Optimal Treatment Sequencing in Metastatic Prostate Cancer "Discussion"

November 15, 2024

At the 2024 Advanced Prostate Cancer Consensus Conference (APCCC), a panel discussion explores key questions in metastatic prostate cancer treatment. The panel debates mechanisms behind docetaxel's apparent harm in low-volume metachronous disease while emphasizing patient-centered decision-making, acknowledging that while ADT plus ARPI represents a clear standard of care, other treatment decisions require careful consideration of individual circumstances and preferences.

Biographies:

Silke Gillessen, MD, Medical Oncologist, Medical and Scientific Director, L'Istituto Oncologico della Svizzera Italiana (IOSI), Bellinzona, Switzerland

Aurelius Omlin, MD, Medical Oncologist, Cantonal Hospital St. Gallen, St. Gallen, Switzerland

Read the Full Video Transcript

Bertrand Tombal: It’s time for questions now. Is there a question from the floor, please?

Chuck Drake: Drake from Johnson&Johnson. I have a question for Nick. You showed pretty reasonable data that there’s evidence for harm in low-volume metachronous disease for the addition of docetaxel. How do you think that happens? What do you think the mechanism is? Is it on the tumor itself? Does it have to do with the quality of life or treatment? I’m sure this baffles you like it baffles many of us.

Nicholas James: I think, if you’ve got a relatively good prognosis and you give quite a toxic treatment early on—one of the things we were very worried about in STAMPEDE, for example, was that we didn’t know what the neutropenic sepsis death rate was going to be up front. So for those patients, for example, you have definitely worsened their survival compared to ADT alone. And as it turns out, we didn’t have any.

But the quality-of-life data shows that you’ve got a detriment that goes on for a long time. And that must be doing something to your underlying fitness for everything else later, I think. And so, I don’t know, but it’s got to be something like that.

I assume there’s also some underlying biology as to why something is behaving in a really quite indolent fashion compared to the very aggressive, high-volume synchronous ones. And as we showed with the DECIPHER profiling from the abiraterone arm, there is clearly underlying biology driving the differences between the volumes—prognostic, but it doesn’t allow us to predict treatment on the data we’ve shown so far.

Chuck Drake: Thank you.

Bertrand Tombal: Thank you. Dr. Spratt.

Daniel Spratt: So this comment is directed at both Dr. Sartor and Jones’ talks. And actually, Nick James, it would be great to hear your thoughts from STAMPEDE. But I’m a little confused, so just follow me for a moment. In STAMPEDE, you guys showed—I realize it’s post-hoc—that in low volume, docetaxel or abiraterone had similar survival. In STAMPEDE’s arm H, treatment of the primary—18% had radiation to the primary, so that’s in the setting of treatment intensification.

Nicholas James: So 18% had docetaxel. We stratified the randomization.

Daniel Spratt: Agreed. But we’re talking about a lack of survival benefit in PEACE-1. But we have shown in STAMPEDE that in high-risk non-metastatic, adding abiraterone improves survival to radiation ADT. In node-positive, adding abiraterone to mostly radiation ADT improved survival. And then the low-volume M1 in a trial—not criticizing PEACE-1—it’s less than 250 patients, which is not its primary endpoint of overall survival. You’re commenting on a lack of OS benefit, when every single mHSPC trial, other than CHAARTED and GETUG-15, is an over 1,000-patient trial. So how do you actually comment on OS? And when you remove the docetaxel from PEACE-1, it’s 45 patients per arm.

Nicholas James: I think the question is for you, Rob.

Oliver Sartor: I’m not sure of the question. Nice pass. Go, Rob.

Robert Jones: Sorry, my charge was not to defend or decry the role of radiotherapy. I take Oliver’s point that these data may be immature in this regard. But it’s not looking great, is it, for an overall survival signal?

Nicholas James: I was on the IDMC for PEACE-1, and the stats got very complicated because you’ve got all these different treatments layered one on top of the other—docetaxel, abiraterone, radiotherapy in different combos, stratification, different tests for interaction. And you do end up with small numbers in some of the boxes. I think probably the best way to resolve this is to redo the meta-analysis that we previously did just with HORRAD, incorporating the PEACE-1 data, to see what the overall patient-level effect is.

