ASCO 2016

ASCO 2016: Highlights in prostate cancer from days 3 and 4

Dr Eleni Efstathiou – MD Anderson Cancer Center, Houston, USA
Prof Kurt Miller – Benjamin Franklin University Clinic, Berlin, Germany
Dr Chris Parker –The Royal Marsden, London, UK
Prof Stephane Oudard – Hopital European Georges Pompidou, Paris, France

EE: Hello, I’m Eleni Efstathiou from the University of Texas MD Anderson Cancer Center and the University of Athens and I’m a medical oncologist. I’m here joined by colleagues, physicians, we attended together a very interesting session on prostate cancer this morning and during this whole meeting at ASCO in Chicago we were able to collect a few more details that might make our practice better. I am joined here by Professor Stephane Oudard who is from Paris and I hope is doing better by the time you get back, from the Georges Pompidou Centre, and of course I am here with Dr Miller, a professor in urology from the Charité Hospital in Berlin and finally Professor Chris Parker from the Royal Marsden, an oncologist as well. So, gentlemen, I’d like to start… well, there were very catchy titles in the trials we discussed today and you were all involved in them with the exception, probably, of FIRSTANA, not a very catchy title that one. But let’s start with PROMIS, and I’m going to be biased and say that I think that it was the most promising presentation today. Of course, Dr Miller, Kurt, you have to comment on that, being a urologist. Tell us about the trial, please, Chris.

CP: So PROMIS tests the role of MRI in the diagnostic pathway. In the past, of course, men with a raised PSA went on to have a biopsy and we tested the idea that you could use MRI as a triage test to decide who should get a biopsy and who shouldn’t. It involved 700 men, eleven centres throughout the UK and the bottom line is that if you’ve got a raised PSA but a normal MRI you’re very unlikely to have a nasty prostate cancer so you don’t need a biopsy. So I think it is practice changing and that in future we should be doing fewer biopsies because we’ll be doing pre-biopsy MRIs.

EE: So I’m going to get a little bit in the nitty gritty before we ask Kurt his opinion. This was started with a 1.5T MRI with all the limitations of doing it in multiple institutions. As somebody mentioned, you don’t have the most educated in the field, sometimes, radiologist, you don’t have the most cutting edge. But you would say for a standard of care practice that’s out there in the community, this would be something that they could apply tomorrow?

CP: This is what makes it such a good study, the fact it was done in multi centres and they weren’t all so called centres of excellence, they were typical centres and there was nothing special about the kit. A standard MRI machine, only a 1.5T, no endorectal coil, so therefore if you’ve got the right radiologic expertise then, yes, you can do this at home, so to speak. There was training of the radiologists so it’s not something that you could do tomorrow but you should be getting this done, you should be getting pre-biopsy MRI and you should be making sure that your radiologist is up to speed.

EE: Kurt.

KM: That’s the problem Chris mentioned, because many of the radiologists haven’t picked up doing prostate MRIs. So I think this is crucial. We do prostate MRIs now for four years and we’ve seen a learning curve with our radiologists so what we do in 2016 is definitely different from what we did in 2013, let’s say. But, that said, I totally agree with what you said so I think the data are now quite mature in saying in about 25-30% of the patients you can avoid a biopsy. In those patients you need to biopsy you can have a fusion biopsy. This was not in the PROMIS trial, actually, they did templates but probably, and we discussed that, before fusion biopsy is within the same range. Then what you see is, indeed, and we evaluated our data and we came to the same conclusion, it’s a PI-RADS classification 4, and if you have a PI-RADS 5 your likelihood of finding prostate cancer is almost 90%. If you have a PI-RADS 4 your likelihood of finding prostate cancer is almost 60% and the cancer you find is more likely to be significant than insignificant. So, in my mind, there are only advantages. The only problem right now is really the availability, not for the MRI, there are millions of MRIs out there, but for the radiologists being experienced in assessing MRIs. Because what we saw is specificity is low which means you have too many false positive MRIs and depending, of course, on your radiologist. But, look into the future, in five years from now that’s what we’re going to do.

EE: This is an important first step because it actually now reached the oncology end of things because you, as urologists, have been pushing the agenda. And to hear one more comment from you, since you’re going to be doing this MRI in the future, wouldn’t you also want to reach the level of technology that will be also informative for you once you do get a diagnosis and you want to decide how extensive that disease would be. I want to get to how much technology beyond a 1.5 should progress to inform you better.

