Alicia Morgans: Hi, I'm so excited to be here at APCCC 2022. Today, we'll be talking to Dr. Elena Castro, who is a GU medical oncologist at the Biomedical Research Institute in Malaga, Spain. I'm also excited to speak with Dr. Colin Pritchard, who is a professor of laboratory and pathology medicine at the University of Washington and the Brotman Baty Precision Medicine Institute. Thank you so much both of you for being here.

Colin Pritchard: It's a pleasure. Thank you.

Alicia Morgans: Wonderful. I wanted to talk with the two of you about how we think about incorporating molecular testing into our treatment paradigms for men with prostate cancer. This has been really disrupted in some ways by recent data that suggests that perhaps patient populations that are unselected for HRR mutations, may respond to combination therapy with AR targeted agents, Abiraterone and Olaparib being an example. We'll start with you, Dr. Pritchard. You have worked for many years to help bring the GU community into the now and think about how we can best perform testing and use testing in our clinical practices. What advice would you have as we're now trying to grapple with this mixed information?

Colin Pritchard: Yeah, I mean, we have a lot to learn about biomarkers. I think that's fair to say. And so, our biomarkers right now for predicting PARP inhibitor therapy, as you alluded to, are not perfect. And so, we have a long way to go. Does that mean that we shouldn't use molecular biomarkers in directing our targeted therapies, particularly PARP inhibitor therapy? My opinion is no. I think we should be using them. I'm aware of the evidence that you referred to suggesting that unselected patients may benefit. My interpretation of that data is that again, that's just another opportunity to identify what are those additional biomarkers for those guys who were BRCA negative, for example, but still nonetheless responded to PARP inhibitors.

And there are some really new, exciting methodologies out there. There's something called the homologous or combination DNA repair mutation signature, also known as HRD. This is analogous to micro-satellite instability, but for homologous or combination genes like BRCA, so it's like the MSI of BRACA, that's the way I like to explain it. And so I think with new biomarker technologies like that, we're going to get even better, but I don't think we need to throw the baby out with the bathwater. I think that biomarker driven therapy, particularly DNA mutation based NGS tests, are here to stay and they're only going to expand.

Alicia Morgans: I have a feeling Dr. Castro agrees. What would your comment be to that?

Elena Castro: Yeah, no, no, no. I totally agree with Colin. My concern here is that outside academic institutions, testing is sometimes very difficult and we need to find a way to optimize testing, so the practicing clinicians don't see this as another burden to their daily work. And because otherwise, if we have so many difficulties in getting our patients tested, my concern is that we will abandon that and then just, if the combination of PARP inhibitors with NHT is finally approved for all commerce, we will stop testing just because it's sometimes very, very tricky to get results.

Alicia Morgans: I think that's such a good point. And I know we've talked before about how somatic testing and germline testing are obviously two different things and germline testing should really be considered outside of the context of this and has its own value, very clearly, for family implications and screening. And when we think about somatic testing, I mean, there's also value there because I think, to Colins's point, there are potentially these signatures that may broaden the spectrum of patients that may benefit from a certain treatment more clearly than just saying an all comer population should be tested.

One of the challenges, to your other point about how we integrate this into practice, is whether we use a tissue based test or a blood-based test. And I saw Dr. Pritchard take a very deep breath because he knows I'm going to ask. What are your comments there? Because Colin, there's been some really interesting data about chip and how ATM mutations in particular can be really identified as false positives, perhaps. And there are so many burdens on the... Or barriers to really believing some of the liquid based tests, but also challenges to getting tissue based data. How do we work through this? And also, if you could clarify the chip issue for the listeners, I think that might be helpful.

Colin Pritchard: Yeah. Thanks for that question. I think, getting back to what Elena was talking about and what you were alluding to, with germline being separate, but important component, it's interesting how this is all getting unified. And the reason I mentioned that in the context of your comment about chip, which is clonal hematopoiesis, which is a... These are somatic mutations that happen over time, normally as we age in our blood cells, and inconveniently, they happen to be in the same genes that also get mutated in prostate cancer. When you test the plasma of an older man, you're often going to detect somatic mutations that are not prostate cancer, and that those are unfortunately frequently misinterpreted as being prostate cancer and then even more unfortunately, drug is chosen on the basis of that interference.

But the good news is it's actually very easy to know what's chip and what's not. The answer is you do a whole blood or a white blood cell control sample, a germline control sample. If we go to a paradigm of germline and plasma para testing, I think that's really the solution. And that's what a lot... I mean, our institution, University of Washington and Brotman Baty Institute, that's what we've been doing for four or five years. It's still not the norm, but a lot of the commercial labs are going that direction, so that's the good news.

The other tie in with the germline somatic is on the tissue side. I mentioned that HRD mutation signature. It's possible to do that from tumor only, or plasma only testing, but it works even better if you have a paired germline and plasma. I think that the germline is important, not just for all the incredibly important reasons for risk and family counseling and preventing cancers and family members, it's also technically really useful in our tumor based testing. I think where we're going, and there's a long way to answer your question. I think where we're going, both in the tumor space and in the plasma or liquid biopsy space, is a paired testing model where we're testing a tumor tissue or a plasma, a surrogate to tumor, and then we're testing a germline sample as paired, both for these technical reasons so you can do things like better HRD, and for a very important reason of removing interference from chip. And then also, because we need to know the germline status in and of itself.

Alicia Morgans: I think that's a really interesting solution, and I'd love to hear your thoughts, Dr. Castro, on how well that might be actually incorporated in a practice. Would it be something that we could do that we could try to get both of these samples at the same time and send them off for testing? Does that seem to work better? Would that potentially work better or be more challenging in a workflow in Spain, for example, or elsewhere?

Elena Castro: No, no, no. I don't think it should be feasible. And you just take both samples at the same time and just send them. No, that shouldn't be an issue. Probably the issue is the education that is needed for ask clinicians to get aware of the importance of testing both type of samples at the same time.

Alicia Morgans: Yeah. Well, and I wonder too. From my perspective, I agree with you. I think to ask for both at the same time may actually be even easier in the workflow just to get it all going and is one of the ways that I approach it. But one of the things that's interesting about somatic testing, particularly a blood bank testing, is that there's the potential, as more data comes in, that we might be doing this over time in patients. And I wonder what your thoughts are on what the potential is of doing something like that.

Elena Castro: That will be fantastic. And actually, germline samples, if this is something we need to get better results from plasma analysis, or CTDNA, shouldn't be an issue to get a germline sample as many times as it is required.

Alicia Morgans: Wonderful. And your thoughts Dr. Pritchard?

Colin Pritchard: Yeah. No, I couldn't agree more. Yeah, I think that's exactly where we're going. It's really exciting and the costs are coming down too. I mean, it's already comparable to doing an MRI scan or something like that, but I think the costs are going to come down even further, so that makes it practical to do that serial testing.

Alicia Morgans: Wonderful. Well, I sincerely appreciate the expertise of both of you and thank you so much for taking the time to share your knowledge with us today.

Colin Pritchard: It's a pleasure. Thank you.