Treatment Selection in mHSPC: ARANOTE, STOPCAP, and the Future of Precision Therapy

At the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, an expert panel convened to discuss the latest research and clinical advancements in prostate cancer diagnosis and treatment. Moderated by Dr. Alan Bryce, City of Hope, Arizona, the roundtable consisted of Dr. Alan Tan, Vanderbilt; Dr. Evan Yu, Fred Hutch/University of Washington; Dr. Priyanka Chablani, UPMC; Dr. Jack Andrews, Mayo Clinic Arizona; and Dr. Chad Tang, MD Anderson Cancer Center.

In the fourth segment, the panel breaks down the complexities of treatment selection in mHSPC, discussing how to navigate the growing landscape of doublet and triplet regimens. The experts highlight the importance of biomarker-driven decisions, patient fitness, and PSA kinetics in guiding therapy choices. They also analyze the latest findings from STOPCAP and ARANOTE, addressing their implications for older patients and ARSI selection.

View the next segment on PEACE-3 and the Role of Radium-223: Rethinking Combination Strategies in mCRPC.

—

Dr. Bryce: Dr. Chablani, I want to shift over, systemic therapy, metastatic hormone sensitive, we have a lot of regimens. So, how do you make sense or talk to the patient about, “You’ve got nine positive trials, doublets and triplets and quadriplets,” Oh my, right? Where do we go with this, right? How do you guide a patient through this?

Dr. Chablani: Yeah. Very relevant question. It’s great to have options. First of all, I’ll say it’s great to be able to discuss different options with patients and throw this in their court a little bit. But I do, anyone with visceral Mets, liver mets, lung mets, I do go for the triplet, and I recommend that. Because we know that liver mets are an adverse prognostic factor, lung mets a little bit less so. High volume, as I was talking about that florid disease, or lots of bony mets on PSMA PET, or conventional imaging, I’ll recommend the triplet. Then for people in that gray zone with three to five bone mets, I will talk to them about ADT plus ARSI, versus the triplet, and say that we don’t have great randomized data between doublets and triplets. We do know that we’re not giving ADT plus docetaxel anymore, that is no longer a standard of care.

But between ADT plus ARSIs, and our different ARSIs and abupred, and the triplet, we don’t have that randomized data yet. So they’re both good options and it’s up to them if they want to be a little bit more aggressive. As I mentioned before, I also look at the PSA as a data point if it’s lots of bony mets, but a PSA that’s like 5 or 3, low PSA, I’m thinking there’s more of a aggressive biology here. I look at the prostate biopsy, intraductal carcinoma, many cores with intraductal carcinoma. That’s an adverse prognostic feature. And then I also look at my NGS. So, patients with high-risk tumor suppressor gene mutations and two out of three PTEN, TP53 and RB1. If they have two out of three of those, I’ll also think that this is more of an aggressive variant prostate cancer, and it needs something more than just hormonal therapy to augment the response.

So with the NGS, the PSA, and I mentioned before as well, the age of the patient, if they’re in their 50s, if they’re robust, and I’m like, “Why are they having all these mets everywhere, and they’re so young? Let’s give them the triplet life. Let’s augment treatment up front to delay time to castrate-resistance.”

Dr. Bryce: Yeah, yeah. And then, maybe we can share with the audience, we saw STOPCAP today. Can you give an overview of that data, because it’s feeding right into this idea of treatment selection.

Dr. Chablani: Yeah. So, the STOPCAP analysis looked at, I think 11 trials in the metastatic castrate sensitive prostate cancer space. And it was a meta-analysis that collated all this data. And basically it did tell us what we know that, ADT plus ARSI is beneficial in terms of PFS and OS in the majority of patients, and we’re on the right track with this. But there was a subgroup of patients of 75 and above, where it seemed that they didn’t benefit as much from ARSI, and particularly abiraterone and prednisone. So I really liked Dr. Dorff’s commentary, where we should in our older patients that have more comorbidities, more cardiac disease, perhaps are less frail, we really should be thinking about which ARSI to use.

And because we have abiraterone and prednisone, but then two apalutamide, enzalutamide, and maybe darolutamide based on ARANOTE results. We really need to be tailoring our choice of ARSI to the patient in front of us, based on the other drugs that they’re on, drug-drug interactions, or other comorbidities performance status. And using a personalized approach to that patient. But just going to the once, “Oh, this is the one I always use.”

Dr. Bryce: Yeah. I think bringing up ARANOTE is so important. Because we’re all used to the triplet therapy. We have ARASENS with darolutamide, ADT, docetaxel. But now we’ve got a data set kind of XUS, showing darolutamide doublet giving the kind of results you’d expect, no real surprise. It works to do darolutamide ADT. You don’t have to have the docetaxel to see meaningful benefit. I would follow up, the point that you made is correct. There’s no role for docetaxel ADT doublets anymore. But the reason is not because it’s a bad combination. It’s because if someone can get through ADT doce, why would you not give daro or abi after? Anybody who’s getting doce should get a triplet. There’s no rationale for a doublet I think is the point. Evan, what would you say? I mean, where does ARANOTE fit in now?

