Genetic Testing in Metastatic CRPC

Daniel J. George, MD: Let me follow up on that point, because I think one of the really challenging things is knowing the opportune time to check for these genetic alterations. It depends a bit on access to tissue; if it's an old archival prostatectomy from 10 years ago, how relevant that is; whether they have soft tissue to biopsy; or biopsying bone. If it's a blood-based assay, what’s the optimal time for that, in terms of having enough tumor burden to find these, and to your point, Eleni, being able to do it before you’ve exposed them to drugs that are unlikely to benefit them, so before chemotherapy? Where do you see this, and can you give me some broad strokes on your approach for genetic testing in castrate-resistant prostate cancer? I’ll open it up, but I’m looking at you, Eleni, because you're the biggest picture on the screen for me.

Charles Ryan, MD: We can't tell who you're looking at, Dan.

Daniel J. George, MD: Oh, you can’t tell. I’m sorry.

Eleni Efstathiou, MD, PhD: You're talking to people who, including yourself, are all about doing biopsies every nanosecond, so it's unfair. You have to go with archival[AC1] tissue. We have some data now showing clearly that at least if you find the DDR defect there—it’s going to be there, right? We have proof of it, but ideally, you would want to go for a real-time and a liquid biopsy. I've had the experience a year and a half ago of a patient of mine coding while having one of those biopsies, and I thought, “I’m not touching this guy again. I'm not doing any biopsies. He's alive. He’s well.”

But all of a sudden, his disease has gone crazy on us and he's having low PSA levels with progressive disease. I did a liquid biopsy, the one that's commercially available, and I got an MSI-high result just like that. There is 2% chance of getting it. He just started today on pembrolizumab, so you have to go for whatever you can get right now that is at least validated to be CLIA [Clinical Laboratory Improvement Amendments]-certified. However, archival tissue, at least for practices out there, is something easy to go for. We have to be practical.

Daniel J. George, MD: Any thoughts on that Tanya? Do you have any other things to add there?

Tanya Dorff, MD: Not really. I agree. I'm a fan of a metastatic biopsy. Bone doesn't always perform, so I prefer soft tissue when available, but the reality is that we use a lot of archival tissue and we use liquid biopsy. The timing is a really interesting question. If you get a ctDNA assay that's negative, did you do it at the wrong time, and when should you repeat it? That's a real nuts-and-bolts question that we have to try to answer.

Daniel J. George, MD: I like to do it while patients are progressing. If there’s 1 lesson out there, it is that once they've started therapy and they show some response, even if they've got tumor burden, I'm less likely to pick that up. Think about it as your patients are progressing, as you're seeing scans that show progression, and as you see symptom progression, as Tanya mentioned earlier. These are all opportune times to think about that before you make that next treatment. You can still go ahead with that next treatment, but check it, because you find things like Eleni pointed out, and that's a lottery ticket for that patient.

Charles Ryan, MD: There was also a really nice oral presentation from Eric Small, MD at UCSF Hellen Diller Family Comprehensive Cancer Center where they looked at metastatic biopsies and they did methylation sequencing and methylation patterns. They essentially identified what looks like an almost new state of prostate cancer. That might be a bit of an exaggeration, but it's something that was distinct from standard adenocarcinoma, distinct from neuroendocrine tumors, and had a very different outcome.

I think it was a better outcome. That speaks again to the point that the more we look, the more we will see. Doing the biopsies, especially for those of us in the academic centers with all the tools that can be presented to us, is very valuable. But even when you're not doing things like methylations and genomic sequencing, understanding if a patient has transitioned into a neuroendocrine type is very reasonable, and that is not rare.

It may be that, by some estimates, 25% to 35% of the patients who are experiencing progression on abiraterone and enzalutamide have neuroendocrine disease. That should be brought out. We should study that, and we should be treating that differently.

Tanya Dorff, MD: Sometimes, it’s obvious, like liver metastases or lytic bone metastases, and sometimes it’s not. I’ve seen it in lymph node disease. I’ve seen it in regular blastic bone disease. In doing the biopsy, you used your cues, like the low PSA levels with visible progression, but I do think those biopsies are very informative.

Charles Ryan, MD: The data, Tanya, suggest that it's not any more common in liver or less common in lymph node. It's everywhere, and some of the limiting factors are how good we are doing the biopsies and the pathologist who looks at them, right? You talk about a field effect. This is an effect that our whole field has to learn to adopt. Even the interventional radiologists who do these biopsies need to become experts at it, and our pathologists give us varying degrees of ability to detect neuroendocrine disease.

Daniel J. George, MD: I want to bring up a couple of things. Tanya brought this up offline a bit earlier, and I wanted to put it on here and get everyone's thoughts on this. As we use more of these life-prolonging therapies in the castrate-sensitive disease state, the biology that emerges in the castrate-resistant prostate cancer is different. A number of the patients in the CARD study had treatment in the metastatic hormone-sensitive or castrate-sensitive state, and then progressed in castrate-resistant. Recognizing that our therapeutic history doesn't start at castrate-resistant disease, but earlier, and that those treatments have implications on how we manage these cases, is a critical aspect of this sequence biology. It impacts our thinking about this and when we do that testing.

One other point from me is that when I have a patient that I'm treating in the castrate-sensitive metastatic setting, I like to biopsy them if I can as they become castrate-resistant because that biology may be very different than had they come through, say, a nonmetastatic castrate-resistant pathway.

Transcript Edited for Clarity