The Prevalence and Impact of Germline Mutations, PROREPAIR-B Trial - Elena Castro

Elena Castro joins Dr. Alicia Morgans at the 2019 Prostate Cancer Foundation Retreat (PCF 2019) to discuss PROREPAIR-B. This was an academic prospective observational study evaluating the prevalence and impact of germline mutations in BRCA1, BRCA2, ATM and PALB2 on metastatic castration-resistance prostate cancer (mCRPC) outcomes.


Elena Castro, MD, Prostate Cancer and Genitourinary Tumors Clinical Research Unit, Spanish National Cancer Research Center, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Norte, Madrid, Spain

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, I am so excited to have here with me today, Dr. Elena Castro, who's a GU Medical Oncologist at the Spanish National Cancer Research Center in Madrid, Spain, has traveled across the world to come to the Prostate Cancer Foundation's event, our annual retreat here. Thank you so much for coming to speak with me today.

Elena Castro: Thank you. It's my pleasure.

Alicia Morgans: Wonderful. So Elena, you have done some of the most elegant work I think, in a very hot area in thinking about DNA repair deficiencies and patients who may be susceptible to targeted treatments with things like PARP inhibitors. But also some of your work has really been around characterizing the natural disease process of patients who have DNA repair defects who receive different therapies over time. One of those was a beautiful tour de force study called, PROREPAIR-B. I'm wondering if you can share a little bit with the viewers about that study, who participated in that study and what some of your main findings were?

Elena Castro: This was an academic prospective observational study in which 38 centers across Spain participated. What we did in this study was to enroll patients at the time of mCRPC and just follow them. So the therapies were entirely at physicians' choice. We didn't intervene, we just observed. And we screened 419 patients that were enrolled in this study for a panel of 107 genes involved in DNA repair. So the aim of this study was to see what was the impact of germline mutations in BRCA1, BRCA2, ATM and PALB2 because we thought when we started this study in 2013, these will be the most commonly mutated genes in prostate cancer by analogy with breast cancer. And we also wanted to analyze what was the prevalence of those alterations. In the meantime, the [inaudible] study came out and they reported a prevalence of almost 12% of patients with metastatic prostate cancer harboring one of these germline mutations.

So in our study the prevalence was a slightly lower than in [inaudible] study, which is probably related to the different genetic background. And we will need more studies run in different populations in order to know which is the real prevalence of those alterations. For the data that we are seeing from the different studies already released, it seems that BRCA2 is the most commonly mutated gene. What depends is the frequency of those alterations in the different populations. What we observed was that patients with BRCA2 mutations have a significantly worse outcome than patients without such mutation. So the survival from diagnosis of mCRPC was halved compared to known carriers. And we also observed that these patients do respond to the therapies currently available. But what happens is that they tend to progress quicker to all these therapies and we observe also interaction between BRCA2 and the treatment these patients receive as first-line in relation to these cause the specific survival.

So from a very exploratory analysis and with very limited power, what we observe is that when BRCA2 carriers receive abiraterone or enzalutamide as first line of therapy, their outcome is not very different from non-carriers. However, if they receive a taxane as first-line of therapy followed by abiraterone or enzalutamide after progression, their outcomes are significantly poorer. So as I said, this is based in a very small number of patients and we have now running a new study, an international collaboration to validate what is the real value of germline BRCA2 mutations as a predictive of response to taxanes.

Alicia Morgans: I think this is so critically important and interesting. Of course, we have to consider that it's a non-randomized population that patients who had chemotherapy first may have had more characteristics of more aggressive disease perhaps or had potentially other reasons for a poor prognosis. But it was fascinating that those patients who had the AR-targeted agents followed by taxane, as you said, did not seem to have such a difference whereas with patients who had taxane first followed by AR had poor outcomes. So really important, and as the person who is leading this study that uncovers this, besides doing another clinical trial, I'm curious does this influence your decision making in practice? And perhaps you don't have all of these agents always available because in different practice settings we don't always have them, but if you had both agents available, say abiraterone and docetaxel equally available for these patients and you knew their mutation carrier status, would you choose one over the other or is it too early for you to really change your practice for this finding?

Elena Castro: No, it's definitively too early. We can not change our practice based on this, so with the data we have on the moment, if you have the possibility to include one of these patients in any trial with a PARP inhibitor, this is definitively the way to go; if not, at the moment, I will just use any of the therapies available. But just be aware that these patients will progress quickly so we have to monitor them very closely.

Alicia Morgans: Yes. Well good. I'm glad that you are doing some further study to help us understand the true meaning of these findings. And can you tell us a little bit about the additional trials and studies that you're doing both in your center and potentially across Spain or even more broadly to answer some of these questions for these patients who have these DNA repair deficiencies?

Elena Castro: We are trying to characterize the tumors to see whether these somatic alterations are present in both germline and patients with germline or we saw germline alterations could also affect the response to these therapies. And we are also starting to screen patients with disease at earlier stages to see also how these can affect the outcomes of patients or the response to the available therapies.

Alicia Morgans: Wonderful. Well, thank you so much for sharing your expertise. I always learn so much when I talk to you and would just wonder, do you have any closing messages for the audience as they think about caring for these patients in their clinics?

Elena Castro: Well, probably my principal advice will be to screen all patients with metastatic disease, not only because we now have PARP inhibitors available, not only because when these patients and our own other standard therapies, they may progress quicker, but also because this will also benefit their families who as their relatives are at an increased risk of breast and ovarian cancer most likely.

Alicia Morgans: Absolutely. Thank you for reminding everyone of that message and just it is in the guidelines now in the United States, but I think is something that we are still trying to implement, so always important to have those reminders. In Europe too, it's in the guidelines, at this point?

Elena Castro: No, the problem is that, outside the United States, it is not in any guidelines, so there's not in Europe, Australia and most of the world, there is no recommendation for all patients with metastatic disease to be screened. This is likely to change in Europe in the ESMO guidelines, but it's up to each country how they introduce in their national guidelines.

Alicia Morgans: Okay. Well, encouraging everyone with influence to think about this and to really follow suit so that we can improve the care of these men with prostate cancer. Thank you so much for your time.

Elena Castro: Thank you, Alicia.