DNA Repair Defects in Metastatic Prostate Cancer - Elena Castro

July 27, 2019

Elena Castro, MD discusses her recent publication in Journal Clinical Oncology on DNA repair defects in prostate cancer.  The primary objective of the study was to determine whether mutations in BRCA 1, BRCA 2, ATM and PALB 2 would affect survival in patients diagnosed with mCRPC. A panel of 107 genes was analyzed.  Patients who were carrying these mutations, in particular, BRCA2, had shorter survival despite being treated with standard therapies.  While patients respond to these standard therapies they tend to progress more rapidly.


Elena Castro, MD, Medical Oncologist. Clinician Scientist at Spanish National Cancer Research Center, 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 Morgan: Hi, I'm thrilled to have here with me today Dr. Elena Castro, a researcher, and Medical Oncologist at the Spanish National Cancer Research Center. Thank you so much, Elena.

Elena Castro: Thank you for having me.

Alicia Morgan: Of course. I was looking through my JCO pile the other day and came across your article, your recent article on DNA repair defects and looking at this in the population and would just love to hear more about that particular paper, a really high profile and high impact paper in JCO recently.

Elena Castro: We started out working in 2013 after we have done retrospective analysis in over 2000 prostate cancer patients, including some with BRCA2 mutations. We thought that it would be interesting to see what happens prospectively to patients with metastatic castration-resistant prostate cancer and to analyze what will be the outcomes not only of those carrying mutations in BRCA2 but also in other genes involved in DNA repair.

The primary objective of this study was to know whether mutations in BRCA1, BRCA2, ATM, and PALB2, how these mutations will affect the survival from diagnosis of mCRPC and then look at other genes. We actually analyzed a panel of 107 genes. What we found was that patients carrying these mutations have shorter survival, particularly those who have a mutation in BRCA2. For those who did not carry any mutation, the survival was 32 months, but for BRCA2 mutation carriers, the survival was halved. It was around 17 months.

Alicia Morgan: Being treated with standard therapies, they still had this differential survival within that population which is really striking. I think that it's important that this coming to our attention, particularly as we counsel patients. Does that affect how you choose treatments though for these patients?

Elena Castro: What we have observed in this cohort is that carriers respond to the available treatment, abiraterone, enzalutamide, taxane, but they tend to progress quicker on these therapies. I don't think there's evidence enough to not treat these patients with the currently available therapies. The other observation we made with this study was that for BRCA2 carriers when the first line of treatment was abiraterone or enzalutamide followed by a taxane, the survival and the time to progression was similar to non-carriers. On the other hand, if the first line of therapy was a taxane, followed by abiraterone or enzalutamide, then the outcomes were significantly poorer than in non-carriers.

Now we are working on the validation of these results because if these are confirmed then BRCA2 will have a value for therapy selection in first line of mCRPC.

Alicia Morgan: Absolutely. That was one of the points that I found most striking in this paper because if it helps us in this mess of sequencing where we really have little guidance and it helps us find some direction based on a fairly easy to obtain mutation status for these patients, that can be really powerful. It also begs the question of whether these patients might benefit from a combination if they do well with an AR-directed therapy, might they do well with an AR-directed therapy like abiraterone and potentially olaparib, like Noel Clarke had seen in his population.

Are there opportunities to do even better? As a first step if you can validate this, that would be really transformative I think in terms of how we choose therapies for patients.

Elena Castro: Yeah and the other thing we want to see is whether this could have also an implication for earlier stages, for instance, patients with metastatic disease but hormone-sensitive disease, whether we should choose one over another therapy-

Alicia Morgan: Yes.

Elena Castro: In that setting, and also whether for those patients with localized disease who are having surgery or radiation therapy whether we should also be doing some adjuvant therapy with an androgen receptor targeting agent as well.

Alicia Morgan: Absolutely. Well might your group have access at some point to STAMPEDE data if they have availability of their sequencing or mutational status, you could, and they probably are already looking at this based on your excellent work, but they could look to see within that data set for those patients with metastatic hormone-sensitive disease, they have both patients treated with docetaxel, those patients treated with abiraterone and could look at that in this setting and certainly move from there. Very transformative work that you're doing.

Elena Castro: Yeah, I think they, and at least I know that they had the intention to look at that. I don't know whether they have germline DNA on all their patients-

Alicia Morgan: Yes.

Elena Castro: Yes, that would be very informative.

Alicia Morgan: Yes, particularly in that sort of the 560 so patients that were enrolled simultaneously. They could look in those patients because otherwise we really don't have any head to head. In any event, now we're just thinking about new trials rather than really celebrating your paper, but I guess what would your overarching message be or take home points for the listeners on this work because, like I said, I see that this is going to I think guide us more in the future, and when you have your validation out, and I think we're all going to benefit. What is your take-home message?

Elena Castro: I think that at the moment we don't have evidence for not using any of the available drugs in our patients, but if we identify a carrier, we should be very careful with the monitoring and pay attention not only to PSA but also to symptoms and be very careful with the radiological monitoring because they tend to progress quicker. The other things is that we cannot exclude a germline mutation based on age, based on PSA and diagnosis, based on a lack of family history, because in our series 15% of the BRCA2 carriers did not have a family history of cancer.

Alicia Morgan: Absolutely. As many of the guidelines, at least in the United States, currently, state anyone with metastatic disease should undergo testing. I believe you're going to have a conversation with one of my colleagues about that, but we can't use things like young age at diagnosis, family history to guide our testing in the metastatic setting. That has to be really, or at least the mandate and guideline is for all comers at this point.

Elena Castro: I think that's going to be a challenge because that will take a lot of resources, like counselors and of course the genetic testing involved, many more visits, but today we don't have any, we are not able to identify who can be a carrier.

Alicia Morgan: Yes.

Elena Castro: Probably clinicians needs to learn or to acquire some skills to do the pre-testing counseling, just five minutes, just to, but yes this is something that should be offered to all patients, at least until we are able to identify those less likely to carry one of those mutations.

Alicia Morgan: Yes, especially in the context where whether you're a carrier of BRCA2 at least, this may have implications for the sequencing of your treatment and the outcome. At this point, important to know all of the currently available treatments do seem to work, carrier or not carrier, but there might be an implication in terms of sequencing maybe AR-directed therapies first, taxane second, rather than the reverse for the best outcomes for these patients and more information to come as we see your validation to work. Thank you so much for your time today and for speaking with me.

Elena Castro: Thank you.