Daniel George, MD, on Precision Medicine Approaches in APC: Part 2

By GU Oncology Now Editors - Last Updated: April 1, 2022

Daniel George, MD, Duke University, Professor of Medicine, Medical Oncology; Medical Oncologist, Duke Cancer Center discusses precision medicine approaches in APC with David Ambinder, MD, Urology Resident at New York Medical College/Westchester Medical Center.

This is the second video in a two-part conversation with Dr. George. Watch part one of this discussion to learn more about medicine approaches in APC.

David Ambinder, MD: In terms of prostate cancer, what genetic testing, or what outcome that is seen on genetic testing, would lead you to recommend prophylaxis? What would be an example of that?

Daniel George, MD: Well, say somebody has BRCA2 alteration, and that’s something that they didn’t know about and their family members didn’t know about. And now they’ve got sisters who they’re undiagnosed. These are the kinds of things where some family members might decide, “This is something we want to do some prophylaxis for.” And again, this would be a referral. This would be their physicians, and talking, and it would have to do with their other health risks and concerns that they would take under consideration. Prophylaxis is maybe an extreme, but screening isn’t. And screening at a younger age, it might affect the type of screening, whether we do just mammograms or MRs for pancreatic cancer. It might open a door to screening that we don’t typically do routinely for pancreatic cancer, but because of these alterations we might begin to do that. So there’s a lot of implications for these patients, with just something like BRCA2.

And then there’s a lot of alterations that we’re still learning what those implications might be, and what the implications are for other cancers. So I think this information, that’s probably the piece that’s probably most disconcerting for patients, is when we have a genetic alteration that they term ‘of unknown significance,’ or it’s an alteration that is rare and we don’t really have particular risks associated with it, but maybe there could be.

So these are the kinds of situations where I think, again, plugging people in with genetic counselors, so that them and their family are followed by a systematic team that’s going to collect longitudinal data that’s maybe nationally with other trends, it’s going to give them the peace of mind that they’re not going to fall through the cracks. This won’t be forgotten and missed. If there’s new information, 5, 10 years from now that’s relevant to this genetic alteration, they’ll be exposed to that and acted on appropriately.

So, that’s the way I frame this, to give people the peace of mind to say, “Yeah, this is all good. This is what we need to know.” And for the patient, this profoundly changes how we’re going to think about managing them, in terms of not just the drugs, but in terms of the sequence of drugs we might use. And we’re beginning to learn how alterations like BRCA2 and other DNA damage repairs may not just interact as a monotherapy, but in combination with other therapies, earlier in the disease. So having that information early on, before we’ve gone through a full line of therapies, is going to become increasingly important in their management.

David Ambinder, MD: Excellent. And on that note, are there any clinical trials specifically in germline testing that you are particularly excited about or are looking forward to?

Daniel George, MD: At GEO ASCO this year, the Genitourinary Cancer Symposium this year, there were two studies presented that were somewhat different messaging. One was the PROpel study, that demonstrated in patients, all comers with metastatic castration resistant disease, patients specifically not tested and known to have genetic alterations, then underwent testing, both with tissue and with blood circulating tumor DNA. But all patients were then randomized to either abiraterone as a first line treatment for metastatic castration resistance disease, or abiraterone plus olaparib.

And in that study, they saw for the entire intention to treat population a fairly robust improvement in the progression free survival from 16 months to 24 months, and by independent review, up to 27 months in the combination arm.

And we see by the force plots, by the subgroup analysis, that those who actually were found to have [amologus 00:13:16] repaired defect alterations, were even more likely to benefit. They hadn’t even reached their median for progression-free survival. So, it really looks like, both in all comers, as well as in patients that have these alterations, there’s a real clinical benefit. We don’t have the overall survival data yet, but these progression-free survival results are fairly robust.

And then in the second study, the magnitude study, we didn’t quite see that story. It was a different study. We looked at patients specifically with HRD mutations and those without HRD mutations. And those without HRD mutations, using a different PARP inhibitor, niraparib, at a different dosing. And in patients that were allowed to have prior abiraterone up to four months, they were randomized to either abiraterone or abiraterone plus niraparib. And there, we didn’t see in the non-HRD mutations, any difference in the PSA progression-free survival, and stopped for futility. In the arm with the HRD mutations, we were able to see a difference in the progression-free survival associated with it. So it looks like we’re getting a little bit of mixed results.

And all this is to say is that we want to see some future studies clarify this picture. And where those studies are being done right now are in the metastatic hormone sensitive setting, where we’re looking again at patients with who are undergoing testing, and with or without HRD mutations are being treated then with another PARP inhibitor, [talopropinib 00:14:56], with enzalutamide in that setting. So enzalutamide, or enzalutamide plus talopropinib. So we’re really starting to see in an earlier disease setting.

