Jacqueline Brown: Thank you for having me.
Neeraj Agarwal: Taking the time. We really loved your presentation on doublet versus triplet therapy at the 2026 American Urology Association meeting in Washington, D.C. Please tell us more about the intensification first. Before we get into doublet versus triplet, we already know that there are a lot of patients out there who are getting ADT monotherapy.
Jacqueline Brown: Exactly.
Neeraj Agarwal: So let's start from there. What are the data in support of doublet versus triplet compared to ADT monotherapy? And we can go from there.
Jacqueline Brown: Well, I think you said the most important thing first, right? The ADT plus ARPI is the minimum Neeraj, and that's what all of our patients should be getting. We can think about what we do after that. We've had triplet therapy data for a half decade now as long as I've been released into the wild practicing independent medicine. And so as we think about PC1 and we think about ARASENS, we know that chemotherapy can help. I think we all agree at this point that the patients who benefit the most are those with our high-volume disease, de novo disease.
But what we really need to know is the timing of that addition. Should it be added out of the gate? Should it be added in that higher risk population who don't get that great PSA response we're looking for? And we're still waiting on that data that shows us a comparison to an ADT and ARPI doublet, which will get in Aspire. So that story is ongoing.
I think we all know that patient in our gut when we see them. We know that patient with the low PSA, the viscerally inclined disease, the symptomatic disease. That guy needs chemotherapy. But that debate is only about one of our triplets. And I think if I could have anybody take-home something from my talk today, it would be that the world of prostate cancer is about to explode and we have to really redefine triplet. We cannot use triplet as synonymous with chemotherapy anymore because of all of the options coming down the pike.
Neeraj Agarwal: So taking a step back, ADT monotherapy is not acceptable for anyone-
Jacqueline Brown: That's right. Right.
Neeraj Agarwal: ... unless there are obvious contraindications. There may be one or 2% of patients who may not tolerate ARPI. But pretty much it is a consensus based on solid evidence, level one evidence, improving overall survival that everyone should be getting ADT plus ARPI, at least.
Jacqueline Brown: That's right. And I think that we have multiple options. We can fit those options to our patient's comorbidity profile. If a patient can tolerate ADT, I consider the ARPI a deck chair on the Titanic, relative to the side effects that are going to be incurred by the ADT. So most patients are going to be candidates. We have to dose adjust. We have to be thoughtful. We have to say, "All you're saying yes to is one day of the drug. If you hate it, if all hell breaks loose, talk to me." Right? That's all we're saying, but we have to have that conversation. We can't assume for them.
Certainly if we think someone has competing comorbidities that they have a life expectancy less than five years. I don't know if that's worth it, right? That's not most of our patients.
Neeraj Agarwal: Correct. So coming to the triplet, which basically in today's definition with the currently approved regimens, triplet basically is synonymized with ADT plus ARPI plus docetaxel chemotherapy, which have never been compared with ADT plus ARPI.
Jacqueline Brown: Right. The study we need.
Neeraj Agarwal: The study we need. And ASPIRE trial is going on, and then the triple switch trial through SWOG. So could you tell us more about how you view these trials? And how they may change your practice down the line? Before we go to discuss newer triplets.
Jacqueline Brown: Absolutely. I think ASPIRE, when patients, and we all have those savvy patients who have read and say, "I want the most aggressive approach, and I saw that chemotherapy is going to be that thing that helps me." I sort of sketch out the trial design and I sketch out the control arm and I say, "I think that we have enough data cumulatively over these many studies to tell us there are people who probably benefit from chemotherapy addition, but that is not what these studies set out to tell us."
And so I explain. I don't have the ASPIRE study open at my center. I look forward to my colleagues enrolling well to that. That's the answer that we really need where ADT and apalutamide is the control arm, right? Who needs chemotherapy is the question. And they've really narrowed in on that de novo population and that high-volume population. So they're enrolling those high risk populations that we know courted the most benefit from chemotherapy in the meta-analyses that we have of the existing studies.
And then of course patients, we are loading on therapies when we need them. We are saying, and everyone does it differently, but, "All right, I'm going to start your ADT. Come back in a month. I'm going to start your ARPI. Are you okay? Come back in a month. Oh, there might be a third level to your treatment cake, so to speak." And they're overwhelmed.
And so I think that triple switch will be really important to say, "Does everyone need it out of the gate or should we be happy with our doublet? And really select that population with the not so hormone-sensitive disease that has that subpar PSA response and then treat them?" And maybe it won't be beneficial, but that's why we do the trial.
Neeraj Agarwal: Great point. And just for our viewers today, triple switch is a SWOG Canadian trial group trial co-sponsored by both organizations. And patients start with ADT plus ARPI. And then they wait until six to 12 months and if PSA doesn't go to less than 0.2, they are randomized to continuation of ADT plus ARPI plus docetaxel chemotherapy. So first trial, which will answer hopefully in the near future, who if these patients, suboptimal responders may need chemotherapy with docetaxel. And the ASPIRE trial is randomizing them upfront to triplet versus doublet therapy.
