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Karim Fizazi: So I would ask to look at ideal sequence after triplet treatment. And as often at APCC, we will speak about a subject without big data. I have to say that amongst my non-financial disclosures, I really don't believe in ideal sequences in general. I think we share that together with Ian. I think we need to personalize treatment based on clinical biomarkers and biological biomarkers, not just an ideal sequence. So triplet systemic treatment works in metastatic castration sensitive disease.

Two trials are essential and PEACE-1 directly showed and demonstrated this, and this is actually indirectly confirmed by a third trial looking at enzalutamide and zamet, with a subgroup analysis. So three trials pointing to the same direction. I think this is clear. It shouldn't be a false positive. And actually, triplet is being used in practice to try to assess that. I did a pre-APcCC survey asking colleagues and friends for from six European countries, approximately 30 colleagues who kindly replied some of them are here in this room and most of them actually are not APCC speakers, other colleagues.

I ask them just a simple question. Do you use triplet treatment for your upfront metastatic castration sensitive prostate cancer patients? Assuming half half repartition between low volume and high volume? And actually about a third of all the colleagues do that in their patients. And it's interesting to see that this ranges from just 10% used to 90% use, which is telling you, this all is subjectivity, but truly, at least one third of patients do receive triplet.

There's also time after treatment with triplet therapy for intervention. I cannot show you a recent data, because PFS was not or RPFS was not captured in ARASENS so this is PEACE-1. So in PEACE-1, the RPFS median was approximately 4 and 1/2 years. So first, it really shows you that we're postponing significantly progression in these main. And the OS is not reached in the trial, but it's likely over six years, which again takes you back to approximately an 18 month or so of CRPC life as a median, so you have time to intervene if you like.

So which treatment are we using? Again, we don't have much data as I said, I ask Dr. Foulon a statistician from PEACE-1 to redo an analysis specifically for APCcC, so this is unpublished data. And at this time we have 144 patients from the triplet arm who experienced a progression event as a first event, not death, obviously. And it's important to see that these main could receive at least one life prolonging treatment for CRPC in 92% of cases.

So really, the vast majority can receive at least one agent post progression. And very interestingly, cabazitaxel was the number one, 69% of these patients received it. Followed by enzalutamide, remember, these patients had received abiraterone at the first place. More rarely the docetaxel rechallenge 28%. Interestingly, 19% of patients received a platinum. So this is at least what we have. So what are the options that you probably should discuss when you're facing a progression after triplet? What do we have from the literature?

So we know that cabazitaxel clearly postpone death in main failing in AR pathway inhibitor and docetaxel. So indirectly I think this data applies post-triplet, even if I recognize, of course, we don't have direct evidence also for patients with clear BRCA alterations, probably BRCA2 for sure, but probably also BRCA1 olaparib or marginally PARP inhibitor improves overall survival, we know that from PROfound. And finally, lutetium PSMA also improves overall survival in main failing an Ar pathway inhibitor and docetaxel.
So those are, I think, very reasonable options to think about. There might be a fourth player, but we don't really know. This is radium 223, we know it improves overall survival post-docetaxel, but we don't really have data post Ar pathway inhibitor, but we will know. The RADIANT phase III trial has completed recently its accrual. So stay tuned. Hopefully, in a year from now or so, we should have data.

There less appealing options in the setting. The second AR pathway inhibitor typically doesn't work, it's been used a lot and suggested some time by agencies. Most of us I guess, don't like it very much. I'm showing here the Canadian data, especially when using abiraterone post enzalutamide, I really don't think this is appropriate. You may argue the other way around and enza post abi, but really abi plus enza doesn't work.

Docetaxel rechallenge. I'm also quite on the fence. We don't really have data for efficacy and toxicity post-triplet, but we do have that in genetics 15 post-docetaxel for mCSPC. And we could show that the response rate was lower as expected, as compared to the docetaxel naive population. Also, the cumulative toxicity is an issue. And if you have access to cabazitaxel, this is a better choice if you have to go for a taxane. Again, those are the data from [INAUDIBLE] 15.

So how to choose between available options? Well I think we can provide guidance. For example, if your patient has alterations at least I would really go for PARP inhibitor quite early at progression post-triplet. MSI high? Same. I would probably try to get a PD 1 inhibitor understanding that of course, this is not approved in most countries ex-US, and certainly not in mine.

And I also recognize that the evidence is weak, but really it appears to be strong. In case of strong PSMA expression, this is a good reason to consider PSMA targeting with lutetium PSMA right now, and potentially in the future, other compounds. For patients, we do see these patients lutetium PSMA, radium 223 are probably a reasonable options, they're mostly quite non-toxic, we may argue.

And in case of long time since the Stacks are used, that might be a good reason to consider cabazitaxel. But also because the Ar pathway inhibitor is being used in the triplet. Maybe, and maybe only, a single Ar pathway inhibitor using enzalutamide post ABI might be an option, at least something to discuss in those specific cases.

But whatever you decide, please don't forget using a bone protecting agents such as denosumab. And we know that for 20 years really. You 20 years ago, we showed evidence. Fred Saad and his group showed evidence that asset is better than nothing. And a decade ago, we showed evidence that denosumab is better than Zoledronic acid. Silke and Bertrand showed also in the PEACE-3 trial, that using denosumab can really prevent the onset of fracture coming from a 25% to 50% incidence, down to almost zero.

So this is a clear demonstration for our practice. But to be honest, I think we should really integrate the biology right now, if not in the future. I think it's really right now, I have tried to simplify the way I see things for the immediate future. First, in a quite important majority of main the main oncogenic driver of the disease has secondary alterations AR mutations, amplifications, slice variants. We will learning more and more how to target those alterations, it's not easy obviously, but I think this is coming.

Steroid inhibitors AR degraders should probably be the answer, or part of the answer in this scenario. Second situation bypass pathways, well, here we will have to learn more about targeting PI3 kinase and AKT, PSMA, B7H3, STEAP1, may be hK2, and maybe others. Again, we're learning and learning, many trials are coming. And finally, we have a third and difficult situation of lineage plasticity with neuroendocrine differentiation.

This will remain really the north face of mCRPC, this is really hard. Targeting DLL3, EZH2, maybe others. Again, we're learning very progressively. I know it's hard. It is as it is. I hope that I could demonstrate you that there is a life after triplets, so we should use them for mCSPC. And with this, I Thank you very much for your attention. Thank you.