KF: Hello, I’m Karim Fizazi, medical oncologist from Gustave Roussy in France, and I’m here for this ecancer event in San Francisco during the ASCO GU meeting which actually is an exciting one. We’ve heard the data from the prostate cancer session yesterday so we thought it was a very good opportunity to wrap up regarding the data for men with castration resistant prostate cancer with no detectable metastatic disease. This is because we had, in the last year or so, a lot of new data for these men so we’re going to try to see what we think about these data. Together with me today I have Nicholas Mottet who is a professor in urology in France; we have Eleni Efstathiou, a medical oncologist of MD Anderson Cancer Center in Houston, Texas; we have Boris Hadaschik, professor in Germany. We will try to see whether there are differences between all our countries, between all our approaches with regards to the use of treatments, imaging, management of patients, all these things. So just to get started, Nicholas, can you summarise for us what was the situation, let’s say, January 1st 2018, so more than a year ago, before we had any data for these men with castration resistant prostate cancer and no detectable disease, what the guidelines said at that time.
NM: Well, something very simple – keep going with the ADT, don’t do anything more if the patient is asymptomatic, reimage every time the PSA doubles or if the patient becomes symptomatic and treat when he becomes castrate resistant metastatic. Very simple.
KF: Wasn’t that difficult clinically, and I’m asking the question to all of you, in the clinic to see a patient with a rising PSA who was castrated and telling him, ‘Well, I’m not going to do anything else but continue your ADT. We’re just going to wait for the metastasis to happen.’ So how was it in the clinic?
NM: It was quite difficult. It was difficult while in France we had the opportunity to say, ‘All the drugs that are available for castrate resistant metastatic are not licensed for non-metastatic so we’re not allowed to use them.’ At the same time we had no idea if treating earlier was better than treating a little bit later but, in fact, it was difficult. ‘Oh, my PSA is rising,’ what do you do?
EE: Absolutely and I think if it’s difficult for a person of your status to say that, imagine in the community practices because patients will go and they’re not… you’re a person who writes the guidelines, who has worked on it. Another practitioner who is more in everyday practice would have the difficulty of actually convincing the patient that, yes, this is what you should do. I think that explains the big uptake of the first generation antiandrogens that we’ve seen or low dose steroids, things that have never proven a benefit.
KF: Indeed, yes. Boris, we’ve heard in the last year that two trials, PROSPER and SPARTAN, were positive by their primary endpoints of metastasis free survival. Can you please summarise the data for us where we currently stand with these two trials.
BH: Yes, last year, here in San Francisco as well, both PROSPER and SPARTAN studies were presented and they remarkably showed the same effect on metastasis free survival by improving this outcome by 70% for men with high risk non-metastatic prostate cancer. This is a novel endpoint, we don’t really know what to do with MFS. You see something on imaging, does this really translate to overall survival? We have to see, it looks like it and also data shown here shows that it seems to correlate with overall survival. But, more importantly, especially in SPARTAN, also data has been shown that by treating these men earlier with novel medication such as apalutamide or enzalutamide we are also prolonging symptomatic progression free survival. So there is a hint that these novel medications given early are really improving patient outcome. So if we decide to treat men early the other question is, besides spending money, how is the quality of life of these men? Reassuringly in both studies the quality of life, and in follow-up presentations that came out last year, it has been shown that despite these men being asymptomatic at the start of the study their quality of life was not reduced very much by adding enzalutamide or apalutamide to ongoing ADT. So I think these were brilliant data that have been shown and that kind of answered the question that earlier treatment makes sense in this setting but we have to know that all OS data is immature yet so we really don’t have a very hard endpoint and we will follow these men longer to find out whether our beliefs have come true that also overall survival is prolonged by giving treatment early.
KF: Thank you. So this year, actually yesterday, we’ve heard the ARAMIS data with a third agent.
EE: From you.
