KF: Hello, I’m Karim Fizazi, medical oncologist from Gustave Roussy in Villejuif, France. I’m here in San Francisco during the ASCO GU meeting ’19 for this ecancer event sitting together with Dr Eleni Efstathiou from the MD Anderson Cancer Center in Houston, Texas but also Greece a bit. We just want to discuss for you what is the current situation for men with metastatic prostate cancer, so basically castration sensitive metastatic prostate cancer. The situation has evolved tremendously in the last three or four years and still now so we will try to summarise that in the coming ten minutes. Eleni, let’s start with what the situation was, say, a year ago in early ’18. We had data about docetaxel and, for example, we saw the updated analysis of the CHAARTED phase III trial. Can you summarise the rest for us?
EE: First of all let me reinforce and comment for those people who probably have not realised you were among the first champions of treating hormone naïve disease, and your group, back from the first GETUG trial. So kudos for that because you were doing it at a time when there were no believers. And the same thing with high risk localised disease, by the way. So I think there’s no more expert than you to comment on these. But over the course of the past year I think we’re trying to refine the treatment. We have a little bit of an unmet need when it comes to recurrent metastatic disease because mainly the bulk of the patients treated were de novo, however, CHAARTED did include some recurrent metastatic disease. But CHAARTED as a trial, and just to remind you because it’s now almost four years, five, that we saw the data, was mainly aimed for high volume disease as defined originally. For reasons that are more logistics, it did include patients with low volume disease so the final analysis showed a beautiful benefit for all patients. However, given the fact that there was that clause for an analysis based on volume we got the mature data that suggests that high volume disease there is no question – patients get a clear, beautiful benefit by the addition of docetaxel six cycles, no question, so on ADT. When it comes to low volume the water is a little muddier in the sense that there’s no obvious benefit and I have to say that we need to keep in mind that using as a surrogate volume is a little bit tricky because it doesn’t always accurately represent what is the dynamic aggressiveness of the disease. We take it with a grain of salt. So that paper by [...] et al last year helped but what came after with the big ESMO presentations of pre-specified and non-pre-specified analysis of STAMPEDE gave us more insight when it comes to use of abiraterone and when it comes to use of local treatment.
KF: Let me stay first on the oligometastatic situation because one limitation from CHAARTED, obviously, is that these patients were rare, as you said, so it’s still highly debated as to whether docetaxel is appropriate or not for patients for oligometastatic disease. Probably we will learn more from STAMPEDE at ASCO this year and for now I’m not sure we can say much. Now, as you said, indeed STAMPEDE tested the role of local radiation for men with de novo metastatic prostate cancer and what they could establish was that irradiating the primary is associated with improved PFS in all comers, regardless of the volume of the disease, and for patients with oligometastatic disease there is also an overall survival benefit from that. So in many countries this is becoming now standard of care, at least in mine, because it’s quite a cheap treatment, depending only, and safe and it’s associated with benefit including overall survival for these men. Moving to systemic treatments, non-taxanes, we have now since yesterday data not only for abiraterone, and I’ll maybe come back to abiraterone, but also with enzalutamide with the ARCHES trial.
EE: Indeed. I’ve shared with you my opinion in the past that when such studies follow on top of the previous reported positive results and they are also positive they reinforce the strength of using that mechanism of action. Having said that, of course enzalutamide and abiraterone have some differences, however it’s the same androgen signalling inhibition. So ARCHES is a trial very similar to what we’ve seen in metastatic hormone naïve prostate cancer with a little extra point of allowing prior docetaxel being used. But, as you were telling me earlier, it was less than 20%, it was about 18%. Still, something to know in the future and we’ll hear more from PEACE, I believe, on those aspects like whether combinations will come.
KF: Actually regarding enzalutamide we might hear more from ENZAMET which is going to be shown hopefully at ASCO and that has more patients with docetaxel so it will hopefully address the question as to whether strong AR targeting helps on top of docetaxel which is a key question. PEACE-1 also has completed its cycle of about 1,200 men; we’re just now following these patients.
EE: Again you’re the champion in that.
KF: So we’ll see. Altogether we’ll have that.
EE: But ARCHES, don’t you think just for us in the discussion with everyone at home and [...], I thought it was a little premature because co-primaries. We saw beautiful radiographic progression free survival data but the overall survival data was not mature yet and I understand that the drug should be available to more people, we’ll hear more about that from the FDA I guess, but I would like to have seen also the overall survival. Maybe in the future.
KF: No, I agree with you there, especially in a situation where we do have overall survival demonstration with LATITUDE. Yesterday we saw the updated analysis even with quite strong use of salvage treatments in the control arm. About 57% of men received either docetaxel, abiraterone, enzalutamide as a salvage therapy for CRPC in the control arm of LATITUDE, we do see that the overall survival benefit remains and it remains very stable, very robust – the hazard ratio is 0.66 so it’s a 34% reduction in the risk of death and that comes together with improvement in time to pain progression, time to skeletal related events etc. So clinically, honestly, it’s more convincing; it’s just stronger than what we saw yesterday with ARCHES. So for enzalutamide we need more data. I think it will come because those drugs are very similar in efficacy so I don’t really see why one drug would work and not the other one in this space but we still need to see the data and also the long-term toxicity.
EE: And, by the way, we’re waiting for the TITAN data as well on apalutamide, right? There was a press release, we haven’t seen the data but the same population with maybe more recurrent prostate cancer.
KF: Correct, and again they said that both OS and rPFS are significantly improved. So we’ll see more. But really these men keep dying, especially when they have a high burden of disease, so really the key question is not necessarily whether we should use enzalutamide or abiraterone or docetaxel but whether we should use both a taxane and AR targeting agents for these men. Even tomorrow perhaps many more agents with new targets – what about PSMA targeting, what about Radium, what about PARP inhibition etc. those are open questions.
EE: So I think you hit it right on the head, the nail, because if you look at all of the supplemental data, STAMPEDE and I think yours too, you’ll have to correct me on that one, it looked like the men who are on the treatment arm are the ones who get also more exposed to subsequent treatments and it could be that their performance status is better. It’s more of a question of is it the fact that they’re well monitored and the sequencing happens there quicker? The question that I have at the end of the day – is it about exposure to different mechanisms? It’s not whether you go for abiraterone or docetaxel first, it’s about exposing your patient to that extra layer of treatment.
KF: It could be, it could also be that targeting stronger the cancer from the beginning when it’s about cancer makes a difference. Again, we need more data on all this but it’s a very nice situation to face currently and we are making progress. Thank you very much for your kind attention, have a good day. Thank you.