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Charles Ryan: Joining me today is Elena Castro. Researcher at the Prostate Cancer Clinical Research Unit at the Spanish National Cancer Research Center in Madrid. 

Thank you for joining us Dr. Castro, delighted to talk to you. You've really become one of the leading voices on BRCA-2 mutation and prostate cancer, and have published on the natural history of these patients. Could you tell us starting from localized disease, what is the likely outcome of a patient with BRCA-2 prostate cancer? 

Elena Castro: Definitely BRCA-2 germline carriers have an increased risk of developing prostate cancer which is around 30% lifetime rate of developing the disease. And they tend to develop aggressive prostate cancer, a Gleason 8 or higher is common in these patients. But still, some patients develop prostate cancer with low Gleason grades. 

It's not uncommon that these patients present with lymph nodes or even with distant metastasis. But even for patients with localized disease, we published a paper some years ago in which we analyze over 1,300 men with localized prostate cancer treated either with surgery or radiation therapy. And what we observed was that carriers develop metastases earlier. It didn't matter whether they were treated with surgery or radiotherapy and died earlier from the disease. 

Charles Ryan: So just to recap, a man who's a BRCA-2 carrier, has a 30% likelihood of developing prostate cancer in his lifetime, he's more likely to have high-grade disease, and he's more likely to experience relapse after undergoing local therapy, is essentially what you're saying. Do patients when you compare stage by stage have a higher risk of death from prostate cancer? BRCA-2 carriers versus non-carriers.

Elena Castro: Yes, that's correct. 

Charles Ryan: What about the patients who do develop metastatic disease? Are they more or less likely to have a durable response to hormonal therapy? Do they have a higher rate or a faster time to the development of CRPC, for example? 

Elena Castro: What we have observed is that they progress into castration-resistance status quicker than non-carriers. And as a whole when they are treated with any the available therapies for mCRPC they do respond, but they tend to have shorter responses. There are other reports that have observed more prolonged responses in these carriers, and others that have shorter responses, and I think the difference is between all these reports may come from the proportion of patients with BRCA-2 mutations included in these reports, may come from in which line of therapy these patients received the androgen receptor single agent inhibitors, may depend on the tumor burden these patients have, and also none of these reports including our last study took into consideration the tumor features. It was just the germline defect, but even with a germline mutation, the tumor features may vary, and these may also be affecting the response to these therapies. 

Charles Ryan: So, tumor features would be, for example, a Gleason score, you could have a BRCA-2 mutation with a Gleason 7, and one with a Gleason 10, and the one with the Gleason 10 is still going to have a worse prognosis than a patient with Gleason 7. Is that what you're referring to? 

Elena Castro: That and also molecular features. Whether they could have MET amplification, RB losses, that could be affecting also their response to therapies. 

Charles Ryan: Do we see an overlap in RB loss and p10 deletions and BRCA-2 alterations in those types of molecular features so far as ... The question would be, does a BRCA-2 patient ... Is he more likely to have an RB loss or some of these other more common alterations? 

Elena Castro: That's it. It's the BRCA-2 loss, is frequently associated to RB loss as well. 

Charles Ryan: And I believe that the RB gene and the BRCA-2 gene are closely located on the same chromosome, and thus could be loss together from what I understand. 

As we think about BRCA-2 carriers and the treatment of the disease, there's obviously a lot of excitement around the development of PARP inhibitors. But I think we also need to think about other approaches for these patients independent of only targeting PARP. What are some of the other directions we can think about for addressing patients with BRCA-2 alterations? 

Elena Castro: What we have observed is that for BRCA-2 carriers that receive abiraterone, or enzalutamide in first-line of therapy, and then after progressing they receive a taxane, the outcomes are not different from non-carriers. But when they receive the opposite sequence, they receive a taxane first, and then abiraterone, or enzalutamide, then they tend to progress quicker, and the survival is shorter. So, the BRCA-2 status may help us to select the sequence of therapies for these patients. On the other hand, these patients may also respond to immunotherapy beyond the mismatched repair deficiencies, it looks like BRCA-2 accumulate deletions and other DNA repair defects have also been associated with a high tumor burden, lymphocyte infiltration, that could also favor the response to immune therapy. 