And I think really where we get the best utility of our novel hormonal agents, does adding a PARP inhibitor improve that, in particular for those with HRD mutations? Because right now, as you know, the label for patients with HRD mutations like BRCA two, is to wait until they’ve progressed into castration resistance and progressed on a novel hormonal agent. And that’s probably not the best use of those drugs. So I’m excited about these frontline metastatic hormone sensitive studies. I’m curious about this biology that’s going on. I’m optimistic that there’s more benefit here than just those with pure HRD mutations, but I think want to see more data at the end of the day, longer data. And I think this is where we’re beginning to recognize true genetic subsets of prostate cancer, and I think more will emerge.

David Ambinder, MD: Absolutely. In terms of your somatic tumor testing, where do you think is the best utility of the instruments we have, in terms of using Decipher, Oncotype DX, Prolaris?

Daniel George, MD: Yeah, so in the upfront setting, there are some multi-gene tools that I think are really useful, that you mentioned, Prolaris, Oncotype and whatnot, Decipher. But the reality is, I think those are really useful early in this disease, when we’re really just trying to understand, either in patients that have relatively low risk profile, are they truly low risk, do we feel comfortable doing active surveillance? Are things changing in that disease when we rebiopsy over time? And I think in that active surveillance setting, they’re really helpful, because right now we’re really dependent on the Gleason score. And as you know, these are low volume. We may not have a lot of samples. We’re looking at small components of three versus four. That’s where I think this score can be really helpful. So I use that really systematically in my active surveillance patients.

And then I think you have the patients who undergo prostatectomy, or were thinking about undergoing prostatectomy. We really want to understand what’s the likelihood that they may have more extensive disease. And we learn a lot from prostatectomy on that risk. You’d really like to know as much as you can before you do that prostatectomy, to know if that’s really the right choice for them.

And so I think that’s another setting that I really use those tests a lot in, in our multidisciplinary clinic setting with our urologists and radiation oncologists. Because we do have alternatives to prostatectomy, and patients are willing to do those if it’s a likelihood that they’re going to end up needing hormones and radiation afterwards anyway. So, that’s where I think those tools are most useful.

They’re not as useful in our patients that have metastatic disease. So that’s where I’m doing more of my FoundationOne profiling, Caris or Tempus. I think these are really good tools to help us understand the genetic components that actually are actionable and maybe driving the biology in the more advanced metastatic set.

David Ambinder, MD: So I think the last question to end on would be about a patient, if I gave you a scenario. And let’s say a patient was treated initially with a local disease management, let’s say surgery or radiation. Now they have PSA recurrence, and they’ve never been tested yet for genetic testing. And a CT scan or a PSMA scan reveals metastatic disease. At this level, what would exactly genetic testing do for this patient?

Daniel George, MD: It’s a couple of things. Again, this is the patient where I would send those original pathologic specimens off for genetic profiling. And I’d also do germline testing. And I’m doing the somatic testing because I want to know, again, what are those early truncal alterations that may be present.

If they happen to have a DNA amologus, a DNA repair defect, that they may be candidate for that [Talopro3 00:19:53] trial that we talked about. If they have loss of P10, we have a study CAPItello, that we’re looking at an AKT inhibitor in combination with abiraterone. So there may be some approaches that would point them towards clinical trials.
If they happen to have MSI-high, that’s something where I’m still going to treat them with my standard of care, but I’m going to be thinking in the back of my head, sooner rather than later I want to put them on a clinical trial with some IO agent, earlier rather than later. So these are things that help me on that front.

The germline information is really critical, because again, as we talked about, I want to be able to counsel that patient regarding whether or not those alterations are somatic or whether they’re germline. And if they’re germline, I want to make sure that we’re involving the rest of his family and everything. Sometimes people are adopted, they don’t know their family history and things like that. So I’m going to test all of those patients, assume they have that family history, but it makes it hard in terms of what you do with that information. So it does help for them for their children and siblings and grandchildren and things like that, so it’s still valuable even if it’s not helping their same generation folks. So that’s how I frame that.

But that’s a patient where I would absolutely want to do the testing, and how I would talk to them about that. Still be thinking about whether or not I’m going to use an antigen receptor inhibitor, or antigen receptor inhibitor and docetaxel chemotherapy. But nowadays I can tell you that somebody with metastatic disease, especially multiple metastatic sites like that, unless there’s a real contraindication in terms of competing mortalities or functional status or comorbidities, I’m going to want to treat them with combination therapy, that the era of using ADT monotherapy alone is really past. And unfortunately, that isn’t ubiquitous out there yet today, so we do need to emphasize metastatic prostate cancer requires multi modality therapy.

David Ambinder, MD: I think that’s why I’m asking that question. It’s a very important point in terms of our management.

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