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Alicia Morgans: Hi, I'm so excited to be here with Professor Ursula Vogl, who is a medical oncologist at the Institute of Oncology of Southern Switzerland. Thank you so much for being here with me today, Professor Vogl.

Ursula Vogl: Thanks for the invitation.

Alicia Morgans: Wonderful. You gave a fantastic debate at EAU 2023 and really tried to help us, as clinicians, think through how do we decide between triplet therapy and doublet therapy in the metastatic hormone sensitive prostate cancer population treatment paradigm? And I think we all know there are no absolutes or black and white, and so it's important to acknowledge that in a debate, we do have to take a firm stand, but it's really interesting, and I love the way you think through this entire process. So can you just share the points that you made, share that talk with us? And then we'll talk a little bit about it when we're through.

Ursula Vogl: Okay. So I think I will just quickly repeat what I shared at the EAU meeting. And as Alicia mentioned, it was a randomly assigned pro side of the debate for triplet therapy. And then we will actually see if it's really all pro and all pro triplet therapy. So I think that you all know, you are professionals in treating hormone hormone-sensitive prostate cancer, but this first slide should show you how actually the treatment paradigm evolved over time. And when we met maybe at EAU some years ago, there haven't been any of those drugs available. And now we ended up in '21 and '22 with the results of PEACE-1 and ARASENS that were confronted not only to use AR targeted agents in the hormone sensitive metastatic setting so very early but also including a triplet docetaxel and one of an AR targeted agent.

This is actually the results of the trials that were ongoing, including triplet therapy. And as you know also, ENZAMET, one of the main gold standards for using enzalutamide in mHSPC, included 500 patients with concurrent docetaxel. But I think the most clear, the most triplet oriented trials are actually PEACE-1 one and ARASENS. And there we have the reports of the results from actually the benefit of adding abiraterone prednisone, as in PEACE-1, or darolutamide, as in ARASENS, to docetaxel. So remember, and also when I continue with my debate, these are trials that are actually showing the benefit of adding an AR targeted agent to docetaxel versus ADT plus docetaxel.

So what we know actually from high-level evidence so far about triplet therapy, actually we know not only from triplet but at least from doublets, and this should be the gold standard and only very, very few patients should receive ADT monotherapy, that the doublet, either with docetaxel or an AR targeted agent to ADT is better than ADT alone. And what we know from the triplet trials actually is that the triplet is better than ADT plus docetaxel. So as the EAU was in Milan and it was very nice weather, I got inspired early to do a comparison with different types of ice cream.

So actually is the triplet therapy, so maybe strawberry chocolate and vanilla, better than strawberry and chocolate? Well, and I had to cite Socrates, so, "True knowledge exists in knowing that you know nothing." And in that sense also if I was a pro speaker, I had to admit that, actually, we don't know. So there has not been any randomized clinical trial done yet answering that question, if the triplet is better than a doublet. But I think one could rationalize and then bring also arguments why in some patients the triplet could be better and patients can benefit from that little bit more aggressive approach.

So there is a rationale, this is a very nice paper of Bertrand Tombal published some years ago actually showing that there are cells that might not be sensitive to AR targeted agents and then escape that mechanism. And so we need maybe chemotherapy to eliminate those clones actually that are AR negative. And also, we know, for example, from the STAMPEDE trial, from the multi-stage platform protocol, at least when they compared in a timely parallel randomization ADT plus docetaxel, then it's about the same as ADT plus abiraterone. So one could then rationalize that actually adding docetaxel gives more than a doublet therapy. But I repeat myself, the evidence is missing. And of course, even if it's a pro debate or was a pro debate, for sure, not in all patients there might be added value. And we know that in clinical daily clinical practice when we do our outpatient clinics, we see a lot of patients that would not concern docetaxel fit or would see them with a triplet therapy in the future.

So we have to do a simple oncological evaluation, we're all oncologists, and that we're using docetaxel for years, not only in prostate cancer. So it's easy. We have to see our patient, and do we assume our patient fit for six cycles of docetaxel with the full dose three weekly with maybe a G-CSF support as they used in PEACE-1? And does actually the clinical presentation, and this is something beyond evidence, of course, give us the rationale that a patient would benefit? One would assume that the de novo metastatic are more aggressive. And actually, we have data that metachronous disease has the better prognosis from the ADT monotherapy area also.

