I, I think as this is rolling out across the world in different ways, it is interesting to see how it's being available or not available in the places where we live and where we take care of patients. So thank you for that. So if you had to give a final message to the listeners about the presentation that you gave, what would that message really be for these patients with BRCA1 and BRCA2 alterations?

David Olmos: I think that in summary from my presentation that we can conclude is that it's very important to establish whether BRCA 1 and BRCA2 have alterations whether germline or somatic or maybe test both to deliver a more precise patient care because we know that we can prevent the poor outcome of these patients by adding PARP inhibitors that are available.

Alicia Morgans: Such an important message from a real world cohort treated in Spain. I think it's so important that we have clinical trial data, but real world cohorts like this with that really in depth analysis from a scientific perspective, give us the insights that we need to care for the patients that we see day-to-day. So thank you so much and that message is clear use of PARP inhibitors can help to overcome the poor prognosis that we see in these patients with BRCA1 and BRCA2. Really important to test and really important to treat. Thank you so much for your time today. Thank you

David Olmos: Thank you to you Alicia.