Charles Ryan: Is there any evidence to show that the BRCA-2 alteration patients have ... Maybe not hypermutated. But are these tumors more mutated associated with an immunotherapy benefit perhaps? 

Elena Castro: They associated with genomic instability that usually consists of these deletions. I think in some trials that are going on at the moment, they have analyzed the response of BRCA-2 carriers, and ATN carriers, but the numbers are still small. They seem to respond better to immune therapy than non-mutated tumor, but I think we still need a more ... 

Charles Ryan: The hypothesis is a responsible one. That patients with altered DNA repair would have more mutations and therefore may have more of a likelihood of neoantigens in response to immunotherapy. Going back to the sequencing comment you made, your observation is that patients who have a BRCA-2 alteration who receive a taxane first, have an adverse outcome compared to those who receive an AR-targeted therapy first. Did I get that correct?

Elena Castro: Yes. 

Charles Ryan: And you're referring to that in the setting of CRPC, not in the setting of hormone-sensitive disease. Correct? 

Elena Castro: That's correct. It would be very interesting to see what happens also in earlier stages of disease. 

Charles Ryan: So finally, there's very interesting data emerging and a few studies beginning to launch now, on the use of PARP inhibitors in patients who do not have DNA repair alterations. And the idea behind those I believe is that androgen deprivation therapy, abiraterone, and enzalutamide perhaps, the efficacy of those therapies can induce a transient loss of DNA repair and create a window of opportunity for the treatment with PARP inhibitors. What are your thoughts on those approaches? 

Elena Castro: I think after all this work trying to identify which could be the alternations predictive of response to PARP inhibitors, I find it very shocking that now we are trying to treat absolutely every patient with this combination. 

Charles Ryan: Right. 

Elena Castro: I would like to see stronger data than the data that has been presented up to now, to really consider-

Charles Ryan: The hypotheses is interesting. The available data is modest at this point, but I think that the potential upside may be that we can exploit a window, find a window where the co-targeting of the androgen receptor and PARP transiently, perhaps may be beneficial for patients. So, it is an interesting angle. 

Finally, in the last minute or two, there are a number of studies now with PARP inhibitors and other approaches that are screening patients for BRCA-2 alterations. As we've discussed there's a wide variation around the world in what types of populations have a high prevalence of BRCA-2 alterations. You know a little bit about this. Tell us about what you've found about where in the world the BRCA-2 alterations are more likely to be found, in what populations. 

Elena Castro: Definitely in Ashkenazi Jews have founder mutations in BRCA-1/BRCA-2, and this population will definitely have a higher prevalence. In other populations, I think we still need to conduct more studies to learn about that. In Spain for instance, the prevalence of BRCA-2 is 3.3%. In the study conducted in the states it was around 5%, but I guess it also depends on which institutions and which patients they attend, and that could affect the prevalence. With the data that are being reported, my impression is that even when they exact prevalence may depend on the genetic background of the genetics of the different populations, BRCA-2 will remain the most commonly mutated gene unless we are talking about a particular population with founder mutation with a very high prevalence. 

Charles Ryan: Right. So the range would be in Spain .... Certainly populations it's even lower than 3.3%. But the Ashkenazi Jewish population, what's the prevalence of BRCA-2 mutation in that patient population? 

Elena Castro: I think one in 40 carries a BRCA-1 or BRCA-2 founder mutations. But I don't really know what is the data exactly for prostate cancer patients. 

Charles Ryan: Correct. If you took Ashkenazi Jewish prostate cancer patients which proportion have BRCA-2 we don't know that quite yet. That's certainly a noble number, we'll have to look that one up. 

All right, well thank you so much, Dr. Castro, for joining us. It's always a pleasure to talk to you. I always learn so much listening to you talk through this topic and reading your papers. Thank you once again. 

Elena Castro: Thank you, my pleasure.