Kristine Lacuna: Thank you so much for having me, and I'm really excited to be here to talk to you today.
Neeraj Agarwal: We really enjoyed your talk at the 2026 Annual American Urology Association Meeting in Washington, DC on metastatic CRPC, treatment selection, and so on. Could you please tell us more about your presentation, especially focusing on treatment selection in metastatic CRPC? Who are these patients? How do you select treatment? And we can go from there.
Kristine Lacuna: That sounds great, and it's certainly a very broad topic, and a lot goes into treatment selection for our patients. Essentially, the bottom line here is that there is no right answer treatment selection. We really have limited data for optimal sequencing, so I will just start off there. I would bucket two patient populations that we're seeing today. One is which we've heard earlier and we've known that in the hormone-sensitive setting that escalation of therapy is the contemporary treatment. That is the recommendation because we know there are better outcomes, whether that's escalation of therapy with ADT and ARPI, triplet regimens, and now we're seeing PARP inhibitors as you know very well. That ultimately is affecting what we're seeing in mCRPC and how to approach mCRPC.
When I think of these two buckets, I think of those patients who fall in the contemporary bucket, those who have already seen ADT plus an ARPI. But then I also think of patients who we are still seeing to this day, maybe referrals from... We're at an academic center, so we often see patients who have previously received an ARPI, but it's still common out there that we're seeing patients who have not received an ARPI, depending on where they're coming from, which location, which country they're coming from. And so I follow the second bucket into patients who have not received an ARPI, and really, that helps determine and is a first starting point of selecting a therapy for these patients.
Neeraj Agarwal: Let's say patient has received ARPI, and has progressed on ARPI, and they have received abiraterone in first-line setting. Is there a role for enzalutamide in this? Because we have option of enzalutamide. We have docetaxel chemotherapy. We have obviously PLUVICTO or PSMA-617, lutetium-177, quite a mouthful. And then we have other targeted therapies, PARP inhibitors, pembrolizumab, or MSI-high radium therapies there, Sipuleucel-T is there. How do you choose one of these treatments?
Kristine Lacuna: That's a great question. I'm going to address your first question, is there a role for enzalutamide after abiraterone? And in some sense, yes, there might be, but I think that there are probably more optimal therapies that we've seen now. Before getting into the optimal therapies, I think we have to take a step back and say, "Okay, yes, prior therapy determines or helps us decide what treatments we should use for future, but two, we have to think of other things like genomic factors that need to play a role."
We've heard time and time again that patient selection in terms of genomic factors is incredibly important, and so that really opens up our armamentarium of what we can choose. So really, when we're thinking about options in the first line setting, we have ARPIs like you mentioned. Typically, for those who have not received an ARPI, chemotherapy with docetaxel, we have lutetium-177, PSMA-617, and then we also have PARP inhibitors, as you know very well, in those who may meet the criteria for getting a PARP inhibitor.
And so really when I'm thinking of a patient who has previously received an ARPI, I take a step back and I say, "Let's test their genomics." This is very important, and that will get us started of what the options are. If a patient has an HRR alteration and it's specifically BRCA2 or BRCA-related alteration, you really want to think about utilizing that genomically driven therapy early on. We know from PROfound as well as TRITON-3 that there is a clear benefit of using these regimens in a patient previously treated with an ARPI. They don't have an HR mutation, and they've already received an ARPI. We had mentioned some options include chemotherapy as well as lutetium-177, which of course is a bigger question of patient selection in that scenario, but then we have to think about the patient in front of us as well.
Neeraj Agarwal: So if you have a patient who has received radium for the sake of discussion before coming to see you, would you consider PLUVICTO lutetium therapy in that patient?
Kristine Lacuna: So you certainly could because we know from the RALU study that it is safe to do that, that sequencing radium to lutetium is certainly feasible. Of course, you want to think about the patient in front of you, whether they have genomic testing, if there are certain clinical situations, their toxicity from prior treatments in terms of choosing therapy, that also is very important.
Neeraj Agarwal: And in patients who have not seen an ARPI and a predominant bone metastasis, and as we discussed, there are patients who had localized prostate cancer biochemically recurrent disease for which they had received intermittent or continuous ADT in the last five years and now they are developing mCRPC. There's a very common patient population out there among urology colleagues and many radiation colleagues. What do you think the role of enzalutamide plus radium is?
Kristine Lacuna: Exactly. So you bring up an excellent point because here, we're siloed in academic centers where we think every patient has already received an ARPI. But I practice at one of our regional sites at Memorial and I commonly see, or not commonly, but it's not once in a blue moon where I do see patients who have not received an ARPI. And again, genomic testing is incredibly important. I'll talk about the genomic testing for that set of population patients, but say they don't have an HR mutation. We know that abiraterone and enzalutamide have overall survival advantage. We also know that docetaxel has overall survival advantage, but the PEACE-3 study was a study looking at patients who were treated with a combination of enzalutamide plus radium-223 in patients with mCRPC with bone metastases, the exact population that you said.
