Insights From ARANOTE and PEACE 3 Trials: Optimizing Prostate Cancer Treatment

In part five of this roundtable series, Dr. Appleman leads a panel discussion with Drs. Mehta, Kelly, Chablani, and Wong on insights from the ARANOTE and PEACE 3 trials. The panel begins by exploring data presented at the 2024 European Society for Medical Oncology Congress, delving into the background of the ARANOTE and PEACE 3 studies. They discuss side effect profiles, drug interactions and combinations, and how the outcomes of the studies will aid physicians in optimizing the treatment of prostate cancer for patients.

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Dr. Appleman:
So at ESMO this year we had an update of ARASENS and then data for the very first time from ARANOTE and PEACE 3. And so if we can start by just refreshing everyone on the ARASEN study and what was new in the poster that was there at ESMO.

Dr. Chablani:
Yeah, I think we talked about ARASENS already with the doublet versus triplet and now we’re using the triplet in some select cases. So, ARANOTE was a trial that was a non-US trial where patients with newly diagnosed metastatic hormone-sensitive prostate cancer were randomized in a 2-to-1 fashion to Darolutimide plus ADT versus ADT alone.

And there was a median follow-up about two years at this point. The results were just presented at ESMO with the primary endpoint being radiographic progression-free survival. And so the ARANOTE investigators, they met the primary endpoint of radiographic progression-free survival with about a 46% reduction in the risk of progression in the ADT plus darolutamide arm versus ADT alone.

And the median PFS was not reached in ADT plus darolutamide arm versus about 24, 25 months in the ADT alone arm. There is a trend toward overall survival, but it’s too early at this point. The interim analysis is showing a trend toward overall survival, but we need more data to see that. And the trial also met its secondary endpoints, not OS yet, but time to castrate-resistance, time to next treatment, PSA progression. So all the secondary endpoints, there was a significant benefit in the ADT plus darolutamide arm.

And I think really notably was that the side effect profile was very good in the ADT plus darolutamide arm with very limited side effects that darolutamide seemed to be adding to the ADT. I think fatigue was 6% with ADT plus darolutamide versus like 8 or 9% with ADT alone. So it was larger in the ADT alone group, and otherwise, it didn’t seem like darolutamide was adding much in terms of side effects.

So I think this is a really nice trial because we finally have our data that ADT plus darolutamide backbone has in a PFS benefit, and hopefully we can add this to our armamentarium of abi and enza and apalutamide for our patients, and maybe get insurance to cover this ADT plus ARSI backbone without always having to use the docetaxel. Because I know we’ve kind of run into some issues and maybe we can talk a little bit about that more whether you guys are using ADT plus darolutamide alone without the docetaxel in practice. But yeah, I think it kind of opens up options for patients and I’m eager to look at the OS data and see what the FDA does in terms of approval of this.

Dr. Wong:
Yeah, I definitely think this was a needed trial. I do have some patients that I pursued darolutamide without the docetaxel for triplet therapy. I had one patient who has very severe heart failure and with his cardiac medications, well for those reasons, I didn’t want to put him on abiraterone/prednisone. And enzalutamide and apalutamide actually interacted more severely with his cardiac medications than darolutamide, for example.

And I think collectively, we all probably already believe that darolutamide is certainly probably no worse than enzalutamide and apalutamide and might have some benefits in terms of toxicity profile and in my case, drug interactions. So I think it’s something that we probably already wanted for our patients to have as an option for ADT plus ARSI. But obviously, if it can get FDA-approved, that’d be a huge benefit. I was a little bit surprised that they were able to have the ADT alone arm in their trial since we already know that ADT plus ARSI is better than ADT alone. But again, if it helps get the drug approved, then I’m all for it.

Dr. Kelly:
And I believe that trial was maybe 70% high volume, too.

Dr. Chablani:
Yeah, The benefit was in high volume and low volume and patients had visceral mets. And yeah, I think that this did come up, that it was like a non-U.S. trial.

Dr. Kelly:
It was non-U.S. trial, right?

Dr. Appleman:
And it was a 2-to-1 randomization, I think.

Dr. Chablani:
It’s 2-to-1, yeah.

Dr. Appleman:
And I think it was all done before abiraterone went off-patent. So at least in the U.S. So there wasn’t really an option that didn’t cost $10,000 a month and assume median income in these areas was sort of at that level maybe. So yeah, I think it fit into its timeframe. I do wonder because there were a lot of high volume people and there is no docetaxel, what the practices were like, were those doctors, did they have docetaxel available? And just like we all thought probably more than half of our high volume patients, we don’t give docetaxel even when we have it that were the patients that were enrolled in the study. And did those doctors also have patients that they thought would tolerate, they didn’t enroll, or was it some scenario where they enrolled patients who might have… was it an access issue to docetaxel or for some other reason that those patients weren’t offered docetaxel? It doesn’t really change in how we interpret the results, I’d be interested to know.

