Testing for Germline/Somatic BRCA Mutations in Metastatic CRPC


A brief discussion on the importance of germline/somatic BRCA1 and BRCA2 mutations in metastatic CRPC, accompanied by practical advice on genetic testing.


Alan Bryce, MD: Let’s go back to Eleni here. Number 1, do you repeat genetic testing in patients at progression? What are the guidelines around testing for germline/somatic mutations? We've touched on some of this, but how do you approach it?

Eleni Efstathiou, MD, PhD: As I mentioned earlier, I do repeat genetic testing in patients at progression, especially if we're talking about these cases that have a long history and their biopsy or radical prostatectomy is more than 3 or 4 years old, which hopefully is the case. We have enough information to include even a potential change in MS [multiple sclerosis] status. It is worthy. I used to have a huge fight with [the] pathology [department] when I would ask for MS status to be reassessed, and they would block it until the paper was published that showed that this can [happen]. And we have wonderful papers from several groups now showing that with the advent of the progression of the disease, we have accumulation of mutational events, so we don't really know at the end of the day which 1 will be the driver. What we do know, based on the data that came from the PROfound Study and the analysis that was done in somatic testing, is that usually if you have a BRCA2 or BRCA1 mutation, this is a driver event still in the far advanced disease, whether it is something that is an archival tissue and of course, always in germline. But my preference is also to repeat, not just for MS status or other events such as you mentioned, that could be found later on, or selected later on. And importantly, to actually look at the TMB [tumor mutational burden]. And TMB does change, as well. Now we're not there yet when it comes to IO [immuno-oncology], but I think there are enough exciting data that it's not far from where we're going to be able to have some more certainty in patient selection groups.

Alan Bryce, MD: Dan, let let's wrap the second and third questions together. What percentage of your patients test positive for a deleterious germline and/or somatic BRCA mutation? And then, what are the treatment options we should talk about for patients with BRCA and ATM mutant disease?

Daniel Landau, MD: Sure. And to sort of echo on the previous points, I think as the ease of testing has gone up, especially with liquid biopsies, we are testing more often in our practice. And coinciding with that, we are finding more patients – often, surprising patients – who are testing positive for mutations that either did not have it before or we weren't expecting it, and it can have direct impact on treatment-making decisions. As far as what to do with the BRCA1-2 or ATM, we're becoming more and more lucky in having more options in this space. We've participated very extensively with the development of rucaparib. We have olaparib, which is approved for a wider gene expression profile. Thus, the options are going up here. And [there are] very positive results, especially in that population with BRCA2 mutations.

Alan Bryce, MD: The controversial population is the population with ATM [mutations], and you get different answers. I've been on the podium and had this debate with my colleagues. I'm of the opinion that ATM-mutant prostate cancer does not respond to PARP inhibition based on the clinical trials, but those are subsets. There is a label indication for olaparib, but the hazard ratio in the PROfound Study trial for patients with ATM mutations was 1.04. There's no signal. In my practice, I would say [concerning] ATM mutations, I want to take you to clinical trials. I want to look at ATR [ataxia telangiectasia and Rad3-related] inhibitors. Eleni, where do you land on that?

Eleni Efstathiou, MD, PhD: I land on what are we going to do now that we have data that says it doesn't matter? I'm still struggling. I'm having meltdowns here looking at the PROfound data. But it's pretty strong data. I keep going back and looking at those hazard ratios. And in the population with DDR [DNA damage repair]—which, hopefully, we're going to get more clarity on—it looks like it's just an amazing response in the combination with abiraterone, so it speaks to earlier introduction. I am with you when it comes to the ATM genes. However, I give the benefit of the doubt because it looked, if you remember that gene-by-gene description, that the hazard ratio was a huge range. It needs to be a little bit more specific. What I would like to refer to is a beautiful trial that I think is from a European group, the PROREPAIR one. I don't know if they’ve a published the paper yet, but they presented it at an ESMO [European Society for Medical Oncology meeting] a year or 2 ago, and they showed that it is not enough to just look at the presence of a DDR event, but to also look at the presence of other events that are happening simultaneously; that maybe thinking over the leads such as NIK amplification and the like, if I remember correctly. And you mentioned a couple of others. This is not a linear presence of 1 event. Going back to what you said, you need to have the whole picture.

Alan Bryce, MD: I think we've seen in some reports that ATM expression by IHC [immunohistochemical diagnostic assay] is more predictive and ultimately—and probably to your point—has to do with some of the comutations that are occurring. It's really not the ATM at the heart of it, right? But we'll see. We'll see. There is more to come, for sure.

Transcript edited for clarity.

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