And maybe are there any other features of aggressiveness that might eradicate those clones when we add docetaxel to ADT and an AR targeted agent? So we might have patients with neuroendocrine differentiation, we might have patients that have a Gleason 10 and might have also bulky disease in the retroperitoneum, which formally would be also a low volume, but those patients might also benefit from a triplet. So I think this is just clinical and oncological experience and rationalization who will actually benefit from the treatment.

And I just wanted to cite in the end also what do the experts think? And since I have the pleasure to work with Professor Gillessen, I had to cite, of course, APCCC TE, last meeting '22. So save the date for '24 in Lugano. So what did they say actually in '22? And also in '22 when only the PEACE-1 data were fully published, or the first presentation, and ARASENS was a little bit pending with the volume. So they also already said that in high volume disease, more synchronous than metachronous, but also in both, the experts would give the triplet therapy. And they were half-half, actually, for abiraterone or darolutamide.

And also the NCCN Guidelines included actually the guidelines' recommendation for the triplet. And after the EAU meeting, also the EAU Guidelines included the recommendation for triplet therapy in selected patients. So do we already have the answer? No, but a lot of people are working on planning a randomized control trial that is actually answering the question if the triplet is better than the doublet, and these are in development. So then at my last slide at the EAU meeting, I challenged Professor De Santis, she was the contra speaker and is also a dear friend, to give the contra part of the talk.

Alicia Morgans: Well, thank you so much, Professor Vogl. That was wonderful. And I think it's always so important, as you said, that we acknowledge what we don't know as we're trying to ensure that we really share the knowledge we have and think about the next questions that we should ask. And so I am, like you, looking forward to the next studies.

When you think about this in the context of the PEACE-1 data for radiation that was presented at PEACE or at ASCO, I should say, just this year, what are your thoughts? And to remind everyone, of course, that radiation to the prostate, the data that was just presented suggested that it might be most helpful for radiographic progression-free survival among patients who are being treated with abiraterone plus standard of care. It was very interesting.

Ursula Vogl: Yeah. I think, well, it was a very nice discussion. Alberto Bossi, who was the first author of that part, as a radiotherapy specialist, brought some ideas also up why actually overall survival was not positive. Well, we know from the STAMPEDE trial that we have a benefit in the low volume population. And at ASCO they presented the outcome parameters for the primary endpoints, PFS and OS, only in the low volume population of the triplet, actually. And there was no benefit of OS. But what was shown, actually, and I think this is important in daily clinical practice, that the GU events, so the complications mostly locally from the primary tumor and this event-free survival to have that GU related event were less when we used radiotherapy added to the triplet therapy. And this was not only the case in the low burden population but also in the high volume here. They presented also the high volume patients.

So I think that the conclusion of ASCO was that we should still use radiotherapy for the low volume patients, that maybe the more intensive treatment they used in PEACE-1 as the triplet and also the requested use of docetaxel from the amendment phase on gave patients... Well, did not lead to an overall survival benefit. This could have influenced or following treatment lines that were better or more efficacious as when STAMPEDE was actually done as a trial. So I think the message should be, don't forget to irradiate the prostate in low burden patients and think of some selected patients maybe also in high volume. But we have to inform patients that there is no overall survival benefit.

Alicia Morgans: Yeah, I think that's so interesting, and I do look forward to seeing more detail on the radiation in terms of those GU complications. As I understand, these are things like need for catheter or stent placement and these kinds of things. And these can be so difficult for patients, burdensome and certainly both morbid and then time to get this procedure that the patient has to deal with and the suffering that goes into all of that. So very, very important. And I agree with you, it's interesting that we may now have a quadruplet or even more approach. We radiate, we use this combination systemic therapy, and how do we really make these best decisions with our patients? It continues to evolve.

So when you think about this in clinical practice, and obviously you were arguing for a triplet approach among patients who were fit for chemotherapy, what are the things that make you say, "Well, this patient's fit," or, "Not fit"? And I know that's a very challenging question for an oncologist to answer because I think in our minds, we can make almost anyone fit for chemotherapy with docetaxel. It's relatively well tolerated, especially with the GCSF support. But are there things that you think about as you're considering with a patient?

