Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU medical oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today, Dr. Karim Fizazi, who's a professor of medical oncology, and a geo medical oncologist at Gustave Roussy, and the University of Paris. Thank you so much for being here with me today.

Karim Fizazi: Thank you very much for having me.

Alicia Morgans: Wonderful. Well, Dr. Fizazi, you have given multiple presentations, and of course, supported the production of lots of data at GU ASCO 2022. And one of the biggest, I would say, initiatives that you've been involved with, that was presented here, was the ARASENS study. I'd love to hear your take on this trial, particularly, since you're also very heavily involved in PEACE-1. As a European, can you tell us a little bit about the ARASENS trial first, just to set the stage, and then we'll dig in a little bit more?

Karim Fizazi: Yeah, sure. So ARASENS is a large Phase III trial, approximately 1300 men were randomized, all of them had a metastatic castration-sensitive disease. Most were de novo. And approximately, I believe, 13% were relapsed patients, so metachronous, and these men were randomized to received either ADT, so castration, plus docetaxel, as a standard of care, versus the same plus darolutamide, until progression, obviously.

The news are good. The trial is positive by its primary endpoint, which was overall survival. These men, receiving the triplet treatment, can enjoy a 32% reduction in the risk of death. And the second great news is that, this doesn't come with basically, extra toxicity. Darolutamide really doesn't add much to ADT plus docetaxel, and it was really well tolerated.

All the secondary points are positive, time to pain, time to castration resistance, time to scattered related events. So all the morbidity overall, is being reduced by the triplet. And I think as you rightly said, I think this trial really confirms what we saw last year in PEACE-1, asking the same question with abiraterone, different agent, but pretty much the same family of agent, indicating that for these men, three drugs is better than two.

Alicia Morgans: Let's dig into that, because one of the things that has come out of multiple conversations, and one of the things I think that we in academics have been saying for years is that, ADT alone doesn't appear to be sufficient anymore. That really, we should be thinking about maximal androgen blockade. And in this setting, that would be ADT plus one of the antigen receptor signaling inhibitors, those newer agents, that really compound that low testosterone signaling. What is your thought on that?

Karim Fizazi: I fully agree. Regardless of docetaxel, we have now, fantastic data from almost 10 randomized trials now, supporting overall survival improvement when the AR is just targeted strongly, as compared to ADT alone. So I do think these patients should receive a next generation hormonal agent on top of ADT, but still remember, we have also clear demonstration that docetaxel, by its own, improves overall survival on top of ADT. And now we have a demonstration that three drugs is better than just two.

Alicia Morgans: I agree. And I appreciate that you bring it back to the docetaxel, because some have said we really just need to focus on ADT plus that second AR targeted agent. And really, that's not what was tested in PEACE-1, or in ARASENS. ADT and docetaxel were actually, the backbone upon which we layered the androgen receptor targeting agent. And so how do you think about that, when you think about applying the ARASENS data, or even the PEACE-1 data, in your clinical practice, how do you choose the patient, and how do you decide?

Karim Fizazi: Right. I guess, the first big thing to consider is, whether a patient is fit for chemotherapy. And of course, very subjectivity here, but this is our job as medical oncologists, is to assess that as best as we can. And not all these patients are indeed, fit. We do see very elderly patients. We see varied comorbidities, and probably, docetaxel is not the best idea in these men. But for many of my patients actually, they are fit.

And when you describe the benefit of all of these agents, they realize that their cancer is dangerous, and most of my patients actually agree to go for a triplet therapy, and actually are quite happy to see that things are doing well after a couple of weeks or months. But most importantly, in the longer term, for example, orthographic progression for survival was postponed by two and a half years, in PEACE-1. It was not looked at in ARASENS, we don't have the data. But CRPC was, and the different is super big as well. And this is indirectly good life for four patients. PSA's under control. They don't have orthographic progression, they don't have clinical progression, they just live a pretty good life. So that, I think, is very important.

There is debate around whether volume should apply, as a good reason to decide for drug X or drug Y or Z, whatever. I think for now, what's fair to say is that, for the radiation therapy question directed to the primary prostate, yes, counting for metastasis makes a difference, and we have STAMPEDE data to support what I'm saying. It should be standard of care for patients with low volume disease. For high volume disease, you might debate.

Now, for systemic treatments, it's much more debatable. For the AR drugs, what we saw in all the trials that were conducted is that, all men pretty much benefit, regardless of whether they have two metastases, or 20, or whatever. For the docetaxel, it was debated charted data supported efficacy for high volume, not necessarily for low volume, but actually, STAMPEDE supported similar efficacy for both, and STAMPEDE have more patients, so greater power.

And on top of that, you might also consider, for the docetaxel question at least, wherever the patient is relapsing, which is rarer, or whether it's de novo man, and for de novo, actually, patients tend to benefit from docetaxel. So my practice, right now is, when I'm seeing with patients with high volume disease, fit, I'm proposing the triplet treatment. When this gentleman is a de novo low volume, I'm proposing clearly, the radiation to the primary ADT and an AR drug. And regarding with docetaxel, I'm more on the fence, and it's more, there are always some inbetweeners in life. So patients with two big bone metastasis, and lymph node metastasis, maybe I will go for docetaxel still, because I think it's more a high volume man, if he has a big pelvic burning metastasis. Now, if it's, just one rib or two, you don't even know for sure if it's cancerous or not, maybe I would not use docetaxel for now.

The good thing is that, we should have more data from ARASENS, regarding this question. I know the volume was not analyzed up front, but actually, the scan, the data from the scans, have been collected, so this is doable in retrospect, and I know its plan, and hopefully, we'll have the data soon.

Regarding PEACE-1, we looked at the volume, and the triplet clearly improved RPFS, in both low volume and high volume. And regarding overall survival, overall survival was clearly improved for high volume men, for low volume. Most of them were alive when we made visualizes, so of course, we couldn't say for overall survival.

And by the way, I'm happy to say, publicly today, that the paper is in press in the Lancet, so we will, because I know many people were asking me the question, we will be able to read it soon. So this is pretty much how I see the current data.

Alicia Morgans: Well, I think, that's wonderful. And thank you so much for breaking it down by volume, by de novo versus recurrent status. And really, also remembering that radiation can be helpful, radiation to the prostate in patients with low volume disease, which of course, we've known for some time, but we can tend to forget that when we're so focused on our systemic therapies.

Karim Fizazi: Sure.

Alicia Morgans: So thank you. I love how you put that into context, and we'd love to give you the opportunity to make a final comment to the audience before we finish.

Karim Fizazi: Wow. Thank you. Well, I guess, you know what? I think we should just change the way we do trials, and we think about the disease. We've been speaking, you and me, about just volume and M1 castration-sensitive disease. And we all know it's much more heterogeneous than just vas. So I really hope the next generation of trial will be oriented towards for biology. And of course, we still need to address whether patients should you say, radiation, stereotactic radiation directed to the metastasis, so based on clinical stuff. But I think now, we need to assess DDR status, maybe p53, maybe PTEN, maybe make some more fine tuning in VAR biology, and start the next generation of trial space. I think this is key for the near future.

Alicia Morgans: I could not agree more. Let's define some hopefully, predictive biomarkers, and actually choose our patients by the molecular status perhaps, rather than just some images that we were able to obtain, which of course, are evolving on their own as well, with novel imaging strategies, or newer emerging strategies.

So thank you so much for your time-

Karim Fizazi: My pleasure.

Alicia Morgans: ... and your expertise, always appreciate your insights.

Karim Fizazi: Thank you very much.