Precision Medicine in Prostate Cancer: A Multidisciplinary Discussion

In a roundtable discussion on metastatic prostate cancer, moderated by Jacob Ark, MD, of Urology of St. Louis, panelists explore key topics, including the definitions and diagnostic criteria for hormone-sensitive and castration-resistant disease, the role of germline and somatic testing, and the integration of precision medicine into clinical practice. The panel shares insights into the latest advancements, including PSMA imaging and genetic testing, highlighting how evolving science is shaping the future of prostate cancer management.

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Dr. Ark: Welcome to GU Oncology Now roundtable discussion focusing on prostate cancer, the whole metastatic space, both hormone-sensitive, castration-resistant. I’m Jacob Ark with Urology of St. Louis, a large private practice group. I’ll be moderating today’s session, and I’m joined by expert panelists today that’ll introduce themselves before we kick it off. Let’s start with Dr. Finnie.

Dr. Finnie: Dr. John Finnie, hematologist-oncologist at Mercy Hospital St. Louis here in town.

Dr. Agarwal: Gautum Agarwal, urologic oncologist, also at Mercy with John.

Dr. Finnie: Same.

Dr. Strope: Seth Strope, I’m a urologic oncologist at Urology of St. Louis.

Dr. Bryan: David Bryan, I’m a urologist at Urology of St. Louis, so with these guys.

Dr. Ark: All right. So, I said covering the spectrum of hormone-sensitive and castrate-resistant metastatic disease. Let’s start just very basic definition of how you get there. Dr. Bryan, what are you using to define that castrate-resistant disease in terms of labs, imaging?

Dr. Bryan: Sure.

Dr. Ark: What are you using to get there?

Dr. Bryan: Sure. Obviously by definition, it’s rising PSA with the castrate level of testosterone of less than 50, usually on androgen deprivation therapy. As far as imaging goes… Well, so back up, certain levels depending on their mode of primary therapy. So, we look for a level of at least 0.2, or after radiation, three consecutive rises. Also look at PSA doubling time, which, typically, you’d like them to be more than four weeks apart. And then I use a lot of PSMA-PET.

Dr. Ark: Yeah. Yeah, I think that’s definitely helped. So, in the grand scheme of molecular profiling, we talk about germline testing, genetic testing. Does that have much of a role in defining between castration-sensitive and castrate-resistant or management strategies on your treatments? When are you using your germline tests, your genetic tests? How are you triggering those?

Dr. Bryan: So anybody that’s unfavorable, intermediate risk, or above, I try to get germline, or always prefer somatic if we can get it. If archival tissue is not available in somebody that may have had remote therapy, then germline, obviously. But then at progression, I like to use ctDNA, circulating tumor DNA.

Dr. Ark: Yeah. And, Dr. Strope and Agarwal, any differences there from when you guys trigger maybe, like I said, germline? When are you getting it somatic, ctDNA, et cetera?

Dr. Strope: For me, no, but I’m not really finding it much for the definition of the disease.

Dr. Ark: Yeah.

Dr. Strope: It’s for what I might do next.

Dr. Ark: Yeah, the management.

Dr. Strope: Right, the management. Right.

Dr. Ark: In that resistance space.

Dr. Strope: Right.

Dr. Agarwal: Yeah, I think I agree with what’s been said. I think the field of precision medicine, as it applies to prostate cancer, is getting better and better. As Seth mentioned, we’re not quite there where we can define disease with it too well, but I think we’re getting there. Recently, a colleague of mine, Aadel Chaudhuri, who used to be at Wash U, and now, he’s at Mayo Clinic, published a paper in the American Association of Cancer Research talking about cell-free DNA and being able to look at stemness. So, the stemness characteristics of these cells in the DNA indicated whether that patient is going to respond well or not to therapy, which could push them into saying, “Okay, this could be a person that very likely will be developing castration resistance and have a much more aggressive course of therapy.”

And it may lead us to that further discussion that we have later about how much do you add to their therapy upfront while they’re hormone-sensitive. So, the definition may not change, but I think it will change in probably the next five to six years-

Dr. Ark: Right, how we’re managing disease.

Dr. Agarwal: … about how do we say it’s castration-resistant. But it may not even be defined as castration-resistant or castration-sensitive. That may just go away and we may just say, “It’s prostate cancer with stemness characteristics,” indicating we should be highly upfront with our therapy or not.

To the germline question, I think that’s a great point because 10% of all malignancies are going to have some germline hereditary component. The more you test, the more you’re going to find something, and it’s not really just about the patient. There’s a patient I had with stage 4 prostate cancer. He tested positive for ATM mutations. So it’s a little lower in the realm of BRCA versus that, but still put him at risk. Implications for his treatment were probably not huge. Could you add a PARP inhibitor possibly with ATM? It’s not as strong as with BRCA.

Dr. Ark: Right.

Dr. Agarwal: But what was really cool about that case was we tested all of his kids. And his three daughters, one of them tested positive for ATM. So, she got a screening mammogram earlier than she should have, and we found a stage 0 breast cancer in her, and she was cured. So, it has implications beyond just that patient, so a cool thing.

Dr. Finnie: Yeah. One thing, risk stratifying who I’m going to do the different testing on, I’ll look at their family history. All patients that are metastatic should be eligible for the genetic testing and, as you noted, unfavorable.

Dr. Ark: Yep.

Dr. Finnie: And so it makes a big difference. I was going to say the same thing you noted that we’ve talked about at our conferences about the ATM mutations, not the response rate is quite up with the BRCA patients, but we’ve been able to have… Just with a nurse practitioner who focuses on genetic risk assessment, she’s identified so many patients with these various genetic mutations. New ones that are being identified has a lot of implications for treatment and for proactive family planning as far as screening. And so that’s how I’ve seen that used, especially get their family history and you can see whether they’re more likely to possibly have a mutation.

Dr. Ark: Yeah, I agree. I think as time goes on, the castration resistance status isn’t going to be quite the same driver as it is now because we’ll have different targets of different data points.