Alicia Morgans: Hi, I'm so excited to be here with professor Karim Fizazi from Gustave Roussy in Paris, France, where he's going to talk with us today about the ENZAMET updates from ASCO 2022, and the way that he considers that data in the context of previously reported PEACE-1 data and the ARASENS trial. So, thank you so much for being here with me today, Professor Fizazi.

Karim Fizazi: My pleasure. Thank you for having me.

Alicia Morgans: Wonderful. Well, Karim, I'm wondering if you can review what was updated at ASCO 2022 in terms of the ENZAMET trial. This was an oral presentation.

Karim Fizazi: Correct, yes.

We saw the first data from ENZAMET back in 2019. That's a large Phase III randomized trial testing enzalutamide in men with metastatic castration-sensitive disease. And as we, I guess, all know from the original presentation back in 2019 and the New England Journal paper, this is a positive Phase III trial establishing probably for the first time that enzalutamide postponed death in the setting, similar to what abiraterone had shown two years before.

The beauty and the complexity from ENZAMET is that it's a mixed bag, with very different population being randomized, including both synchronous and metachronous metastatic disease, so relapse after local treatments versus de novo, but also some patients with oligometastatic disease or low volume disease versus men with multiple metastases, what we call high volume disease. Also, patients could be treated with ADT alone or with ADT plus docetaxel cell in the control arm, actually in both arms, as the standard treatment. And those men were randomized to received enzalutamide yes or no on top of that.

So, what we knew, and this is confirmed with longer follow-up, is that generally speaking, enzalutamide improves outcomes. And what they did at this ASCO meeting is that not only they updated analyses with twice as many death events, so stronger power to demonstrate things, but also they were able to dig into details amongst those various and diverse population of men. Of course, you might argue that this is perhaps too much digging or too much subanalysis to be very cautious, especially when it comes to small numbers.

But still, I think the big thing that we're able to provide was that for men with synchronous disease who received ADT plus docetaxel as a standard of care, adding enzalutamide improves outcome, including overall survival, which is significantly improved, at least for these men. And this is supporting indirectly what we showed before in PEACE-1 and ARASENS. So, in other words, we now have three trials basically showing the same thing. Three drugs are better than two, at least in some men.

Alicia Morgans: Yes. And I thank you for pointing out that subanalysis because I think this is where it gets a little bit tricky. And Professor Davis was very cautious to say that this is exploratory and very helpful, but often called de novo metastatic, or synchronous metastatic patients with the high volume disease burden, did seem to benefit from that addition of enzalutamide.

Interestingly, I think in this update, they previously had presented an all-comers survival curve that presented all of those patients who received docetaxel and really demonstrated that there didn't seem to be a difference in overall survival in that population for the addition of enzalutamide. And they didn't present that curve again. They did present some subgroup analyses that didn't necessarily suggest that there was a huge difference if you look at that all-comers population to the addition of enzalutamide.

But again, when they showed this exploratory subgroup analysis of the de novo high volume metastatic patients, that did seem to demonstrate the benefit. What are your thoughts on that? It still actually, to me seems consistent with the PEACE-1 data and ARASENS data, which were actually selected to only really focus on that population and perhaps is underpowered here.

But what do you think?

Karim Fizazi: Right. Well, first, what they showed initially back in 2019 was that for these men, all-comers treated with ADT plus docetaxel, there is a strong benefit in radiographic or actually clinical progression for survival. And at this time, really overall survival was immature.

I think they should probably not have shown it in retrospect, because it's always a bit misleading when you're showing things very premature, because, not only you can have curves diverging just by chance, and it's actually an artifact, but also the opposite, curves merging. Although, at the end of the day, there is a difference, a true difference. So, that's always the issue I have with early analyses.

But this time, you're right. They didn't really show the [inaudible 00:05:30] curve for best these men. What they showed was the subgroups analysis in a table or in a figure. And I think there was an 18% reduction in the risk of death, not significant, but the trend was there. And then we had to dig into more details.

But generally speaking, as I said before, the limitation from ARASENS is that versus really mixed bag and where ADT plus docetaxel population remain a subgroup. And it's not a super big subgroup, to be honest. When you compare this to PEACE-1 and ARASENS, it's much smaller. So, of course, they don't really have sufficient power perhaps to show true things.

But I'm looking at this data as something supportive, if you will, confirming, at least as a trend. In PEACE-1, there was a significant difference when abiraterone was added on top of ADT plus docetaxel. And there were actually many more men receiving ADT plus docetaxel cell as their standard of care in the trial. And this is even more true with ARASENS, where all patients in the trial received ADT plus docetaxel. And the data, I think, are crystal clear with a brutal, if you will, overall survival benefit with three drugs versus two.

So, basically, ENZAMET, I think, pretty much confirmed this data. It's not antagonist to this data. It's just that they don't necessarily have the power to nicely and clearly demonstrate it. But I think, to say simple things, I think all the three trials point to the same direction, separately.

Alicia Morgans: I would definitely agree with that. One thing that's interesting that's come up, but not necessarily answered actually in any of these trials, is what the addition of docetaxel is to this benefit. And we should be very clear that in ENZAMET, though not all patients received the docetaxel treatment, it wasn't randomized. So, really difficult to answer that question, I think, with any of these trials. But what is your thought?