Dr. Mehta:
Yeah. In community, as we tend to see a little more older patients and they have diabetes, they have heart failure. I think there is definitely a drug interaction, prednisone-related hyperglycemia, which usually needed in abiraterone. So we certainly think that we always struggle to make decisions whenever I go through the pharmacy check and some of the agonist as we talked about, enzalutamide or apalutamide where we have to change some of the medicines or dosage.

One thing I have seen that not having skin rash issue with darolutamide is great because I think these are all patients are male and they tend to not as good patients in my experience, to deal with the rash management. When they have a rash, they have a very low threshold to stop and their rash tends to be worse, much worse than I think, in my opinion.

So I have been shifting more towards darolutamide based treatment. At least we all think they are all similar. Their data point outcome is very similar, but I think tolerability has improved and compliance have improved when we have less side effects with this medications because we are expecting these patients to stay on this medicine, especially on hormone-sensitive case up to 2, 3, 4 years.

Dr. Chablani:
Yeah.

Dr. Mehta:
A median time. So I think compliance is a big challenge.

Dr. Kelly:
Yeah, fall risks, seizure risk, brain fog. And similarly, I like Risa have had issues with getting darolutamide approved without docetaxel, which has been a challenge when you know that the side effect profile is better, fewer interactions. So I think this is great that we have this.

Dr. Appleman:
Would anyone need to see an overall survival benefit? Assuming it gets approval in this space, would anyone need to see an overall survival benefit to feel comfortable prescribing it?

Dr. Kelly:
My answer is no.

Dr. Chablani:
I think we’re probably all… are we all doing this already? It sounds like we’re all-

Dr. Mehta:
It’ll be helpful and just solidify what we think. But I think we all know from the other studies they are similar and there is already a trend. So I think it’s already practice-changing and hopefully payers also agrees. I agree as Dr. Wong said that I had challenges with payers to get the darolutamide and they’d say, oh, patient is not getting chemotherapy, we are not going to get approved. So now this, we have a data to support that it does help. And ADT plus darolutamide is a very valid therapy for even in a low to high-volume disease. And one thing I would say that it at least helps us also when patient are not a chemo candidate to go to the high volume patient just using ADT plus darolutamide.

Dr. Appleman:
So I think we can talk about the next study, which was, I have to admit, I was pretty shocked by the result and it was so exciting to see that this was a oral presentation at the presidential session of ESMO. I really wish I was there to see Dr. Gillison present her data. This was an investigator-initiated study run by the EU RTC for patients. And it was enrollment began in 2015 and it was for patients with castration refractory metastatic prostate cancer.

It was really just at the right before the combination of an ARSI plus a GNRH analog became the standard of care in hormone-sensitive disease. So all but 11 of the 440 patients on the study had ADT alone without abiraterone as an accompanying agent. And so the design, they enrolled 446 patients, a 1-to-1 randomization of enzalutamide versus enzalutamide plus six doses of Radium 223. And the eligibility, as you might expect, patients had to have predominantly bone metastasis.

They were allowed to have received docetaxel in the hormone-sensitive setting as per CHAARTED, STAMPEDE. And 30% of the patients had in fact received docetaxel in the hormone-sensitive setting. The primary endpoint was radiographic progression-free survival, again using our old friends, a bone scan, and CT. And the top-line result, the study met its primary endpoint with a hazard ratio of 0.69 in favor of the combination of enzalutamide plus radium-223 versus enzalutamide alone.

The median progression-free survival was 19.4 months versus 16.4 months. The 24-month radiographic free survival at sort of the landmark analysis at two years was 45% versus 36%. And strikingly the overall survival results had the exact same hazard ratio, 0.69 overall survival advantage in favor of Radium plus enzalutamide versus enzalutamide.

And to be honest, having seen the results of the abiraterone plus radium-223 study, I would’ve said that would be almost impossible to imagine. But those are the data, the median overall survival is 42 versus 35 months. And so those are really the top line data. What I thought was interesting is we know from the original ALSYMPCA study that radium in somewhat more advanced setting and patients who had to be symptomatic. This study was for minimally symptomatic patients. But for symptomatic patients, there was an improvement in terms of symptomatic skeletal events.

In this study, in PEACE 3, there was no benefit in terms of the rate of symptomatic skeletal-related events, nor in the time to pain progression, which I think is really interesting. I don’t know if anybody has a hypothesis why that might be the case in the face of the RPFS and OS data.

Dr. Chablani:
I think an important just comment to add to great overview of the trial is that the trial is amended partway through after I think 119 patients had been enrolled to mandate the use of a bone-strengthening agent so denosumab.

Dr. Appleman:
Great point.

Dr. Chablani:
Because of the results of the ERA 223 study of abiraterone plus radium versus radium or abi alone where they saw a large number of patients have skeletal-related events and the trial didn’t meet its endpoints. So I think that that was very smart of the ERTC investigators to go back mandate the use of a bone-strengthening agent. And then I think it allowed them to meet the primary endpoint of RPFS and there was a OS benefit as well. It’s still interim analysis, but there’s also an OS benefit.

