Discussing New Game-Changing Studies in Prostate Cancer

In a roundtable moderated by Tanya Dorff, MD, of City of Hope, panelists Michael Morris, MD, of Memorial Sloan Kettering Cancer Center; Benjamin Garmezy, MD, of Sarah Cannon Research Institute; and Yu-Wei Chen, MD, MS, of the University of California, San Diego discuss new treatments and therapy considerations in the field of castration-resistant prostate cancer.

In part 3 of this series, the panelists review the latest game-changing studies in prostate cancer and CRPC from ESMO 2024.

Watch the fourth part of this series: Barriers to the Use of Radioligands and Navigating Patients Through Multi-Disciplinary Care

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Dr. Dorff:
Now that we’re on the topic of ESMO, there were some big studies presented in prostate. ARANOTE was one, this was metastatic hormone-sensitive ADT alone, or with darolutamide. Any thoughts about how practice-changing this will be?

Dr. Chen:
Yeah. I think the result is quite consistent with the previous ARSI doublet in a hormone-sensitive setting. There are some differences in terms of the testis profile comparing to other ARSIs. I think if it has, for example, become FDA-approved options, certainly, we can add more tools in our clinic and to discuss based on patients and to consider what is the right ARSI doublet for them.

Dr. Dorff:
Yeah, I had been getting rejections if I wasn’t using docetaxel together with darolutamide. Any thoughts on the toxicity profile or some of the other data that were presented?

Dr. Morris:
I thought it was pretty interesting that in a number of domains, the doublet was better in terms of toxicity than just the ADT plus the placebo. That was a surprise. I would’ve expected not to see more dose reductions in the single agent arm than the double agent arm.

I wasn’t really surprised in terms of the RPFS data, and I think that the OS data is really early to be taking a look at and to be comparing it to ARASENS is really unfair. It took three years for the ARASENS survival data to mature such that the upper confidence bound was less than one. I would say let’s give this trial a couple of years before we make an assessment on OS but I’m with you.

I think that this is a really practical trial in a sense. I hope the insurers will allow us to use darolutamide. I don’t think any of us have had our minds changed in any way by that study, that ADT and a placebo is worse than an ADT and darolutamide. It’s only that insurers have been interfering with allowing our patients who need this drug access to it because of the lack of data on that ARANOTE provides. Hopefully, it will remove that impediment to getting care that these patients should be getting and not having the insurance and third-party payer issue interfere with that.

Dr. Dorff:
Especially if there’s a drug-drug interaction with the other [inaudible 00:03:04] receptor antagonists. It’s really awful when the insurance tries to get us to prescribe something that’s not actually good for a patient.

I was also really impressed at the diversity in the study. I think they had about 30% Asian and 10% black, which was missing maybe in a lot of the other metastatic hormone sensitive trials. It was nice to see that additional component. P3, so enzalutamide with Radium-223 versus enzalutamide alone in metastatic castrate-resistant prostate cancer first line, so in patients that had not progressed on an AR pathway inhibitor, although about 30% had docetaxel in hormone sensitive.

Let’s talk about this trial. What are the impressions? Maybe we’ll start with you.

Dr. Garmezy:
Yeah. Look, it’s a good trial. It’s a good data set. How clinically relevant is it to us in America is I think, a bit more challenging. What is it telling us? It’s telling us just like with PARP inhibitors and HRR mutations or in this case, an unselected population, but I guess selecting for bone meds, because how this drug works that intensifying is better than not intensifying. We’re seeing an OS benefit with the addition of now an ARPI and Radium-223 versus an ARPI alone. I don’t think that that’s too surprising. The question is who do we give it to if we’re practicing in America where most of our patients should have already seen an ARPI in the hormone sensitive setting, does this data apply? The answer is maybe, maybe not. It probably applies for whoever you would give Radium-223 to, potentially.

But my concern is these patients don’t really exist in our clinics. We will hear from everyone that, well, we’re not intensifying ADT enough. X percentage of the population is on ADT monotherapy when they’ve progressed to MCRPC, which is true. However, are these patients that are out there that are on ADT monotherapy also going to be in a place where they’re going to get exposure and access to Radium-223 at the same time as they get their first ARPI. I think that’s a challenge that’s going to limit uptake.