Ultimately, what we've seen in the last year or so is that there is such a profound overall survival advantage as well as an rPFS benefit. And although cross-study comparison is quite challenging, when you line up the outcomes based on abiraterone alone or enzalutamide alone, you can see a real deep benefit for the P3 regimen. And so even though I say it's less common to see patients who have not received an ARPI, that is why we need to recognize these patients because when we do and we have a patient sitting in front of us where they haven't received an ARPI and they have bone metastases, you want to really think about using the P3 regimen in that setting.
Another kind of set to this is that say they have an HRR alteration, and I'm speaking to the guru of knowing this data, but if they have an HR alteration specifically BRCA, you want to take the opportunity to potentially consider combination ARPI plus a PARP inhibitor because we know that there is profound effects for those patients where we don't know what the benefit is for those previously treated with an ARPI, but we really see in the studies that those studies really showed that the benefit is really focusing on an ARPI-naive population again for those with BRCA2 and BRCA-related alterations.
Neeraj Agarwal: And just to cover the genomic sequencing part fully, if you see MSI-high or TMB-high tumors, and if you combine these two, we are looking at 5% of mCRPC patient population. There's a large number of patients.
Kristine Lacuna: It is.
Neeraj Agarwal: When do you use pembrolizumab in these patients?
Kristine Lacuna: It's a great question and I think we don't know. The first thing that I said in this talk was that there's no optimal sequencing. I think that typically I use it after those first line treatments that I talked about where I've used either abiraterone, enzalutamide, or the PEACE-3 regimen, but you could make the argument depending on the patient, depending on how they're progressing, depending on their history for using it as first line therapy, it's possible to use. I think there's a lot of different other special situations and clinical scenarios where you could consider non-traditional first line therapies, so MSI-high, but say they also are only progressing in a few spots. You can consider metastasis-directed therapy in those select patients with a multidisciplinary discussion between the radiation oncologist as well as yourself. You could also consider for patients who have aggressive variant prostate cancer a combination of platinum agents plus taxane agents. It really just depends on the patient in front of us, and ultimately, we do need better biomarkers for patient selection and sequencing of these trials.
Neeraj Agarwal: It may be a tough question, but patient progressing on ARPI, you have both lutetium therapy available and docetaxel available.
Kristine Lacuna: Yes.
Neeraj Agarwal: How do you choose which treatment to offer to the patient? Or I wouldn't say offer because it's always a decision made by our patients in our clinics, but what factors make them receive docetaxel versus lutetium?
Kristine Lacuna: It's a good question, and it is often the scenario that we're faced when someone is presenting to us, someone who's already received an ARPI, we're choosing between docetaxel and lutetium. And ultimately, it's a question that the field has been asking. The PR.21 trial was just presented at ESMO last year, and ultimately Dr. Chi presented that there was no difference in progression-free survival amongst docetaxel and lutetium-177. There was suggestion of slight benefit in the docetaxel arm, but that could have been affected due to crossover effects. There was more toxicity with the docetaxel, and so when we're asking that question to ourselves, there is no right answer, there is no right sequence. It really depends on the patient in front of us. Obviously, if a patient has to be PSMA PET positive to be eligible for lutetium and the higher PSMA avidity, the more likely they'll be able to respond, but ultimately we need better biomarkers in order to select patients who will optimally get the most benefit from lutetium-177-
Neeraj Agarwal: It's good to have options at least.
Kristine Lacuna: Yes.
Neeraj Agarwal: Lastly, before we conclude, what is your practice of using bone-modifying agents in patients with mCRPC? Knowing that we looked at Flatiron database recently, a substantial number of patients are not receiving bone-modifying agents. My question to you is, in a very simple way, what message we should give to the community, how often these agents should be used and what else they should be doing to make sure they don't suffer from skeletal-related events which often result in death or patients going to hospice. If they happen, it's a bad news for our patients. How do we make sure that we prevent skeletal-related events or fractures in our patients with mCRPC?
Kristine Lacuna: That's an excellent question, and I think the one sentence point is that we should be using them. We should be using either bone-modifying agents like Zometa or Denosumab, and they should be utilized routinely and in every patient with mCRPC to prevent bone skeletal-related events, especially if you are considering the PEACE-3 regimen, that's absolutely necessary because we know the goal of treating mCRPC is not only to extend life, but to also improve quality of life outcomes. The worst thing that can happen for a patient with mCRPC is that they suffer from a fracture. That is really the best thing that we can do as clinicians and we're not good at it.
If you look at the data, just like you said, we're not giving enough bone modifying agents in this scenario for CRPC. There's a little bit of discussion in the mHSPC setting, but really for CRPC, we should be utilizing them. And in my practice, everyone is different, but I tend to use it every three months due to preventing lower calcium levels, but that's also up in the air in terms of how you practice, but bottom line is we should all be using them in the mCRPC.
Neeraj Agarwal: Plus calcium and vitamin D.
Kristine Lacuna: Exactly.
Neeraj Agarwal: That's wonderful. Thank you so much for taking the time to share your insights, and congratulations again for the great presentation you did in AUM meeting.
Kristine Lacuna: Thank you so much for having me, and for inviting me in this wonderful discussion.