Alan Bryce: Hello, I'm Alan Bryce, medical oncologist from City of Hope, here today at ASCO 2025 meeting with Dr. Michael Carducci, Professor from Johns Hopkins, to talk about some of the consensus statements that came out of the US Prostate Cancer Consensus Conference last spring. The US Prostate Cancer Consensus Conference was a meeting of key opinion leaders, where we debated some of the shades of gray, the unanswered questions in the prostate cancer field.

And Mike, thank you very much for being here. I'd like to ask you about some of these consensus recommendations. And maybe you can inform the listeners about what was the reasoning behind some of this?

Michael A. Carducci: I think there's a lot of unanswered questions out in practice. And those of us who see a whole lot of prostate cancer still have questions. And so trying to get a group together to come to recommendations to make it easier for just those in general oncology.

Alan Bryce: Absolutely. I want to walk through some of these recommendations. If you could maybe give us the background. What were the pros and cons and the nature of the question that the first recommendation in the PARP inhibitor section here? The experts recommended that for all patients with metastatic prostate cancer, you should receive somatic HRR alteration testing of primary tissue, metastatic biopsy, or ctDNA. This is consistent with recommendations from other guideline-issuing bodies. But what is the point we really want to make here for our listeners?

Michael A. Carducci: I think we have drugs now that target these mutations. And so we really have to know. So it really is raising the bar, increasing the number of individuals who have testing-- both by next-generation sequencing, looking for HRR alterations so that we can pick and choose when to use certain drugs. If you don't know, you don't know to use them. And patients are deriving benefits from the drug, so we have to know.

And so it's very clear that a patient presenting with metastatic disease, you should reflexively get their genes, do sequencing. And again, it's easy to do it on primary tumors. But if you don't have that available or it's too old, it doesn't result, then we'd really reflex to ctDNA or a new biopsy.

Alan Bryce: So how do you approach it in your own practice? When do you test patients? What's your preferred method?

Michael A. Carducci: A lot of it depends on how they're presenting. Those folks who just come in with newly diagnosed metastatic disease, it's very overwhelming. We have different clinical trials that may want to know right away. But usually, that first or second visit, we start the process. Clearly, if there's strong family history, we're doing more germline testing first, but then moving to the sequencing once we have the tissue available. And if it fails, then moving to ctDNA.

Alan Bryce: So I think there's a nuanced point in there about the failure of testing, perhaps, because the second recommendation from the committee was to say, in patients without HRR mutations on primary tissue testing, that the results should be confirmed by second testing-- either ctDNA or metastatic biopsy. So I guess what's the reasoning behind that?

Michael A. Carducci: I think there are failure rates from tumor tissue that the ctDNA and other new biopsies can pick up cancer mutations. I think it's about 16% of the time that you'll find something even if you look again. And so from that perspective, I think it was high enough that we have drugs and that may have benefits that we should at least double check.

Alan Bryce: I mean, I agree completely. I think it might be an underappreciated point out there. Like you say, the 16% number is significant when you think we can treat patients, if we find it. In the last couple of years, of course, we've had all this new data about PARP + ARPI combinations, androgen receptor pathway inhibitors. And lots of questions about where we might apply this.

So a couple of different angles on this I'm going to ask you about. One-- the committee said for patients who are ARPI-naive and now have mCRPC and a pathogenic HRR gene alteration, the committee recommended the PARP + ARPI combination therapy as opposed to anything else. Whether it's ARPI monotherapy or PARP monotherapy. Can you speak to why the consensus really was that a combination is the best option?

Michael A. Carducci: Yeah. I think a number of studies really have shown that the combination makes sense for those with metastatic CRPC that has not had an ARPI. That population has really narrowed and closed down. Most of us are using doublet, triplet therapy for those who are newly diagnosed metastatic hormone-sensitive disease. So the nuance of the significant big studies, multiple types, different PARPs, all different combinations with your ARPI showed that the doublet with a PARP inhibitor makes a whole lot of sense for with those HRR alterations that are most likely to benefit. So those being certainly BRCA2, less commonly BRCA1, the PALB2 or PALB2 that make sense to use those combinations.

Alan Bryce: And what about anybody that this says, why not sequence-- one after another, as opposed to combination? Because of course, we don't have level 1 evidence for all of these nuanced questions. But I guess, what's the thought process there?

Michael A. Carducci: In my practice, I tend to do more sequence for that person who is in the metastatic hormone-sensitive disease. Got an ARPI then when they progress and they have a mutation. I use sequencing in that sense. I think we couldn't come to a consensus as to whether you should switch to the other ARPI and add in your PARP inhibitor or just use a PARP inhibitor.

But in this setting, it is hard to use the doublet because you use an androgen receptor pathway inhibitor, they're going to get a response. So trying to make attribution to which drug, when it's both drugs are doing that. And the duration that they're salvage therapy is longer now because of the doublet therapy. So it does make it hard. So I could see where some folks say, hey, let's test one and see how it does. Then we can add in another one. We just don't have that kind of data to say that. But studies like the BRCAAway study saying that doublet earlier makes more sense. I think the data is pretty consistent.

Alan Bryce: Understood. Absolutely. All right. Let me pivot a slightly different scenario. So now we're talking about, again, patients coming to mCRPC who are chemotherapy-naive but don't have one of the pathogenic HRR mutations. The consensus was that at that point-- and they've had an ARPI. So they've had an ARPI, they haven't had a taxane, their HRR are wild type, and the consensus is that the next line of recommended treatment would be a taxane, as opposed to a PARP + ARPI combination or an ARPI switch.

And to remind the listeners, if they don't know, we define consensus as a 75% threshold-- that 75% of the panel had to agree. So can you speak to why is there this consensus that really taxanes are the next step in this setting?

Michael A. Carducci: I think this was certainly before the change in label for lutetium PSMA, and docetaxel plus platinum makes sense for those who are changing and progressing. Those who've already had a mutation still might benefit even if they've had a PARP inhibitor. And so the sense is you can be a bit more aggressive in that patient population. And so it makes sense.

Many of these folks having visceral disease, if that's a feature of their disease, there's probably a shift more to the docetaxel. Although we're seeing clearly with the change in label for lutetium PSMA to even give it at that point, knowing that you still have the chemo combinations. So I think maybe that's what this year's consensus will talk about.

Alan Bryce: Let me ask you about something else where we didn't have clear consensus. Earlier on, you touched on the mutations you consider to be more highly responsive to PARP inhibitor therapy. But of course, there's a varying lists of drugs that fall under the HRR label or not. I guess in your own practice, which occasionally cited HRR genes are you less excited about treating with PARP inhibitors and which ones are you more supportive of treating with PARP inhibitors?

Michael A. Carducci: BRCA2 clearly. I don't remember if BRCA1 or ATM or the next most common. But clearly, ATM to me, just data after data says that these drugs are less likely to work-- probably not going to work. But if you are going to use it because the label says that mutation is in the qualification, you're just going to watch those patients closer, because if they don't have a response, then you can see if they do, and if they don't, pretty early move on to something that's more likely to benefit them.

And I think the other one is CHEK2, is one that folks have tried immunotherapy in. And yet, for the PARP inhibitors, just limited activity. The CDK12 is right on the cusp, but probably enough to again, try and go for it. The BRCA1s also, but they tend to be lumped together. And all that group of patients sways the data. And so these folks that have less immune mutations or alterations for HRR that aren't likely to benefit, and those who are just wild type, you just have to see.

Alan Bryce: Fair enough. Well, Dr. Carducci, it's a pleasure to talk to you. Thank you so much for spending time with us.

Michael A. Carducci: Great, Dr. Bryce. Thank you.