Dr. Yu: I think the ARANOTE study was useful and helpful. I mean, I’ve heard various people take different takes on it. I think you brought up the key issue, that it was done outside of the United States. There’s a lot of people that are really focused on the fact that, “Oh, a doublet at a minimum is the standard of care. How did these patients get less than a doublet?” Well, not everywhere in the world or is there great access to all of these agents. And I think we have to recognize that. And so, I do think that the data that was gleaned from that study is important. When I look at that data and I say, “The RPFS benefit is very significant, yes. The OS data is not yet mature.”

But it looks very similar to what we saw in ARCHES with enzalutamide. Where we saw significant RPFS benefit, the curves, the hazard ratio, all that looks pretty similar. And then later we saw an overall survival benefit. From my perspective, and again, I’m not a regulatory agency, but from my perspective, I don’t really see a difference in whether I need to see overall survival, to be able to give a doublet with ADT darolutamide. Now, third-party payers and regulators may see a difference now, and they may not want us to do that. But I think it’s going to eventually read out with very similar overall survival data. And I think that’s helpful, for the exact reason that was just kind of discussed in STOPCAP. Because the more advanced age a patient is, the shorter the anticipated lifespan. I think we have to be honest with that.

And although a doublet is standard, or a triplet is standard, there may be patient populations that have a lot of comorbidities and be of advanced age, where agents like abiraterone have a higher cardiovascular risk. Enzalutamide may induce more fatigue. A seizure risk is tiny, but it may induce more fatigue and restless leg syndrome, and risk of falls, and coming with falls or hip fractures. Those things have major morbidity risk. The one thing I’ll point out in ARANOTE that was most helpful to me, so I’m very glad and grateful that the study was done, is, I was really surprised to see that the treatment arm actually had less fatigue than the control arm. And I don’t know what other oncology studies you see where that occurs. There was more treatment associated discontinuations on the trial for the control arm, than for the treatment arm. So for me, I would love it if you have that option available as a doublet in the future. That’s just my two cents.

Dr. Bryce: Well, all right. So we know in the surprising real-world data in the US, the majority of patients getting darolutamide somehow don’t get docetaxel, right?

Dr. Yu: That’s because of the label. So, how the label’s written is that, you can start the doublet with ADT darolutamide first, and then add the docetaxel later. Because let’s be honest, that’s what most of us do when we do a doublet and we’re going to add the triplet later. Is you start-

Dr. Bryce: I start this today, doce comes in down the road.

Dr. Yu: Right. The lupron gets started, the ARPI gets added in there once the insurance clearance comes through, and then maybe a little bit later the docetaxel gets added. So, sometimes for whatever reason, the docetaxel may not be added. I don’t know.

Dr. Bryce: Yeah. Alan?

Dr. Tan: To add something to that too. A really compelling trial that will answer this question too is the CCTG trial that triple-switched, and just opened two weeks ago. So basically it’s dealer’s choice ADT, ARSI. But for those patients that don’t have the optimal response, all we see is patients that don’t hit less than 2 on their PSA. We think they’re probably going to have castrate-resistance sooner. So, I think it’s an easier discussion to have with patients, “Hey, let’s start with ADT ARSI. You’re going to feel much better in a couple months, maybe even sooner.” And then when we actually get more information based on your PSA kinetics, maybe even genomics like the PTEN, the TP53 and the RB1 loss. And maybe even SPOP is another one that shows that you have a more indolent course. I think that’s going to be incorporated in the future of precision selection here.

Dr. Yu: Can I just add, I’m glad you brought up that study. The CCTG SWOG Triple Switch collaboration I think is phenomenal. Because, we have to recognize the fact, I think everybody here knows, but I’m just going to bring it up, is the fact that all the triplet therapy studies had a control arm of ADT docetaxel. And we just got done saying that the NCCN guidelines in the United States don’t recommend that. They use it a lot more in Europe. But in the United States, our doublet is not ADT docetaxel, it’s ADT plus ARPI.

Dr. Bryce: Well, it was when the studies were designed.

Dr. Yu: Right, right. But we don’t have robust data. And I think we need that robust data to show that you really need the docetaxel. And I think it’s really good to start with a patient population that’s PSA doesn’t go undetectable. Because we know going undetectable, you could drive a truck through those curves, if you don’t go undetectable versus going undetectable. And then there’s the Alliance study, where they’re really intending to look at those with the tumor suppressor gene alterations. You got to have a P53, PTEN alteration. That being said, I don’t think it’s part of the eligibility, but they’re doing sequencing, they’re doing immunohistochemistry, they’re doing testing I believe on everyone, and then they’re going to splay that out. And that’s a key question in that study. Do those patients preferentially do better with docetaxel? There’s some preclinical data. We know they have a worse prognosis. So these are the things of the future where the control arm is a doublet with an ARPI. I’m glad we’re doing it.

Dr. Tan: Yeah. That’s a clean study. That’s with apalutamide. But the TP53 and RB1 is more of a strat factor. I think they’re answering two different questions, but similar population.