KF: The data from me, indeed, yes, whatever. So that was ARAMIS with darolutamide, very similar design as compared to SPARTAN and PROSPER that you just described. Darolutamide is perhaps a different beast, at least chemically speaking. It’s structurally distinct and maybe thanks to that it doesn’t go into the brain and that’s probably the main difference. What we saw regarding efficacy was actually pretty much the same thing with MFS being the primary endpoint, very dramatically improved with darolutamide. We also saw that overall survival was improved with a risk reduction of about 29% while pain progression was also improved with about a 35% reduction in the risk. So we do have MFS but also clinical improvement with these agents and hopefully a longer follow-up will tell more. Now, in ARAMIS with darolutamide the safety seems to favour this drug. We were actually surprised to see that there was basically no difference between darolutamide and placebo for most of these adverse events, mostly CNS related events such as fatigue, cognitive impairment, seizure, really no difference but also falls and fractures were no different between placebo and darolutamide.
EE: I’m sorry to interrupt you, you mentioned that you were including even patients who had histories.
KF: Yes, of seizures.
NM: Yes, they were allowed.
KF: They were in the trial.
EE: That’s very different, though [...]
KF: And still the seizure incidence is really the same and cardiovascular adverse events were also very, very similar with placebo. So we now have three drugs and hopefully they will be approved and reimbursed in our different countries. But the field has maybe changed since we conducted this trial some years ago and, depending on our countries, we now have access to next generation imaging. For example, in Germany I believe PSMA PET is quite easy to get, so what is your experience and does it really change the way you treat these men?
BH: First of all congrats to the great study yesterday, I think darolutamide is really promising and it makes life more interesting for us if we can choose between three drugs, at the moment we only have two approved but it’s nice. So in Germany this is absolutely true, we do a lot of next generation imaging because access to it is reasonably easy and the price is not as high as, for example, in the States. But we always have to remember that we don’t know whether that stage migration that is caused by a next generation imaging is really translating to any oncologic benefit. So, for example, we presented data on SPARTAN-like patients last year at SUO and we will also show this data at EAU and AUA. If you apply next generation imaging to men with non-metastatic CRPC, and conventional imaging, you will see in more than 50% distant metastases. So we know that these men at high risk of progression because of a short PSA doubling time, they do have at least micrometastases. So now we have three trials showing that these men benefit with systemic treatment. So the value of really doing next generation imaging in that setting is not as high as in the setting of biochemical recurrence where we aim for cure. So imaging used to be done a lot, or not a lot, but it used to be done in the nmCRPC setting to see metastases to get access to drugs with approval for metastases. But these drugs were approved on conventional imaging as well so at this point in time for a patient with no metastases on conventional imaging I don’t care about the result of PET because I know I can provide benefit with one of the three new drugs.
KF: It makes sense. Nicholas, would you agree with that?
NM: I completely agree but even if the three trials are very positive in terms of primary endpoint, as a simple minded clinician I just don’t want to have less mets, I want my patients to live better. I’ve never seen any quality of life benefit in any of the three trials; there is no detrimental effect of the drug but, at least to my knowledge, there is no benefit yet, probably it’s too early. On top of that I want my patients to live longer and I’m still waiting for that. All that only applies to those patients with a very rapidly progressing PSA; those with a slow growing PSA we are still in trouble: ‘Sir, your PSA is rising. I’ve nothing to offer to you.’
KF: It’s true. Eleni, regarding imaging and whether this is convincing enough to be ready for prime time and be used in, let’s say, fit men with a PSA doubling time of less than ten months. Is that convincing enough or do we need more clinical data if you see a patient tomorrow?
EE: You’re referring to imaging, I think I would agree and echo the comments of both urologists here that, indeed, there is no place unless you’re planning to include in a trial that’s interrogating a specific issue. Especially in the rapid PSA doubling time there’s a lot of data associating with metastases happening very soon and shortly. Going back to the data, I think that Fred Saad’s publication in The Lancet Oncology did the analysis based on the benefit of quality of life. What they did in the SPARTAN analysis is that they did not take off the patients who were progressing from the analysis and it shows when progression starts happening the benefit that the patient is on apalutamide. You’re absolutely right, probably because these men are symptomatic, in none of the trials have I seen them get better. Having said that, because you are the king of guidelines, it’s up to you now when the time comes to update to make it clear to us and the community that now that we’re going to be treating with these new agents the first thing to look at is to actually try to make lives better and cause no harm. That’s going to be very personalised, is my impression, because we saw through the trials that, even in big institutions and great places, we may not be doing exactly what’s best when monitoring their other morbidities and comorbidities. So that’s my fear.