KM: We’re routinely using 3T MRIs for that, that is one thing. The other thing we did not discuss is, of course, this type of defining the disease with the MRI is the prerequisite of doing focal therapy. That means abandoning the paradigm of always treating the whole prostate and now making the step to treating only a part of the prostate or only treating the tumour, which has been done for many other tumours, as we know. So the technology of coming from 1.5T to 3T to making more sophisticated, softer algorithms with the MRI is just at the beginning, not at the end. So we will see definite progress here.

EE: So, just to confirm the European, because I’m looking at you as the European practice, and Stephane, tell me what is happening in France. You do not use endorectals anymore.

SO: No, no.

EE: And you also apply the same technology, 1.5?

SO: Yes, but as Kurt said, we have a learning curve for MRI so I completely agree that now from time to time it’s going to be accepted by urologists, oncologists and also radio-oncologists that you have the great methodology, that you have the of always going to take advantage of this new technology.

EE: For me, a big first step because we hadn’t seen any trials on imaging and we desperately need more of those. But then I want to get to the next trial that I know is closer to your heart, again the PROFIT trial, because that’s a step forward. That’s going to be imminently or already, as we mentioned earlier, practice changing. Can you share your thoughts on this specific one?

CP: Yes, the PROFIT trial is a trial from Canada and it’s for men with intermediate risk localised disease and it’s comparing two radiotherapy fractionation schemes, so a standard eight week schedule and the experimental four week schedule. What they showed in a trial of 1,100 patients is that the four week schedule is non-inferior in terms of efficacy and the toxicity was the same. So, given that this is a major benefit in terms of patient convenience and in terms of resource use and given that there are two other trials that have shown exactly the same thing – the RTOG-0415 and the CHHiP trial, then this does change practice and people should use a four week schedule and they should not use a seven or eight week schedule.

EE: So, Kurt, I can’t help but go to you, you’re the urologist. You’re going to tell me intermediate, come on.

KM: Yes, you’re right, that should happen. I’m really keen to see if it’s easily and quickly adopted by the radio-oncologists, which I actually don’t. That has a number of reasons, maybe some financial reasons, some other reasons. But I think, as has been discussed in this session in the morning, the data are quite mature and I think from tomorrow on people should go on four week schedules.

CP: Yes, in the UK everyone has switched to four week schedules.

KM: Has it really?

CP: Oh yes, but of course there are no financial incentives in the UK. I picked up in the meeting today that there is some reluctance amongst US radiation oncologists to switch to a four week schedule.

EE: I think it’s a matter of time. But I wanted to get… it’s beyond the point but from a urologist’s perspective who is very involved with what’s going on, do you see more of a shift of intermediate disease, with the exception of the groups with comorbidities, to be becoming more exclusively your end? Just a comment, not related to this trial of course, but as a urologist.

KM: Of course. We know that since a number of medical associations have been voting against PSA testing the low risk cancers are not diagnosed anymore. And also, by the way, if we use MRIs in the future the low risk cancers will not be diagnosed even more so. And then we see more intermediate and high risk cancer, definitely, for surgery and for radiation therapy. That’s what happened during the last three or four years.

EE: So, talking about being a comprehensive practitioner, whether you are an oncologist or a urologist, I’d like to bring up the first trial that challenged us today on chemotherapy, actually presented by a urology group, your group, the PRINCE trial on intermittent versus continuous docetaxel. That was with some pretty interesting data that one may say came a little late, in the sense we wanted it earlier, but tell us a little bit about it.

KM: Right. It started actually, the trial, in 2005 and that was in a time when there was no abiraterone or enzalutamide around. And just to offer the patients a nicer perspective of having only four cycles of docetaxel and then a break, a holiday, how you call it, and then going in again which is a better perspective than having at least nine, ten, twelve cycles of chemotherapy. So we had a phase II suggesting that, yes, if you go in again after that chemo holiday it works again so we designed a phase III study. I don’t want to go into the details but what’s happened is the study was originally designed for 400 patients, we needed to stop it with 187 because at that time all the new drugs with their registration trials came in as a competition and that took all the patients away. So at the end what the result is that with the primary endpoint being one year survival there’s no difference. So intermittent is non-inferior. There’s no difference, however, also when you look at toxicity, which is not a surprise because the breaks are normally three or four months. And we were not able to sample quality of life data. So at the end if you have a patient today where docetaxel typically is given in second line, third line, whatever, you still can at least consider doing it not in the conventional way, giving it until progression, but rather giving him four cycles no matter what schedule you use - 75, some gave 50 every two weeks or whatever – and then make a break and then go in again.

