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Alicia Morgans: Hi, I'm thrilled to have here with me today Dr. Karim Fizazi, a Medical Oncologist at Gustave Roussy in Paris, France. Thank you so much for coming to speak with me today.

Karim Fizazi: Thank you. How are you?

Alicia Morgans: Wonderful, thank you. So, Karim, we've talked a few times before and I so appreciate our conversations because I think that your insights into this evolving landscape of systemic therapies in both the non-metastatic castration-resistant and metastatic hormone-sensitive space, which has really been a tumultuous space recently is exceedingly valuable. And I'd love to hear your thoughts on this approach of earlier AR targeting and how we are hoping to really shift the trajectory of disease by doing that. So, so what do you think?

Karim Fizazi: You know, generally speaking, we've been using drugs that we've developed in the last decade in very advanced stages, mostly. And well, I mean, patients were improved by those drugs abiraterone, enzalutamide, taxanes, and everything. And this was true for duration of life, quality of life or symptoms. But the magnitude of benefit was not super big. It's just true.

Now we need to remember that in oncology when you have a strong oncogenic driver and you have a good weapon to target this oncogenic driver, it works and it works even better if you're using it earlier. And if you think about it in prostate cancer, the main AR, the main driver actually of the disease is the androgen receptor. So, I'm not that surprised to be honest, that using these drugs earlier in the course of the disease for now in, for example, CRPC M0 or M1 castration sensitive disease makes a difference actually a big difference.

But it's cool to have now the data. We didn't have this data until basically two years ago and now we know that these drugs are associated with better outcomes. It's true for overall survival in the M1 setting. And for the moment it's true for metastasis-free survival in the castration-resistant M0 setting, which is great. So I mean of course it has to be balanced with side effects and cost and this is very important and lots of debate around which drug is better, where the taxane should fit in the story, etc. and this makes all sense, definitely. But again, generally speaking, early AR targeting seems to make a big difference every time you're facing a man with bad prostate cancer. Of course, if it's not bad prostate cancer and if the man is most likely to die from something else, then probably it's not the best approach. But if you're talking about CRPC M0 and a rapid PSA doubling time or patients with M1 disease, de-novo M1 disease which is bad also, sustain AR targeting makes a difference. This is what we're seeing now in these trials.

Alicia Morgans: Absolutely. I think it's interesting though too that although we're seeing these differences, there are still a number of men even earlier on in these trials who have disease progression both in the non-metastatic CRPC setting and in the metastatic hormone-sensitive setting. And if we focus on the metastatic hormone-sensitive setting, we also have docetaxel potentially there. Do you see a role or an opportunity potentially to have the synergistic activity? I would imagine so given your work with the PEACE program, but ...

Karim Fizazi: Yeah, that's right. I mean at least we have the hope and I think it's a reasonable hope that we'll see synergy or at least activity between AR targeting and taxane in the space of a disease and perhaps in other spaces by the way. This is exactly what we are testing at the moment in the PEACE 1 Phase 3 trial, we completed accrual last year. We're now waiting for events, but I mean when you think about the experience that we have in CRPC, metastatic CRPC, plus or minus abiraterone or enzalutamide can salvage failures from docetaxel. We know that from the first generation 301 and Phase 3 trials and even by overall survival and actually even if we don't have Phase 3 data, it's probably true vice versa.

If you're using a taxane in a man who has already seen abi or enza in most patients you'll see activity, not in all of course, but still at least part of your efficacy is maintained in these men. So bringing these two agents or these two families of agents together earlier in the course of a disease to treat patients with really bad cancers makes some sense. Now whether it will make a difference, I mean data will tell. Hopefully, we'll have first data from the PEACE 1 Phase 3 trial in say a year or something. And this, of course, will depend on events, but I really have some hopes that yes, we will end up with a triplet for men with M1 disease, probably especially those with a high burden of disease.

Alicia Morgans: True. Well, you know there are other ways I think for the M1 setting, in addition to targeting the AR and potentially adding chemotherapy that we recently learned may benefit survival and with relatively low toxicity it seems. So we heard from the STAMPEDE, a report that came out at ESMO that for men with low volume disease, we may be able to use radiation to do this in that population and prolong survival. So what are your thoughts on that particularly given that there was some controversy in the field about how this was not preplanned from the initial development of the STAMPEDE protocol was developed and designed prior to analysis, but was not at the very start? So, what are your thoughts on that?

Karim Fizazi: Actually I buy the data, to be honest. I buy the story. Again, you're right. This was no pre-plan. When the design of the trial but this was preplanned before running the analysis. It's very important. And also, we're talking about two big groups of men in the trials, about 800 men at low burden disease in STAMPEDE and were randomized to get radiation yes or no. So, 400 in each arm is a minus. I mean that's big. And the likelihood for this data not to be true is minimal. It's just minimal. I would be very surprised, I mean and again it's being supported by data from the HORRAD trial. They had only a small number of these patients with oligometastatic disease, kind of a maybe 100 in each arm and the trend goes to same way supporting a better activity for radiation.

And again biologically speaking it makes more sense. If you have say 80% of your disease in your prostate and 20% outside of the prostate and you can get rid of the 80% with the radiation or even 70% or whatever, but the majority of cancer cells are being killed, it's quite likely that the patients will benefit eventually even by overall survival. Now of course if you have a much higher burden and say just 10% of your disease in your prostate and everything else is outside then local radiation will not probably improve your overall survival, perhaps your local symptoms but not your survival. So it makes all sense.

We will have after actually confirmatory data from PEACE 1. We have more sustained systemic treatments, generally speaking, because you were using ADT, abiraterone, docetaxel in PEACE 1 and we are also randomly testing the role of radiation. So we will know whether this finding from STAMPEDE regarding the radiation benefit is also true when you're using a more sustained systemic treatment. So it's just nice because every 6 months or 12 months we're really learning more for the setting of the disease as opposed to what happened in the past 50 years, where there was no real progress.

Alicia Morgans: No. And I'm really looking forward to PEACE 1 as well. I mean for many reasons, but one of them is this optimized systemic approach, almost the kitchen sink systemic approach. And then we can also see that whether there is a benefit for radiation. So that will be really enlightening. Hoping that it's powered at least to show us a trend in the high, low volume kind of situation because both the STAMPEDE study and the HORRAD study showed that probably overall if we're looking at all comers, there may not be a benefit to radiate in the primary. It's really in the subgroup, like you said, who have the majority of their disease in the prostate and that makes biological sense. So I'm hopeful that we'll be able to see that in PEACE.

Karim Fizazi: Right. You know in PEACE 1 we have in total almost 1200 men randomized, and it's pretty much half/half between low volume or low burden. I actually tend to prefer burden then volume because it's not necessarily a volume.

Alicia Morgans: True.

Karim Fizazi: Whatever, so it's half/half, which means that we should have probably about 600 men with oligometastatic disease randomly who receive randomly radiation therapy. So I don't know whether this will be under power or not for this subgroup of men, but it's, I mean it's not ridiculous. I mean 600 should be big enough to see at least a meaningful difference let's say. And even if we end up with a trend which is non-significant with a P value is .06, .07 whatever, I mean it means that it's just for same story as for STAMPEDE, but data will tell.

Alicia Morgans: Data will tell. And thank you for continuing to work in this space, looking at AR, looking at the non-metastatic CRPC, metastatic hormone-sensitive disease. You span it all. And I really appreciate your insights and ability to bring all of that together for us. So thank you.

Karim Fizazi: Thank you. Alicia.