And my other personal opinion is, I think in PEACE-1 we were probably looking at much earlier abiraterone salvage on the ADT/RT arms than we were in STAMPEDE, which was carried out in a different era. And the timing of the recruitment of the trials may be having a factor here, although exactly what, I don’t know. I’d be interested, if Karim’s in the audience, I’d be very interested to hear Karim’s view on this as well.

Bertrand Tombal: Thank you. So we come back to you. But we alternate with a question online. We have a question for Mike from Anwar Padhani, which you guessed would be about whole-body MRI. Why didn’t you allude to whole-body MRI? And by the way, I don’t know if we can say it, but there’s going to be a very nice paper accepted in European Urology by an Italian team looking at the predictive value of measuring whole-body MRI. So what do you think about whole-body MRI?

Michael Morris: Oh, I can reassure Anwar I have nothing against whole-body MRI.

Bertrand Tombal: Anwar will be happy.

Michael Morris: However, I would say—

Bertrand Tombal: He’s happy. He put a smile on.

Michael Morris: Oh, there you go. But I think the same issues would apply for whole-body MRI. We just need to know what the response biomarker is and what the association with survival is in a serially conducted prospective study. And unless we have that in place right now, it’s in much the same place as our other proposed novel biomarkers.

Bertrand Tombal: Thank you. And then another question, before we move to [INAUDIBLE]. I’m the only urologist here, and there is an important question. Because by the time you guys say that one of the benefits of prostate radiotherapy is the prevention of urinary symptoms, why not recommend prostatectomy then?

Because if you have a guy with, what I like to call an affordable prostate—meaning one—you can get only the prostate out. What’s your position? I know it’s hard. None of you are urologists. Or maybe if there is a urologist in the room, you may comment. A little data would go a long way.

Sandy Srinivas: Well, SWOG-1802 is going to address that question.

Bertrand Tombal: But in the meantime, if you advocate for local control, why would it be a problem recommending a radical prostatectomy?

Nicholas James: I think you’d have to say, as per the discussions earlier on today, it’s significantly more morbid than doing radiotherapy. I do think, though, that patients with very disrupted prostates do quite badly with radiotherapy if your issue is bad local symptoms. So I think there is a limited role. But the data is with radiotherapy. And as Sandy said, that’s what we really need—data.

Matthew Smith: I think there can be a role in highly selected patients—young patients who have basically a palliative prostatectomy either for severe obstructive voiding symptoms or prostadynia, where I imagine those are the type of patients that you’re thinking about.

Bertrand Tombal: I’m not thinking, I’m just teasing. It’s different. Anna and then you.

Anna: So does anybody worry that we might be missing some clinically meaningful long-term toxicity from radiation that is not captured in grade 3, 4? Grade 1, 2 recurrent hematuria in an elderly man that has to go through repeated cystoscopies is not minor. And I worry that sometimes we may be missing some of those. And if we are, and there is more toxicity to radiation to the primary than we recognize, then should we be asking the question of how is treatment of the primary working?

If it is because we delay local obstructive symptoms, then could we design a trial where we ask the question—can we monitor those patients that are destined to have local symptoms, and then apply the radiation, or surgery if that proves to be successful as well, at a later time point in that patient’s disease course?

Nicholas James: So we have partly looked at this in STAMPEDE, and we’ve looked at it two ways. So we looked at symptomatic local events, which include things like you described—hematuria, cystoscopy, things like that. There was no difference between the control arm and the radiation arm in STAMPEDE.

We then subsequently looked at upper tract instrumentation for lower tract obstruction. So by this time, you’ve gone all the way through TURP, radiotherapy, or whatever, depending on which arm you were on. And as with PEACE-1, that was halved by upfront radiation. But the point about how many need to have cystoscopies and stuff like that, I don’t know the answer to that, but we can go and look at it.

Anna: How long was your follow-up, and what was the attrition?

Nicholas James: I can’t quote you the median follow-up straight off. But we reported the primary outcome measures seven or eight years ago, and the more recent one, the data lock we did was last year. So the median follow-up is very long.

Anna: Thank you.