I do think there are patients out there that could go on this. It’s those patients who thoughtfully and intelligently decided to be on something like intermittent ADT from a toxicity quality of life standpoint. Maybe they’re progressing and now, they want to intensify because they are seeing their lifespan now shorten as they’ve transitioned to castration resistance. So I do think there is a patient out there for this combination, I just think it’s not a ton.

Dr. Dorff:
Yeah. How would you prioritize, if you have NGS showing a homologous recombination repair alteration in a patient who would be eligible for P3, which would you prioritize?

Dr. Morris:
I would prioritize the actionable genetic mutation with contemporary therapy. Of course, the combination issue comes into play with the PARPs as well and is it appropriate to combine in second line therapy. But I probably would say that for the 80% of patients who do not have a homologous mutation, that P3 has something to say. I agree that those patients aren’t readily available who have not seen a second line ARPI But I do think that this was a really important study on two grounds. One is that we habitually look to the newest and the most shiniest penny for survival and now, this is the second trial where an older drug repositioned or recombined, I think I’ve charted as the first, which was just plain old doce, moved earlier, changed. It was an Earth moving event for the prostate cancer world.

Now, we have this trial, which is again, older drugs newly applied or combined and I think it’s important to recognize also no trial has shown more than a four-month OS advantage that’s FDA approved. This is a seven-month OS advantage in the sense and that is breaking a certain new ground and a new metric for what do we think of as an OS advantage and this is in first line metastatic CRPC. We always say, “Well, we’re going to lose OS because of all of the downstream therapies.” This was upfront and granted these patients didn’t have the benefit of first line ARSI treatment, true, but I think there are some really important lessons to be drawn.

There is an ongoing phase three study of doce plus or minus radium called the DORA trial and that’s open in the US, Spain and Brazil and the Netherlands. Let’s finish that one up because that does apply to contemporary treatment patterns and paradigms in the current population. That only has another few hundred patients to go, it’s 80% accrued, so let’s really accrue to that study effectively so that we can get a result quickly and perhaps change the standard of care again with an older drug.

Dr. Dorff:
Now, it was interesting to me that ERA 223, which was a similar study design, but using abiraterone did not find a benefit. One hypothesis is that this study learned from the increase in fractures that were seen on ERA 223, and therefore bone-supportive agents being used in this trial. Do you think that that’s the difference between these or do you think there’s a different synergy of these drugs or some other explanation?

Dr. Chen:
I personally don’t think there is a true differences there, but I know the protocol mandate would add on the bone-protecting agents after the first few, roughly a hundred patients. We do see the toxicity profile, there is still slightly increase of a fracture within the [inaudible 00:09:26] arm. But my guess is that I don’t see the true difference or I don’t know what is the true mechanisms, explain the differences there but since we do see a slight increase with the fracture, I think aiding on a bone-protecting agent is reasonable here.

Dr. Dorff:
They excluded patients with baseline osteoporosis and I think they amended the trial partway through to require four bone meds instead of two. I don’t know. Anything else you can think of that might explain the difference in the outcomes of those two trials?

Dr. Morris:
I think ERA 223 was abandoned too early. If you had done what the piece three group did, which was swiftly intervene, stop the trial, intervene, give adequate bone protection, then restart the trial, you might have had a similar outcome. We’ll never know. But I do think ERA 223 was devastating to radium early and kudos to the investigators of Phase three for working it out.

Dr. Garmezy:
I think one of the other questions that may or may not play a role, it probably doesn’t, but the steroid use. There’s other parts. We treat all the ARPIs the same, but they’re not the same. They’re completely different mechanisms of action here that are having different interplays within, potentially, the bone microenvironment. I think it could be drug and mechanism of action, it could be supportive medications required when we give drug. It also could just be as simple as fracture risk is a big problem to keep people on drug safely, we need to just provide something as simple as a bone strengthening agent. I think all these things are possible and it’s going to be hard to tease that out.

Dr. Morris:
Excellent point about the steroids, really. I think that could also really, like you just said, be a real contributor to the fracture rate.

Dr. Dorff:
You were probably using five BID since it was CRPC, which would be a little bit super physiologic, I think, since now, we know we can get away with five daily with abiraterone. That’s a great point, yeah.