EE: You’ve definitely sold me, I’m going to do it to some patients. Are you going to do it?

CP: No, no.

EE: No? Why?

CP: Continuous treatment has to be the standard. My priority is to get all five life-prolonging therapies into patients and if you’re going to do that you have to move on from one to another fairly promptly. So if you’re spinning out the docetaxel for over a year with this intermittent treatment I think they’re less likely to get radium, I think they’re less likely to get cabazitaxel. What I think is helpful is that if you’ve got a patient who is on continuous docetaxel and then they want to go off and have a holiday for three weeks, then you can reassure them, OK, having a six week gap is no problem at all.

EE: Very much. Stephane, would you reply?

SO: We made a study on the free interval between last dose of docetaxel and re-challenging with docetaxel, so it’s almost the same kind of study. But for this study patients had to have six cycles of docetaxel and we found that if you had a free interval of more than six months then you can re-challenge a patient and half of those patients do respond again to chemotherapy. So in your study it was four cycles, around four cycles, allowing to have holidays for around the same period of time, around 12-15 weeks. Well, I don’t know now in terms of inducing resistance to docetaxel whether or not what you have done is helpful for the patient but I’m sure that for toxicity it’s OK. So now regarding resistance I don’t know so far. So maybe now since we have tools with CTC and so on to see whether or not you have the beginning of a resistance or due to the pressure that you are doing on your patient maybe you need to stop and maybe to move to another drug and then maybe re-challenge your patient with the same drug later on maybe could be a good strategy. But so far I would prefer still to go for six cycles at least, then to go for a few cycles and then holidays and then re-challenge the patients.

EE: So I would be the last person to have any objection to your argument, however, I know you don’t have quality of life data but I was just listening to the presentation and I realised the fourth cycle is right when most of the toxicity hits my patients and the idea of having that holiday is special in some people is quite alluring and is what you said. You at least feel that you’re not compromising the impact. So I will consider it but, again, we will see. Each one forms their own practice, especially with docetaxel of course. But talking about quality of life there comes the two trials, FIRSTANA and PROSELICA, one a non-inferiority, another a superiority trial. But I walk away with similar messages and I know you’re involved closely with the FIRSTANA and I wanted your thoughts and impressions.

SO: The FIRSTANA trial is a phase III randomised study comparing docetaxel to cabazitaxel, two different types of dosage, in hormone resistant prostate cancer patients. So the primary endpoint was to look at overall survival, it’s a superiority trial and, as you know, the primary endpoint was not reached, the OS is the same, but the OS is quite good because we are reaching around 24-25 months so saying that both drugs have a great effect in terms of efficacy regarding those kinds of patients. So I would say now regarding the toxicity profile, while we have different toxicity profiles maybe docetaxel induces more alopecia, mucositis, neuropathy of course. No change as regards to cabazitaxel which induced more haematological toxicity in the arm of 25mg/m2 compared to 20mg/m2. So I think that maybe in the future we need to look at comorbidity, especially for patients who have neuropathy at first and we should maybe go for caba and if the patient has no comorbidity maybe we should go for docetaxel first. Because we don’t know so far if cabazitaxel… we know that cabazitaxel works after docetaxel but we don’t know so far the contrary. So that is. And the PROSELICA study it was almost the same question regarding the dose of cabazitaxel, so cabazitaxel 20 is as good as cabazitaxel 25, at least at the tolerance level. So the conclusion is maybe that we can use 20, maybe reach to 25 if the patient has not toxicity in order to have the greatest efficacy in terms of PSA response, objective response rate, maybe leading for some patients to a greater PFS and a greater OS.

EE: Tell me something, because I probably didn’t listen well during the description. Were you using necessarily G-CSF or only if needed for the cabazitaxel in FIRSTANA?