Jacqueline Brown: Exactly.
Neeraj Agarwal: Now moving forward, what is the field looking like biomarker-based therapy more specifically?
Jacqueline Brown: Yeah. Already as of December 2025, we have the approval of abiraterone plus niraparib in our patients who have BRCA2 mutations in their germline testing or on their somatic testing. So we already have an FDA approved option that needs us to break that connection between triplet and chemotherapy. Because we have a new triplet and you are the master of this space Neeraj. But to say that the addition of niraparib to abiraterone and ADT improved progression-free survival. The OS data was immature at that time and it seemed like the benefit from the addition of the PARP inhibitor was really driven by those BRCA1/2-mutant patients. And so that's an option.
And we're going to have to weigh, right, the toxicity incurred by PARP inhibitors. There is no get through this 18 weeks of treatment, although it may end up being like that. So it's us modulating the quality of life that our patients and we expect in hormone-sensitive disease, with the potential side effects incurred by these drugs like PARP inhibitors.
However, we know that these are patients who have a worse prognosis and now we have a potential to modulate that early in the disease course. It's just a balancing act as it's always been. So that's our next triplet that's ready to go prime time in May of 2026. It's an option. I think it highlights we have to be testing. We do not know what we do not know. We need to send germline and somatic testing in all of these patients, or we don't know what our armamentarium holds.
Neeraj Agarwal: And the upcoming trials such as trials which have been presented, but we don't have the approval yet.
Jacqueline Brown: Yeah, exactly.
Neeraj Agarwal: Would you like to talk about those trials?
Jacqueline Brown: I would. So I think you're referencing PSMAddition. So we're thinking about the addition of six cycles of lutetium to ADT and ARPI therapy in a hormone-sensitive population with at least one PSMA-positive lesion. We saw an improvement in PFS, OS. We didn't see an improvement at the time of immature data analysis. And so this is an option. I think as we've been treating our patients with lutetium therapy in the hormone resistance setting for a long time, I think we all have questions about the biomarker. It's clearly more complicated than did you have a PSMA-avid lesion?
We have those patients who get lutetium therapy and have a beautiful response, those who do not. And they all had a pretty high SUV. So we need to refine that, but it's a great option and our patients are really interested in it. It feels personalized to them. And as I said in the beginning, our patients are going to drive a lot of our conversations about these things. And then the other triplet that you're referring to is capivasertib in a PTEN-deficient population. We know that patients who have PTEN-deficiency have poorer outcomes. We can use an AKT inhibitor, capivasertib in these patients to target a downstream upregulated pathway.
We saw an improvement in progression-free survival, not yet overall survival with the addition of that drug. Again, like PARP inhibitors has a new side effect profile that we as GU medical oncologists have to get used to. Our breast colleagues have used this for a while. It's newer to us. So we're thinking about the rash. We're thinking about the diarrhea. But again, this is a higher risk population. It's hard to know you have a patient who's going to have a worse prognosis and sit on that information.
But we will again have to define that biomarker. What is PTEN-deficiency and how is that defined relative to the potential benefit of the drug? But I think we got some encouraging voting from ODAC recently and so we'll see how that goes. Not yet prime time, but I expect it will probably come down the pike. And then the triplet we've used for several years now in radiation. Who do we refer for consideration of radiation to the primary? STAMPEDE told us those with low-volume disease we can consider it. But that was the ADT monotherapy era.
I think S1802 will help us to define the role for local intervention to the prostate in the doublet era, and what type of intervention. Should that be surgery? Should that be radiation? And how do we pair that with SBRT to oligometastatic lesions? The study isn't setting out to answer that, but these are the things we're thinking about intensifying for all of our patients.
Neeraj Agarwal: So a lot of triplets out there.
Jacqueline Brown: There's a lot of triplets out there.
Neeraj Agarwal: Any final points for our viewers today regarding ADT intensification therapy?
Jacqueline Brown: Yeah. I think the main points are we only have the luxury of having a discussion about triplet intensification if we're doing doublet. So we have to do doublet. That's the first take-home. We have to do biomarker testing. And pretty soon we're going to have to expand our definition of biomarker testing. I expect not only from our genomic analysis of the somatic genome of the germline genome, but also thinking about IHC should CAPI come to market as well.
And then beyond that, our patients are going to guide us. I may have the strongest feelings in the world that this patient should get a PARP inhibitor or should get lutetium therapy or should get chemotherapy. But if he's not interested in that for whatever reason, I'm going to let him guide me. And I'm going to sleep fine at night knowing that I got good doublet therapy into him.
Neeraj Agarwal: Wonderful discussion.
Jacqueline Brown: Thanks Neeraj.
Neeraj Agarwal: Thank you and congratulations for the wonderful presentation. And look forward to hearing more about doublets and triplets from you in the near future.
Jacqueline Brown: Thank you, Neeraj. Thanks for having me.