Dr. Appleman:
Yeah, that’s a great point about the bone-strengthening agent. I think it tells us we have a lot to learn about what’s happening in bone with radium and the effect on the osteoclasts and osteoblasts and versus the cancer cells just there’s a lot we have to understand about the biology. It’s interesting, radium has not really been used that much in its current approval. I think a lot of people have had the experience. It doesn’t affect the PSA, it doesn’t… it used in the setting where it’s approved, I don’t think I’ve seen a lot of obvious responses in terms of radiographic.

Again, bone scans are really difficult to interpret, I think, as part of the issue. So I think these are really striking data in that setting. And I think the big question is we assume this leads to approval in the setting, they conducted the trial, castration refractory prostate cancer. How are we going to apply it now in the era where most patients are getting enhanced ADT in the hormone-sensitive setting?

Dr. Mehta:
And that’s a question I always… I tend to right now mainly I’ve been using Radium 223 is the patients who have isolated boney mets with a slow PSA rising on a novel AR or gone SOR, where I see the PSA going from two to four or five. We do the bone scans, there’s no visceral met on a CT scan.

And I tend to discuss with my nuclear-met colleagues and decide, is this the time to use radium-223 and kind of bank the Pluvicto-based treatment for future. But certainly, there’s some risk of bone marrow suppression and so forth. But I’ve been curious how you have been using, especially with this data, and if it starts getting approval in that right setting.

Dr. Appleman:
Yeah. Another question I’d really love to know the answer to is there some special synergy between enzalutamide and radium-223 that led to these results? And you wonder, this might be a potential trial design patients who are on let’s say abiraterone plus GnRH analog in the hormone-sensitive setting, and now they become castration refractory.

Then let’s say enzalutamide plus Radium versus maybe docetaxel as a randomized trial. Is there something really special about that combination? Or I think you have a great point that Radium may work better the earlier you use it. And I remember especially when we were waiting for Radium to get its FDA-approval and become available in that year, I forget what year it was, but we didn’t have a lot of other options. And patients were really pretty sick.

They already had low counts. They were very symptomatic, huge burden of disease. And the radium didn’t really help those people. A lot of them got really, as you said, cytopenias. So I think that’s maybe really not the setting to use it. Like you said, probably earlier it works a lot better. But I really wonder is there’s something kind of magical about the enzalutamide combo and how do we test for that?

Dr. Chablani:
And we know from so many trials that there’s a synergy between radiation and hormonal therapy, radiation to ADT radiation plus ADT plus ARSI from STAMPEDE. Very high-risk patients. So I feel like this is again another form of, there might be some sort of radium-inducing double-stranded DNA breaks in prostate cancer cells and then coming in with the hormonal therapy and this exploiting this synergy between these two therapeutic approaches that we’ve seen so many times in prostate cancer.

Dr. Wong:
I believe there’s some data for continuing or having enzalutamide on board with Pluvicto as well-

Dr. Kelly:
Trialing, absolutely.

Dr. Mehta:
That was at ASCO of this year.

Dr. Appleman:
Yeah.

Dr. Kelly:
And we’re doing that, so, yeah.

Dr. Appleman:
I think some of that is hypothesized to be due to up-regulation of PSMA expression, which you wouldn’t think would apply to radium, but I think there’s just a lot of work that needs to be done. And just now that we see this activity, it just hopefully will generate some trials with clinical endpoints and some translational studies.

Dr. Kelly:
I think the other point too is, are you seeing these patients who are the patient population really in your clinic, in the trial? Folks who were just on ADT monotherapy, which comprised the majority of folks on this trial, really they’re seeing there was only a small percentage of folks who had seen abiraterone on previously and a small percentage of folks who’d seen docetaxel.

So really you’re seeing the person who comes in for ADT alone. And if so, is that really the person who you’re thinking about starting enzalutamide and radium on? Or were there decisions that went into just let’s give you a hair of ADT and see how you do?

So I think that in addition to all the other things that we have in our armamentarium for castration resistant prostate cancer, Pluvicto, we’ve alluded to, making sure they don’t have BRCA mutations, these homologous recombination repair deficiency. And then obviously we never want to miss an MSI high. So we do have other things in different trials. And so I think it’s a loaded question, but very exciting data.

Dr. Appleman:
Great point. And I’d love to ask the investigators, did they collect samples for translational studies to just exactly what you mentioned, can you predict who’s going to respond to radium based on mutational analysis or gene expression analysis?

Dr. Chablani:
Yeah, I agree with Dr. Kelly that this is a vanishing kind of population that everyone’s getting treated up front with ADT plus ARSI hopefully in the hormone metastatic hormone-sensitive setting. And so who’s really presenting that hasn’t gotten enza or abi or now darolutamide maybe in the metastatic hormone-sensitive.

But again, it’s great to have options for our patients. It’s great to be able to say, based on the person in front of us and your comorbidities and the biology of your disease, these are the things we can do. Of course, if they have a visceral crisis, they have mets in their liver, they have a ton of pain, docetaxel will probably be the way to go, but great to have options.