Cabazitaxel is a New Standard of Care for Third Line Metastatic Prostate Cancer - Bertrand Tombal

Bertrand Tombal presents the recently published results from the CARD trial: "CARD: A randomized phase 4 trial comparing cabazitaxel and an androgen receptor (AR)-targeted agent in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and an alternative AR-targeted agent".  Enzalutamide in Metastatic Prostate Cancer (mCRPC) is highly heterogeneous with the coexistence of AR-dependent and AR-independent tumor clones. AR-targeted agents (abiraterone acetate, enzalutamide) and taxanes (docetaxel (DOC), cabazitaxel - specifically developed to overcome DOC resistance) are the backbone of mCRPC therapy. The rising concern of cross-resistance between mCRPC therapies and the evidence that some patients may not respond to all available drugs have increased the complexity of managing mCRPC. This Phase 4 trial was designed to help define the optimal sequence of therapies to optimize patient outcomes involving 79 sites in 12 European countries.   Ronald de Wit, MD, Ph.D., of Erasmus Medical Center in Rotterdam, the Netherlands presented the results of the CARD trial at the recent 2019 European Society for Medical Oncology (ESMO) annual meeting in Barcelona, Spain. The results were simultaneously published in the New England Journal of Medicine.  The conclusions of the trial indicate that switching to cabazitaxel instead of another androgen receptor-signaling inhibitor improved survival in men with metastatic castration-resistant prostate cancer (CRPC) who progressed on docetaxel and one of the newer androgen-blocking agents. 

Biography:

Bertrand Tombal, MD, Ph.D., Professor and Chair, Université Catholique de Louvain, Brussels, Belgium

Thomas Keane, MBBCh, FRCSI, FACS, Professor and Chairman of the Department of Urology at the Medical University of South Carolina, Charleston, South Carolina. He holds a U.S. patent for BNCT in prostate cancer and sphingolipid derivatives and their use.
 
 

Read the Full Video Transcript

Thomas Keane: Hello, everybody. This is Thom Keane coming to you from UroToday in Charleston, South Carolina. And there is one that I would like to really highlight, which was actually recently published in the New England Journal of Medicine and it was by a group of European urologists. It was an extremely interesting presentation entitled "Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer". And as you can see from the slide that's up now, it's a randomized open-label study of cabazitaxel versus abiraterone or enzalutamide and metastatic castrate-resistant prostate cancer. Professor Tombal, please take us away.

Bertrand Tombal: Yes, thank you, Tom. So it's a pleasure. I'm a big fan of UroToday, so it was an honor and a pleasure of inviting me. So just a little bit of background. Cabazitaxel is a chemotherapy that is being developed on docetaxel-resistant prostate cancer cells. So it's a second-line taxane chemotherapy. And actually we had the idea of this trial a few years ago when we realized that there were absolutely no sequencing trials to help a urologist and medical oncologist in the field. To set up the scene, that would be the kind of patient we are speaking about it's the patient, well actually, I came with metastatic prostate cancer. He received degarelix and six cycles of docetaxel. He had a good response for a while but then started rising again and you know, we did like, I guess everybody's doing now in the US.

We started enzalutamide with that patient, once again, he had a nice response and then progressed quite rapidly with a rapid rise in PSA, alkaline phosphatase on enzalutamide and the development of a bone metastasis. And this is a kind of a metastatic CRPC patient we have today, meaning that we giving enzalutamide and abiraterone earlier and earlier. It's kind of the new maximum androgen blockade and we have absolutely no idea what to do with the patients that are progressing on enzalutamide and basically you have three choices. You could add a second-line of abiraterone on the top of enzalutamide. To replace enzalutamide, You could give radium-223 and then cabazitaxel. And what we notice is that probably because it's a chemotherapy, it's actually usually the third choice and that if you look at data around the globe, most of urologists or medical oncologists would go for a second-line of androgen receptor-targeted agent like we're going to see in the presentation.