SO: G-CSF was not allowed for the first cycle but was allowed later on; it was not recommended. But we have less neutropenia than in the TROPIC trial, nevertheless we still have some febrile neutropenia.

EE: Now, I’m going to ask Chris because he comes from where also NICE and all the regulations that help us understand the financial end of things are probably more organised than in our countries. But I can tell you already, in the US as of tomorrow or in a month, I will have a little bit of difficulty to prescribe first cabazitaxel on the basis of neuropathy, let’s say, for diabetes because we have a trial that was designed as a superiority trial and it did not pan out. So that’s my concern with that presentation. But Chris, you’re more strict. You need to tell us what does FIRSTANA mean for you?

CP: To me the most important thing is comparing the two different doses of cabazitaxel. So they’re practice changing studies because we’ll all switch from 25 to 20mg/m2. In terms of the choice of docetaxel or cabazitaxel, well it confirms our current practice, we’ll carry on using docetaxel first line.

EE: So Kurt, what do you think? What’s going to happen?

KM: Yes, the same thing. I think that is the end of the dream getting cabazitaxel into first line even in patients in the subgroup of patients like diabetic, neuropathy, it’s not approved and it probably will not be given. What will happen is that 20mg will be the future standard of care, I would think that is the situation. Now, with that being said, Eleni, back to your trial. I, as a urologist, can talk about it because it involves surgery of the prostate. So it’s about neoadjuvant treatment and it’s about the effects of different combinations of drugs on the prostate. Tell me about it.

EE: So today we presented a study trying to compare abiraterone plus enzalutamide plus LHRH versus abiraterone plus LHRH in those truly high risk, as you saw; you saw prostate cancers that are localised. This is in a series of studies that we’ve been doing to try to explore what is happening in the tumour microenvironment and try to look to identify that heterogeneity that is obvious to all of us but we cannot yet understand how we should sequence and combine our agents. So it is more of an informative trial and it was based on some data from castrate resistant prostate cancer but also last year’s presentation that showed that the combination of abiraterone plus LHRH in this setting may be of value for at least a subset of these patients. So projecting the data from mCRPC we did the comparison. Now, to make a long story short, on all measures of outcome one can at least say that there’s no difference in the signal. If somebody wants to be strict, because this was two to one randomised in favour of the three drug combination, the data look a little bit better from a readout of residual tumour from the end of abiraterone plus LHRH, raising a lot of eyebrows, a lot of concerns about where we’re going with three drug combinations. But here’s the cautionary statement, apart from the size of the trial because I don’t think that’s a point. The point is that we clearly select for a very high risk group, a group that a year from when we saw them might likely fit the criteria for the CHAARTED trial or within your STAMPEDE trial would be the ones that don’t perform as well, these are 9s, 10s, big tumours. We are trying to focus a lot on those markers that may guide us to select what is the right treatment. This is not about the combo, this is not about using one of the drugs, it’s about essentially maximising androgen signalling or resorting to some other treatment.

KM: The interesting question from me is there have been other studies, like I remember Mary-Ellen Taplin adding avodart or another hormone active agent and they all showed some, what we call, pathologic complete remission in a small subset of patients. But it’s about the concept of if we throw all the drugs we have together at the same time on the tumour, that’s what we don’t do now, now we sequence all the drugs. So is that a concept that would… after now, is that what should be abandoned or is it just we don’t have the right drugs? On the other hand, we have CHAARTED and STAMPEDE showing that the combination of chemo and hormones is quite good. So do we just need more drugs or what’s the point?

EE: We need to be a little bit more careful about eventually being led to a molecular classification of this disease. I think that’s the missing part of the puzzle and you as urologists, the Gleason scoring, however easy it is to use, it’s condemned us to this lack of molecular classification. Like breast cancer we at some point need to all engage in that effort. I think the types of trials that we’ve been conducting are trying to peel back to that. I think this year has helped change of practice, potentially for radiation, is paving the way to using newer technology to diagnose the disease correctly and to spare some patients from some morbidity, I would say. It’s definitely raised a lot of questions regarding the future of sequencing versus combination that we will continue to discuss in these meetings. Of course, hopefully in a few years from now we’ll eventually have reached that point of the reclassification of the disease. Thank you very much for being with us, from all of us.