Thomas Zilli: Thank you. Just another comment concerning radiotherapy. So I think that in all these trials, we use a lower-than-standard dose that we are delivering. So, for example, in PEACE-1, we had a very strict RT QA assessment, and finally, we had very few deviations from the protocol. So I think this is quite sure radiotherapy that we can deliver for this kind of patient now.

Francesco Sanguedolce: OK. Francesco Sanguedolce from Barcelona. I was very interested to listen to what Thomas was showing before, especially the attractive idea of using the SBRT as a treatment to postpone [INAUDIBLE] therapy. And he actually nicely showed how complex it might be to identify the patients, especially in an era where we are moving to the PSMA PET.

And whether you look at the PSMA PET or integrate the PSMA PET information with the conventional imaging, that means we need to define the ideal patient and why not summarize in a better way the conventional imaging so far to identify that the patient is oligometastatic on PSMA PET, no metastatic on conventional imaging, as a factor, actually, to identify more precisely the patient that may be part of this algorithm?

Thomas Zilli: I fully agree with your statement. So I think this could be certainly a positive predictive factor for a good response to MDT or an MDT strategy alone or combined with androgen suppression. This is for sure, that we can combine both. And the value of PSMA PET in selecting the patient and treating all disease spots that are visible on PSMA has been clearly shown by the REAL trial, in which, when we treat all the spots, we can achieve better disease control compared to using conventional imaging.

Sandy Srinivas: So a practical question from online. For those of you who do triple therapy, what’s the sequence in which you start with the ARSI or docetaxel? Maybe, Matthew, you can tell us how it was in ARASENS and how you do it in clinic.

Matthew Smith: So first I want to point out we should be careful with the terminology because “triplet therapy” was used in a variety of different contexts here. So here, we’re talking about triplet systemic therapy. In ARASENS, it was very clear: ADT, darolutamide, and then docetaxel was added within six weeks of enrollment. So you start with doublet therapy—ADT, ARPI—and Karim is standing at the microphone. Perhaps he can comment on PEACE-1.

Karim Fizazi: Well, the same applies to PEACE-1. We used ADT first and then, at randomization, docetaxel and pathway inhibitor abiraterone in PEACE-1. So I think using these drugs together might actually be important.

We did that in ARASENS and in PEACE-1. The two trials are positive by overall survival. We don’t really know whether using these drugs sequentially would be associated with the same benefit. So I think if you go for systemic triplet, you should use them all together.

Bertrand Tombal: You had your question, now you can ask it.

Karim Fizazi: Thank you, sir. So actually, I saw some comments about PEACE-1, so I just wanted to provide a few insights. Regarding the abiraterone equation, first of all, when looking at the benefit of the trial—as I guess you showed—it’s positive by both rPFS and overall survival, doublet or triplet. And when looking at the benefit by subgroups—low volume versus high volume—for rPFS, we see a very consistent benefit of adding abiraterone to standard of care. And actually, the hazard ratio is quite similar for both low volume and high volume, 0.45 and 0.55, so same range really.

Where the overall survival was positive for high volume, it’s not—or it was not—for low volume, but really the number of events when we did the analysis back in ’21 was quite low for patients with low-volume disease. We will update the analysis this year. By the end of the year, we will do a sweep for overall survival, and we will again do a long-term assessment of the benefit of both abiraterone and radiation therapy. So we will be probably in a better situation to address the question of overall survival for abiraterone in the low-volume subgroup of men.

Now, for radiation therapy, basically, what we showed in the trial was that immediate radiation therapy prevents the onset of relapse—whatever you call relapse. That’s PSA-based. Time to CRPC is significantly improved. rPFS, which was measured—and Oliver, that was clearly positive in the entire population, favoring the radiation. And for the first time, we were able to show that symptomatic progression is prevented with the irradiation, which I think is clinically very important.

Overall survival is not. We may debate as to whether this is the case, as opposed to what was observed in STAMPEDE low volume. But again, HORRAD is also negative for overall survival. At the end of the day, when you put this into maybe a greater context in oncology, often for metastatic disease we use a local treatment to prevent local progression—breast cancer, colorectal cancer. We may argue for kidney cancer, for other cancers. And actually, local treatment in metastatic disease is rarely beneficial for patients in terms of overall survival.

I think prostate cancer is actually quite similar. We can prevent local progression, and clinically it might be very important to the patient. But of course, this is something we should discuss with patients on a one-by-one basis, I think.

