Prof Karim Fizazi - Institut Gustave Roussy, Paris, France
Dr Cora Sternberg - San Camillo and Forlanini Hospitals, Rome, Italy
KF: Hello, I’m Dr Karim Fizazi, a medical oncologist from Gustave Roussy in Villejuif, France. I’m actually here in Barcelona during the EMUC meeting. I’m joined here with Dr Cora Sternberg, also a medical oncologist, from Rome, Italy and thanks to ecancer we will try today to discuss the very important new data that we’ve learned in the last two to three years for men with advanced cancer. First of all, Cora, I think one of the big changes since, let’s say, 2015 has been the earlier use of active drugs in men with castration sensitive disease, not only in the castration resistant space. Can you elaborate a bit and tell us where we currently stand with this regard?
CS: So we’re talking about prostate cancer and we’re talking about patients with hormone sensitive prostate cancer where in the past we gave everyone ADT when they’ve presented with metastatic disease, ADT alone. What we first had was data from the French and the Americans and also the English, from STAMPEDE, the Americans with the CHAARTED study, showing that by giving early docetaxel chemotherapy we could improve survival significantly. This was then looked at together in a meta-analysis and at least a 10% improvement in overall survival. So there was a trend towards giving early chemotherapy for patients with hormone sensitive disease, giving six cycles of docetaxel chemotherapy.
KF: Are you doing it in your practice at the moment?
CS: I am, I’m doing that for those patients who are healthy enough to do it. Not for very elderly patients but patients who are healthy, we are giving the patients who have considerable disease. I started out based on the CHAARTED data from America on patients with a high volume of disease but the guidelines have been more and more towards giving patients with new metastatic disease. But since then things have changed because we’ve had some really interesting data presented by yourself and presented also by Nick James from the STAMPEDE group with the early use of abiraterone. These were presented at last year’s meeting and published in The New England Journal last June showing that by giving abiraterone acetate which is a novel hormonal therapy we could obtain in patients who have metastatic disease who are hormone sensitive, giving together with ADT the same kind of results that we saw with chemotherapy, or very similar results. Would you agree with that?
KF: I do and actually we were surprised the nice way by the magnitude of the benefit that we saw in terms of both PFS but, most importantly, in overall survival.
CS: Exactly.
KF: To think that in the LATITUDE trial that was the first interim analysis and it was already significantly positive and so it was big positivity.
CS: 37% reduction in the risk of death, right?
KF: That’s big.
CS: That is big, very big.
KF: The good news is that two weeks ago or so the EMA granted approval for abiraterone in this indication which means that very likely in the next year we will have this drug approved in all the various European countries and hopefully reimbursed as well. So let’s say that we are in that situation next year and let’s anticipate about it, even if we’re not official. What will you do next? Will you use ADT docetaxel or ADT abiraterone for your next patients or will you stratify? What will you do in your practice, do you know?
CS: I work in Italy so it’s going to be partly a problem of reimbursement but let’s say it’s reimbursed. I think that we really don’t know which is better to use first. There are different side effects with each one of the drugs, both abiraterone and prednisone and both chemotherapy and prednisone have different kinds of side effects. So I think one has to look on an individual basis of the patient and decide which side effects they are more or less willing to tolerate. If you look at the quality of life data from the CHAARTED study and chemotherapy, the quality of life goes down initially when they get chemotherapy but then after a year it’s back to normal. Last year Kim Chi presented from your study quality of life data was very, very good with abiraterone acetate so I think it was quite impressive , that data, how good it was.
KF: Also at ESMO you were referring too to Kim’s presentation and also at ESMO we had some data reported as to whether abiraterone and docetaxel are the same in terms of efficacy. I was interested to see on the one hand the indirect comparison between the two drugs using a Bayesian methodology supporting perhaps a slightly higher efficacy by PFS and OS favouring abiraterone and then the direct comparison from the STAMPEDE trial where at a given time they were able to randomised patients to get either ADT or ADT docetaxel or ADT abiraterone. What they decided to do is to compare the two experimental arms, even if it was not pre-planned, and of course we can debate methodologically speaking, because the number of patients is rather large I think that’s acceptable. What they suggested with a slightly short follow-up, I should say, for this comparison is that abiraterone might be better for failure free survival based on PSA relapses but when it comes to overall survival or stronger endpoints they don’t see much difference. So I guess this is going to be in the coming debate.
CS: This was a part of the STAMPEDE trial, it’s a wonderful trial because they have a multiple arm trial and they keep adding on arms and adding on arms. By 2025 they will probably have ten randomised trials. But they took patients randomised in the abiraterone arm and patients randomised in the docetaxel arm during the exact same time period and compared them head to head. They weren’t exactly the same kind of numbers - it’s an opportunistic retrospective kind of analysis. The difference in progression free survival was really just PSA based so we don’t really know what that means because there really was not an overall survival difference found. So we’re at a standstill because of that.
KF: Well it’s actually good.
CS: It was an interesting way of doing things but it wasn’t an overall survival difference, it was a PFS difference and I don’t know what that means exactly yet.