Ursula Vogl: Well, as you mentioned, it's just as we did before. Before triplet was a topic, we used charted, and then we were motivated to use six cycles of docetaxel a long time ago. So I think it's the same procedure, actually. You just look at the biology. But if you say that the patient is actually fit for docetaxel and also has the compliance, the patient has to be well-informed also that adding docetaxel to an AR targeted agent, an ADT, has not yet proven an overall survival benefit in the comparison, but that patients are motivated and compliant to proceed with six cycles and also with the full dose. Because I sometimes saw colleagues giving a biweekly or a reduced dose. I think if a patient is docetaxel fit, it has to befit the patient for the 75 milligrams per square meter, dose three weekly. So it doesn't make sense to do any adaptations when we have stomach ache, yes or no. You have to be 100% convinced that the patient is fit for docetaxel and has the compliance, of course.

Alicia Morgans: Yeah, I think that's a great point. We're in a non-curative setting. We are really trying to intensify therapy. If the patient's not fit for the intensified therapy, don't do it. And if you can't do it all the way, then it really doesn't make a lot of sense. So that's a great point and not one that I've really heard discussed so frequently. So thank you so much for adding that, that especially important pearl, into the conversation and into the mix. So if you had to sum up and give a recommendation, again, a fantastic debate and a debate against a mentor, colleague and friend, so never the easiest thing either, what would your recommendation be to the listeners who are trying to think this through in their own clinical practices?

Ursula Vogl: Well, I think the first step is always that the patients are presented at the tumor board and the oncologist sometimes doesn't know the patient yet. So the urologist or somebody else is presenting the patient. So we only have the biological background. So we have this histology, we see the images, and then we think, "Well, ooh, this is a patient, de novo high volume," for example, "full of bone metastasis, Gleason 9. So this would be a candidate for the triplet." Maybe 75 years old.

And then you see them in clinics. And of course, then you have to rationalize and say, "Okay. Although we have that aggressive features, that histology, the patient might have a lot of comorbidities, might not have the compliance to do chemotherapy, might have a diabetes with a poor neuropathy," everything that actually hinders us from giving docetaxel. Then we have to say, "Okay, we don't want to harm the patient." As you mentioned, it's a palliative setting, although we have patients that survive very long. Also, the high volume, it's de novo hormone sensitive. We have a lot of treatments, also an mCRPC available. But then, of course, we have to take a step back. And I have to admit that in the beginning when the infusion came up with triplet, I also gave a patient the triplet that actually I had to quit after two cycles because he had, let's say, an asthma that actually I didn't assume to be a problem with docetaxel. But then in the end he had recurring infections during docetaxel. So I stopped after two cycles.

So I think the message should be don't be overwhelmed with the histology and the features that might be aggressive and say like, "This is a typical PEACE-1 or ARASENS patient." See them in clinics and then rationalize if it's really fit. But also don't stop yourself to evaluate patients for the triplet and say, "Well, we know that ADT and AR targeted agent works and there's no need to add docetaxel." So I think you should sit down, look at the patient, comorbidities and the histology, and then decide. And if you have difficulties deciding, involve your colleagues. I mean, this is a multidisciplinary discussion. There are always more than one oncologist in your team, so do a shared treatment decision-making, I think.

Alicia Morgans: I think those are all great messages, and I would say that I don't think that you did anything wrong by evaluating your patient during treatment and making adaptations and discontinuing the docetaxel if that's not the right way for that individual patient. We don't always know from the moment we start treatment how things are going to go. And not giving the chance to the patient or the opportunity to the patient to benefit I think would probably have been the wrong decision in that situation. And you were able to make that decision through that adaptive method and keep the patient well and do the best that you could.

So I think that our message is very clear, that each of our patients is an individual. We will have to make these very complex decisions with those patients, and we may have to change those decisions over time. But ultimately we can get to a better place, I think, and improve outcomes for patients if we really do apply the knowledge that we have and continue to investigate the questions that emerge. And we'll just take it one step at a time. So thank you so much for your time and your expertise, Professor Vogl, and congratulations on an excellent debate.

Ursula Vogl: Thank you very much, and for the pleasure having you, as an expert also for especially the fragile patients in prostate cancer, as an interview partner.

Alicia Morgans: Oh, thank you.