Alicia Morgans: Hi, I am so excited to be here today with Professor Karim Fizazi, who is joining me from Gustave Roussy in France after a wonderful presentation at EAU 2024, also in France, in Paris this year, where we heard him talk about treating metastatic hormone-sensitive prostate cancer and the idea that it is beyond just counting metastases. So, Karim, thank you so much for being here today. And please let me know, where did this come from? Why have we been counting metastases to treat metastatic hormone-sensitive prostate cancer?

Karim Fizazi: Right. Good morning, Alicia, and thank you for the invitation. First of all, and I guess most importantly, I'd like to recall that the last decade was really fantastic in terms of the delivery of phase three trials in metastatic castration-sensitive disease, with probably now dozens of trials, all positive, and all mostly showing overall survival benefits for all patients. So, that's very important. But you're right. Actually, since CHAARTED, which was one of the very important trials demonstrating first the role of docetaxel chemotherapy for overall survival, since that trial, people have started thinking and splitting their patients with metastatic disease into two main groups, low volume versus high volume, based on the number of bone metastases. And it's true that metastatic prostate cancer is mostly a bone disease. Of course, I think we all agree about the prognostic value of counting metastases. It's obviously worse to have 100 bone metastases compared to just one or two, but probably we put too much emphasis on that number of metastases, low volume versus high volume, for treatment decision-making.

And indeed, until last year, let's say, when I was speaking with most colleagues, they were telling me, "Well, if I see a patient with low-volume disease, I will typically go for ADT and an AR pathway inhibitor, probably no docetaxel, and probably I will also integrate, at least if it's a de novo man, radiation therapy directed to the primary with the hope that this will improve overall survival."

On the other hand, in men with high-volume disease, the same person would typically tell me, "I would probably be convinced by PEACE-1 and ARASENS, so we'd probably go for triplet systemic therapy and then... So, ADT, docetaxel, and an AR pathway inhibitor, and I will not use radiation therapy directed to the primary." But I think the evidence probably does not support anymore the separation into two groups and the quite different therapeutic strategies. I think we have new data, and we should integrate those data into our practice.

Alicia Morgans: I completely agree, and I have to say I think we've been very used to doing this high volume, low volume, and really kind of parsing it out this way. But to your point, new data has come in in the last year or so that has really upset the apple cart in a way and has caused us to rethink a lot of what we do. And can you share some of that?

Karim Fizazi: Well, yeah, sure. So, I think there are mainly two main pieces of information. One comes from the meta-analysis of randomized phase three trials testing docetaxel, reported by Claire Vale in Lancet Oncology and also presented at ASCO. So, what they did was look at a subgroup of men according to the timing of the metastasis and also the volume of risk. And what they showed was that actually paying attention to the timing of metastasis is probably more important. So, when I'm speaking about the timing of metastasis, I'm referring to a patient who had local treatment, and then some years after that, a relapse with metastatic disease. So, say after a prostatectomy or radiation therapy, for example. Typically, these men, by the way, relapse with low-volume disease, very rarely high volume. And on the other hand, you have patients with de novo or synchronous disease who are diagnosed today with both their prostate cancer and their metastases.

And actually, the prognosis of these two scenarios is very different. The first group of patients, those relapsing, will live at least eight years after the diagnosis of their metastasis. You've heard me, and I want to emphasize that at least eight years, and it's probably much more than that now with current treatments. On the other hand, the de novo patients typically don't do well, even those with low-volume disease, by the way. So, what Claire and her group showed in the meta-analysis was that docetaxel chemotherapy doesn't have any benefit in patients with relapse and low-volume disease, thus explaining the negative findings in CHAARTED for these patients, because CHAARTED actually included patients with relapses. On the other hand, the same meta-analysis also shows that all patients with de novo disease, regardless of the number of metastases, actually derive a benefit from docetaxel chemotherapy. So, this is true for both low volume and high volume. So, I think this clarifies the situation.

And actually, if you look at triplet treatment, because we know now that if you're using docetaxel, you should use an AR pathway inhibitor. And this was analyzed also in PEACE-1 and ARASENS. In PEACE-1, we showed that both subgroups of men, low volume and high volume, understanding that they are all de novo, benefit from triplet therapy in terms of radiographic progression-free survival. And for us, the jury was out three years ago when we analyzed the trial, we're actually updating the data this year. Hopefully, we'll have data by the end of the year or early next year. So, this is for PEACE-1 and for ARASENS, which probably had a greater power for OS regarding this question. There is actually a benefit in both high risk and low risk regarding the use of three drugs instead of two.

So, just about drugs, I think counting the metastases is really not sufficient. It's much more important to look at whether the patient is a de novo man and then actually triplet therapy should be considered. I'm not saying that all patients should get it, of course, but it should be considered, especially if young, fit, and with bone disease as opposed to patients with a relapse, who should not get it. And the second, and I think very important piece of data, but I'm biased of course, that we saw last year is about PEACE-1 and radiation therapy. We tested radiation therapy with these men with de novo disease receiving intensified systemic treatment: ADT-docetaxel, ADT-docetaxel-abiraterone, or ADT-abiraterone. And what we found was that number one, there's no overall survival benefit related to radiation therapy directed to the primary. So, we now have three randomized trials: HORRAD, STAMPEDE, and PEACE-1.