Bertrand Tombal: Thank you. Dr. Waltz.

Dr. Waltz: We heard excellent talks on the doublet, the triplet, the MDT, the local treatment. And still, I think it is unclear what the optimal treatment would be for a specific patient. So I would expect that the patient takes an important role here in the decision-making.

How do we make sure that the patient really understands what the ups and downs of each treatment might be, given that we do not have a clear vision on it? What is your comment on it? And maybe David Matheson can also comment on it, what the patient perspective would be with this challenging decision-making we have in this situation.

Bertrand Tombal: Somebody wants to comment? Maybe I can start. There are levels of certainty and levels of uncertainty. What is certain is that in somebody who has real metastatic disease, they should be told that a maximum androgen blockade is the basic treatment. Yes, there is an excess of toxicity, but we may even discuss stopping escalation.

And then when there is uncertainty, everybody has to speak with the patient and try to make his own view on what is against and what’s for. But we should not confuse them on points where we have no confusion. We all agree today, I guess from all the rating, that ADT plus an ARPI is the standard of care for these patients with metastatic disease on standard imaging.

The rest is complicated, especially when you speak about docetaxel. Because something we never discuss here is: do we believe that docetaxel is still the second-line treatment when they progress? Because if yes, the discussion is not about triplet versus doublet; the question is about docetaxel now or later—later when it’s still going to have the same toxicity and less efficacy. So it is a very complicated matter. We’re running now, as a university in Belgium, a discrete choice experiment to try to better understand the pros and cons. And a typical patient does not exist; they all have different expectations, and it’s up to us to find a way to explain this to them. But it’s complicated.

Sandy Srinivas: Well, let’s hear from David, from the patient’s perspective.

Patient 1: David.

Patient 2: Sorry, sir.

David Matheson: Thanks. Sorry to skip the queue there. It’s a very important point, really thinking about the livability of particular treatments and so on. And I think it’s one thing to actually look at survivability, progression-free survival, and so on, but general livability is something that Rob highlighted with his patient, born in 1930, died in 2020 with fatigue, sarcopenia, et cetera dominating at least the last few years of the person’s life.

Now, how livable was that for him? Would it have been different if he’d been treated differently? We don’t know. It’s a question, then, of educating the patient—assuming the patient’s compos mentis sufficiently to actually understand the ups and downs. All of these things come at a cost. Are they costs that they wish to bear, or is it too much?

And this comes down to, I think, never assuming that the patient is—regardless of their level of formal education—unintelligent, but adapting the discourse to actually suit them, to be as understood as possible, so that they can then make not just an informed choice, but a properly existentialist, authentic choice, knowing—or at least being made aware of—the possible outcomes of their decision.

Robert Jones: Can I—

Sandy Srinivas: Well said.

Robert Jones: —make a comment?

David Matheson: Yes, sure.

Robert Jones: One of the things I find myself saying to patients about the ARPI question is that nearly always, the side effects are reversible if you stop them, certainly in the short term. But then, actually, I find it very hard to persuade patients to stop when they’re struggling with side effects from these drugs. Because that’s the key: with radiotherapy and surgery, once it’s done, it’s done, you can’t undo it. But with these ARP therapies, you do have the opportunity to stop. And I think, collectively, me and my patients are not good at making that decision to stop.

Bertrand Tombal: Last question to Dr. Jereczek.

Barbara Alicja Jereczek-Fossa: It will be a short comment, and then I will ask Dr. Zilli. Can you comment, Thomas, on the timing of radiotherapy? Because it’s not very clear in the studies. Sometimes it’s done very early in the disease, sometimes after docetaxel, which means some months after the diagnosis. So if there is an indication for radiotherapy in this kind of patient, when would you suggest doing it?

Thomas Zilli: Thank you for the question. It’s for the de novo setting, right? So I think that, based on PEACE-1, radiotherapy started just after the six cycles of docetaxel. In the other trial, I think it was inherent in the first three months, I think the same in STAMPEDE. Then I think that sometimes you can wait. Just if you have a bulky tumor, you can wait for the role of neoadjuvant therapy to have the debulking, and then you can treat a lower volume of prostate in a safer way.