KF: Actually the median age in these three trials was almost 75 years.
EE: Older gentlemen.
KF: So this is not exactly what we saw in metastatic castration sensitive disease or even in mCRPC, men who are younger in the trial. Here we’re talking about a mostly elderly population and I agree with you, we need really to take into consideration the comorbidities, likelihood for survival. What about bone health, for example? What do we know now regarding whether we are arming these patients with super-castration or super-AR targeting when they are 75 years old, M0 CRPC men? What do you think?
EE: I have to speak from the side of practising more in the US, already you have a gentleman who has been on androgen deprivation, walks in the room, probably not being coached that you should not be obese, you should not have a metabolic syndrome, it’s already in place, sarcopenia is in place with muscle loss. Usually, more than often, nobody has done even a baseline bone density or a vitamin D assessment or what have you and you don’t see any preventive measures in place. I have to say, I’m not speaking just about the community, even within my department, which is a premier cancer centre, we are not even following the algorithms of breast cancer. So I think that the previous two trials, maybe darolutamide has a little bit of a different spin to it when it comes to the impact it has, but the data showed that in all three trials, and you showed it yesterday, very few patients were on bone protective agents. So that’s up to you now to fix because we’re obviously not showcasing as much the need to actually take care of bone health.
NM: But if I may answer for that point, specific point, we clearly said in the guidelines that when you give ADT you have to check the bone, that’s the first thing. We also clearly said that there is no place for bone protective agents provided they are not osteoporotic.
EE: Or osteopenic going to osteoporotic. It’s very close.
NM: Very close, if they are very close to -2, probably you have to consider it.
EE: How about counselling on resistance training in the leg which is a hard thing?
NM: It’s strong, evidence level 1, recommendation. It’s completely written on the table.
EE: And it’s also cheap.
NM: It’s almost for free but the real issue is who is reading the guidelines, who is taking care of the guidelines? You have to be quite disappointed with that.
KF: People are reading them.
EE: We are. I read your guidelines.
KF: Let me ask you a simple question and please provide your most honest and fast answer. If tomorrow you would see a patient with M0 CRPC, a PSA doubling time of less than ten months, no or minor comorbidities, and let’s say that in your country those three drugs are available and reimbursed, or at least one of them, regardless of which one that is, would you recommend that to your patient? Boris, what would you say based on the current knowledge?
BH: I would recommend it because I believe that we see a small benefit in quality of life because the detriment is delayed by two years. So that is something. And you help the patient. In the trials PSA was blinded but in routine clinical practice the patient is happy if he sees his PSA going down and I can guarantee it because all trials showed that the PSA is dropping.
KF: So you would use it?
KF: Okay, thank you. Eleni?
EE: I’m already using the two agents. I have to say that comfort zone is very important, I’m not yet exposed to using darolutamide. It’s a matter of time, I guess, in the United States. So as soon as I get comfortable with that agent I will be very happy to actually explore it in the clinic. The results with using either enzalutamide or apalutamide in this setting in this past year to six months have been exactly like you described, quite reassuring. But these patients need monitoring, we must not forget that.
KF: Nicholas, would you advise your patients to get one of these three drugs?
NM: Absolutely, yes. For me the main argument is the benefit for symptomatic progression that was clearly deferred in one of the three trials.
KF: Actually two because we have pain progression in ARAMIS. It’s two now.
NM: Correct. For the two published trials.
KF: Well, it’s published.
NM: I can tell you the guidelines clearly say that for the M0 CRPC with a PSA doubling time of less than ten months it’s standard of care now to use one of these drugs. So the guidelines have changed based on the three trials.
KF: Fair enough, thank you very much. So thank you for listening to us today, that was fun doing. Thank you very much, we enjoyed this ecancer event. Bye-bye.