Karim Fizazi: I agree. And I think we should not over-analyze all the trials when they cannot address the question. If we really want to address this question, we need to do a randomized trial. If some people want to do it, they can do it. That's the only way to appropriately address the question in a clean way.

So, what I think ... And it's opinions here, it's not about facts. But what I think is that we were able collectively to demonstrate that adding the docetaxel to ADT alone improves overall survival by approximately 20% reduction in risk of death if you take into account CHAARTED, STAMPEDE, and GETUG-15. Okay?

Now, we also very clearly showed, I think, that any of the next-generation hormonal agents can also do that. And that's true for abiraterone, apalutamide, darolutamide, enzalutamide and added on top of ADT alone, it's approximately 45% reduction in the risk of death. So, maybe greater effect, even if it's hard, of course, to do cross-trial comparisons.

Now, just thinking about biology and what we know about these drugs, basically in [inaudible 00:09:07], we all know that some cancers are sensitive to next-generation hormonal agents. Some others are sensitive to docetaxel. Some others are sensitive to both families of agents. And some others are just resistant unfortunately to everything. So, we have at least four scenarios.

And because some cancers are sensitive to just one drug, but not the other one, you may simply hypothesize that using these two drugs together, even not thinking about any synergy between the two, will just treat better some of these men. And this is very likely what's happening with the true plan. And I think that we don't have a biomarker, as we're speaking. We don't know who should we give docetaxel cell to? Who should we give abiraterone or enzalutamide?

But we know that using these two families of agents, taxane and next-generation hormonal agent together, does a better job.

On top of that, and this is at least predicted by some preclinical data, using the two together might actually be even more efficient in some sensitive cancers. So, I think this is really my opinion and my scientific explanation of why we do see a better outcome for three drugs versus two. And I think, with my main opinion, that if we were to randomize ADT plus an NHT versus a three plan, including a taxane, the triplet would win. But again, nobody has this data as I'm speaking.

Alicia Morgans: I would agree with you, of course, as it seems, I usually do, Professor Fizazi, because I think that, until we can really pick out those patients who will not benefit from docetaxel or pick out those who will with biomarkers, and we may be able to do that in the relatively near future, it is really difficult to know. And for fit patients with high volume synchronous or de novo metastatic disease, for those fit patients, I'm offering the triplet. And patients are tolerating it quite well. And at least, I think, better with six cycles than 10 and perhaps better earlier when they're younger and presumably a little more fit than when they're older and things may have changed in their fitness. So, I completely agree.

As you sum up all of this data, what would your recommendation be? And how do you view these trials in your clinical practice?

Karim Fizazi: Sure. And again, I agree with you. I think the acceptance from patients, if you are explaining to them very honestly with what we know, what we don't know, most of my patients actually agree to receive a triplet and also understanding that, especially for de novo metastatic disease, it's not a good disease to have. I mean, these men still die from their disease and more early than late. Even if we probably won a couple of years to them in the last decade, still they died. So, targeting stronger cancer probably makes sense in many of these men.

So, to address your question, for patients with de novo, at least high volume MET, I'm very confident that we should recommend strongly the triplet treatment. Of course, as far as the patient is fit to receive chemotherapy and of course, as far as if he is willing to receive it. I think we should be very honest about it.

For patients with low volume and de novo, I'm on the fence, because we clearly have a demonstration in PEACE-1 that radiographic progression for survival is dramatically improved with a triplet for these men. But OS is a major, so stay tuned. And maybe in one or two years from now, we will have an updated analysis with more events and we will be able to know whether OS is also improved or not.

So, I would have this discussion with my patient and we will make the decision on a one-by-one basis if a patient is fit, of course.

Now, for patients with metachronous disease, it's really harder to make a recommendation. These patients are rare in all randomized trials we've been conducting in the last decade. And it's always subgroup and subgroup analysis. They generally do better, especially those with oligometastatic disease. So, those with oligometastatic disease, I would probably be more conservative perhaps with using an HT, no chemotherapy. And we are randomizing the role of stereotactic radiation therapy directed to the metastasis, so to speak. So, that would be my recommendation.

And for the very rare set of men with relapse and high volume, I just don't know what to recommend because they're so rare. Probably, I would be more keen to recommend the triplet if the patient is fit. In a subgroup analysis of HORIZONS, this was suggested to be active for these men. But truly we don't know for sure.

I hope I was clear enough.

Alicia Morgans: You were absolutely clear. And really in those areas that are more gray, I think certainly we try to use shared decision-making and being honest with our gaps in knowledge. And letting patients really contribute to that conversation can help the patient choose the right treatment. And for some patients, perhaps a radiographic progression-free survival advantage is something that is very meaningful to that individual. And perhaps to others, it really is a decision where they would choose to avoid the triplet to really focus on current quality of life rather than time with chemotherapy. And these are conversations that allow us to still practice the art of medicine, I think, rather than simply be computers in our clinic.

So, thank you so much for providing that guidance. I think it's extremely helpful. And we always appreciate your time and your expertise.

Dr. Fizazi: My pleasure, really. Thank you.