KF: No, I think we will still have to struggle as to whether we should use ADT abiraterone or ADT docetaxel for our practice, probably starting next year. Honestly, to me, the main important question is should we use a doublet, whatever that is, or maybe a triplet because when you think about it abiraterone and docetaxel have very different mechanisms of action and the cross-resistance between the two agents is not that big. So we may really hypothesise that using both drugs up front might even make a bigger difference and this is exactly what we’re currently testing in the PEACE1 trial. I’m glad to say that we are actually already at 900 men randomised, something like that.
CS: But you amended the trial to add the chemotherapy because there was such a desire to add chemo with abiraterone.
KF: Absolutely, so that we will have the answer and I think that’s very good.
CS: And there are other trials going on like the ARASENS trial with darolutamide and the ARCHES trial and the ENZAMET trial, they’ve all added on chemotherapy when the initial question had been a novel hormonal therapy plus ADT. They’ve all added on chemotherapy as well so we will have an idea. Prostate cancer is heterogeneous and it’s possible that the combinations will be better, it’s really possible.
KF: Yes, so we will know. Now, you know what, another very interesting situation which is really associated with lots of anxiety for all our patients is that of patients who have failed local treatment who are on ADT but who are now failing ADT so progressing by PSA, if you will, with no detectable disease. I think we’ve heard that we will soon have data testing these new agents in this particular setting of M0 CRPC.
CS: This is a very special situation where many patients are put on hormonal therapy early, partly they don’t even have a radical prostatectomy or radiotherapy because they’re elderly or for whatever reason. They are failing and they just have rising PSA but no metastatic disease. There are two trials, the SPARTAN trial which has already filed at the FDA with apalutamide and the PROSPER trial which has put out a press release with enzalutamide, showing important differences. They haven’t given out the numbers yet but I think we’ll be hearing about them very soon, about giving these drugs very early on in patients with just rising PSA. So we are moving earlier and earlier and earlier. First we started with M1 patients from the LATITUDE trial and STAMPEDE trial. The STAMPEDE trial also showed that the M0 patients were benefitting, particularly those with lymph nodes, but probably benefitting as well, and now we’re going to be hearing data that’s important data on patients with only rising PSA and M0 CRPC. So that may change our outlook on giving these drugs even earlier on.
KF: Yes, and that’s really tomorrow. Actually, coming back to metastatic CRPC I think it’s fair to say that all our main weapons in this setting, including next generation AR targeting with abiraterone and enzalutamide, taxanes, with docetaxel, cabazitaxel, and bone targeting with radium-223 and denosumab. What do you envision in terms of the next next generation of weapons for the coming years in this setting?
CS: We’ve learned a lot about the genetics about prostate cancer. We’ve learned that looking at 690 patients published by Pritchard, not particularly with any family history at all, that there were 12% of patients had germline defects.
KF: It’s a lot.
CS: This is a lot and this has a lot of implications, not only for the patients but also for their families. In the TOPARP study where patients had some kind of a defect in their tumour fourteen of sixteen patients who had been really heavily pre-treated responded well. So what we are looking now is to test patients with advanced disease looking both somatically and at their germline to see if they can be treated with PARP inhibitors, with cisplatin or platins. So we will have new arms for these patients as well. These are patients, for instance patients with BRCA2 defects, who tend to have a poorer prognosis. They do respond to therapies but they respond less well and if we have better arms for them it would be something really important. There are quite a number of trials ongoing looking at that.
KF: Absolutely, I totally agree. I think one very interesting piece of data is also about PSMA targeting with the radioisotopes and the first data that we saw a couple of months ago are promising. Finally, but probably that is my bias, I would say that really immunotherapy should find its way in this disease because in some patients we do know on an individual basis that it works sometimes like magic. This is true for CTLA-4 targeting, we just learned last year that it might also be true with PD-1 targeting. The issue is that we need a biomarker to help us with decision making because it’s really a minority in prostate cancer. Also we need to better understand how to turn these cold tumours mostly into a hot one so that immunotherapy may work.
CS: The first thing you spoke about was PSMA. Most of the scans that we’ve done have been with technetium, most of the studies we’ve done with technetium scans. In Europe we tend to use choline scans which are not nearly as sensitive as PSMA scans. PSMA scans show more lesions even if the PSA is only 0.5. But hooking up the PSMA scan with a radionuclide like lutetium or actinium you can see incredible bone scans where the tumour seems to completely disappear. These are new studies; we heard about a study that was done in Australia by Hofman et al, very interesting, they’re called Theranostics I believe, with the lutetium. The problem with that is we don’t have long-term follow-up, we don’t know anything about leukaemia, xerostomia.
KF: With the salivary gland irradiation might be also an issue.
CS: Exactly.
KF: I think it’s really promising. So thank you very much Cora.
CS: My pleasure.
KF: It was really fun to do that. And thank you very much for your kind attention, we were glad to take our time here at EMUC Barcelona. I would like to thank ecancer for providing the opportunity. Thank you very much.