And two of them... Actually, three of them are negative by overall survival and two of them are also negative even for patients who have low-volume disease, and STAMPEDE is the outlier, but this is the least. But actually, perhaps even more importantly, what we could show in PEACE-1 is that using early radiation therapy in men with metastatic disease prevents the onset of local nasty symptoms such as bleeding, pain, obstruction, which of course makes all the patients' lives miserable, and the effect is actually quite strong. On top of that, it appears that we see a synergy between abiraterone and radiation therapy, which is obviously good news. So, the incidence of those symptoms is almost zero in patients receiving ADT, abiraterone, plus or minus docetaxel, and radiation therapy. And by the way, this positive effect, favorable effect was found across the board, again, both patients with low-volume disease and also patients with high-volume disease benefit, which means that all of a sudden, yes, we don't have OS with radiation.

But yes, also, we should perhaps consider using radiation in both low volume and high volume. And to be honest, this is what I'm doing now mostly in my practice, or at least I'm discussing it with my patients. So, I think those are very important things. So, I think that the current standard of care has changed in just one year. Docetaxel may now be considered in low volume and de novo disease together with an AR pathway inhibitor and radiation therapy indications should be extended not only to low volume but also to high-volume de novo disease. So, we are really changing how we're treating these men.

Alicia Morgans: Yeah, I think these are such important updates. And I also think that we saw this coming to some extent. We've been talking about this de novo versus recurrent phenotype for some time and really, especially when we saw in STAMPEDE that there might be a benefit across volume. We talked about how there were many patients within STAMPEDE who had de novo metastatic disease and far fewer with recurrent disease as compared to CHAARTED, for example. So, I think this is making some sense and is coming from, of course, this data informed the meta-analysis, but it is coming from what we've learned and it helps us to evolve. I think it is really interesting to think about the radiation data though as well as another way for us to try to support our patients, as you said, maybe not in terms of improving overall survival but in terms of reducing those complications. And I wonder, is there a specific population who may be most benefiting from radiation to the primary? Enlarged prostate? What are you thinking about when you're really pushing a patient to think more fully about that and if they're reluctant?

Karim Fizazi: So, we are actually looking at this data as we are about to submit the paper. And to be honest, the baseline characteristics do not seem to predict. So, we saw a benefit across the board. This is, for example, true for T3, T4 disease as we might expect, but also in men with T1, T2 disease. One thing we still need to test is actually basically the patient voice taken from the quality of life questionnaire at baseline. We will try to extract some sentences from the FACT-P questionnaire, for example, related to local symptoms and try to see whether this actually may or may not predict. So, let's see. But right now, based on the data we have, it appears that, actually, all patients, statistically, of course, can benefit from radiation therapy directed to the prostate.

Alicia Morgans: Very important lesson there then. That's very important to know. And we're talking about using these clinical characteristics and perhaps the patient voice, which is so important. But I think the future will hopefully involve biomarkers and perhaps new ways for us to select patients and even perhaps to alter and adjust the metabolic pathways, which may also be affecting some of these outcomes. I wonder if you can tell us what the future looks like from your perspective, Professor?

Karim Fizazi: Yes. It's hard to look into the crystal ball, but let's do our best. Well, let's speak about facts, not crystal balls. So, we have candidate biomarkers, obviously, BRCA1, BRCA2 are obvious, and I'm happy to say that phase three trials, testing PARP inhibitors in metastatic castration-sensitive disease such as the TALAPRO-3 trials, and others have completed their accrual. So, we're following these men. Hopefully, in the coming years, we will know how early we should use a PARP inhibitor in these patients, mostly with BRCA alterations. The same applies to patients, for example, with PTEN loss. We're talking about 20 to 25% of this population, typically with nasty cancers, very aggressive. Whether Akt inhibition can help, we don't really know. There was the first phase three trial in CRPC with some caveats, obviously. So, we are testing this hypothesis in mCRPC as well. Targeting PSA using PSMA PET as a biomarker to look at expression was also done in the PSMAddition phase three trial, which also has completed its accrual.

So, all this is going to come probably in one, two, three, four years from now, depending, of course, on events. But you're right, there might be some other simple things to do in these patients, typically elderly, typically receiving ADT and actually in intensified hormonal therapy for a long duration. And very simple questions are currently being addressed such as, should we use metformin? Yes or no? This was addressed in one arm of STAMPEDE, enormous recruitment, very impressive, and I think and I hope we will see the data this year. And Silke Gillessen is heading this part of STAMPEDE and I think this is maturing. Also, we tested the use and potentially the benefit of statins or aspirin in the PEACE-4 trial which is currently recruiting patients. So, we will need to be more patient and hopefully accelerate the accrual. But I think all this will become more and more important, all these treatments can help all the patients from a metabolic standpoint, obviously, but also potentially from an oncologic standpoint. They also have a rationale as anti-cancer drugs. So, I think this will be very important to pay attention to.

Alicia Morgans: Absolutely. And we know that the main competing risk for mortality in this population is cardiovascular disease. So, even if nothing else, if there's an impression made in that setting or something that can change the needle there, I do think that we'll be doing better for patients. So, very exciting studies to come out and so much work to continue to learn from. I so appreciate your time and your expertise today. Any final words you'd like to leave the listener with?

Karim Fizazi: Well, no, I think stay tuned, all. Metastatic castration-sensitive disease, and that's true also for many other situations of prostate cancer, but specifically this one is evolving rapidly and we should adapt what we thought was right five years ago is not necessarily right anymore. And this is true also for what was right maybe one or two years ago. So, it's really important and educational, such as what you're doing often, and congrats for that, is very important to help all the colleagues and all of us, obviously, to progress as a community for the benefit of all the patients. I think this is truly important.

Alicia Morgans: Well, thank you so much for that and thank you for your many contributions to UroToday. We so appreciate your time and your expertise.

Karim Fizazi: Thank you very much, Alicia.