Although we know that there is a lot of cost resistance and that basically if you give abiraterone after enzalutamide it doesn't work well. There will be many very important studies in published. There was the cabazitaxel trial, but in the Lancet Oncology, a few weeks from now we're going to have a second trial by the group of [inaudible 00:03:15] who is confirming that whether you use abi after enza, or enza after abi, there is no good response? That observation here is crucial for understanding the study is that we already noticed a few years ago that when patients progress on docetaxel or abiraterone they still possess a high sensitivity to cabazitaxel. Not necessarily to docetaxel but to cabazitaxel. So if you have received docetaxel and a novel-AR targeted agent, still the likelihood to respond to cabazitaxel is very high. And this is because it has a perform different mode of action than docetaxel. And it's very active in what we call the aggressive variant.

So with a group of European investigators, we kind of convinced Sanofi to embark into that trial, which we believe was extremely important for the community. So basically we selected patients with metastatic castration-resistant prostate cancer who had received docetaxel and one line of abiraterone or enzalutamide. Docetaxel could have been given first or second in the hormone-naïve or in the hormone-resistant setting, but the progression on the androgen receptor-targeted agent should have happened within 12 months.

So we were selecting that kind of non-responder drifter that we only know when you give the enzalutamide they progress rapidly. So they were randomized cabazitaxel 25 milligrams per square meter. This is still in Europe, the approved dose. There were a lot of discussion 20/25, versus abiraterone or enzalutamide depending of what they had received before. The idea was to cross over to the other agent. Stratification factor were very basic and the primary endpoint was radiographic progression-free survival, but also very important, the number one key thing and that the endpoint was overall survival. So these are the key inclusion criteria. Once again to repeat, we are speaking about patient progressing within 12 months of starting the prior alternative ARTA. 

So I'm going to leave you the statistical considerations. Basically it was an almost 240 patient trial, and this is actually, to be honest, the first randomized trial in third-line setting, very important. There's not been many trials in that setting. So this is the patient characteristic, typical 70 years old prostate cancer patient with fair number above 75 this is very important because we often hear that these guys come get chemotherapy, which is absolutely not true. 16 and 19% had visceral metastasis and very important as you can see here, most patients actually progressed on pain and hydrographic progression. So we are speaking about rapidly progressing against this patient.

It was a mix of abiraterone, enzalutamide. There was a mixed of having received docetaxel first or not. So that's a typical population for which we raised the question. These are the biological data at randomization. There is no big imbalance in PSA hemoglobin, alkaline phosphatase, LDH and NLR. So that's very interesting. As you can see, the median duration of treatment was almost double in cabazitaxel treatment than in abi or enza confirming previous data that actually if you give a hormone after a hormone, it's usually for a short time. As you see many patients had dose reduction, not only with cabazitaxel, 20 people, but even more with abi or enza, something that is actually happening in a quite very advanced population. And if you look at the reason for treatment the continuation, you see that it's mostly a disease progression, so very important. Once again it was 20 people for adverse event in cabazitaxel, which is in line with the previous treatment. And disease progression was clearly the number one reason to stop the treatment and this is actually what we all expected.

This is the primary endpoint of radiographic PFS and as you see even in third-line, the hazard ratio is quite impressive with the value of all points 54 so a 46% reduction with a median radiographic PFS on abi/enza, which is very short, which is been actually shown in other trial as well with an eight month PFS in cabazitaxel. We tried to look at various groups to see whether there was a trend to one specific group. This is a relatively short study. It's you know, small study, 255 patients. So this is analysis some small number but clearly you see no patient for which the difference is dramatically different from the intent to treat analysis. Especially in regard to giving you docetaxel first or not. Why is it important? Because there's been that discussion that actually if you give docetaxel after abiraterone or enzalutamide, you could resensitize the androgen receptor so that the problem of cost resistance was less, we don't show that. I mean, why does docetaxel comes first or second, we still see a benefit in favor of cabazitaxel.

This is actually even more important and more enthusiastic is that we see a major overall survival benefit. The overall survival is 13.6 versus months with a hazard ratio of 0.64. So we believe that is clearly a game-changing, practice-changing trial that's really confirming that when your patient is progressing on abi or enza, especially those quick progressions within one year, clearly it's a matter of prolonging survival to switch over to cabazitaxel. This is the radiologic plus symptomatic progression of death from any cause, so it's a slightly different definition of progression-free survival and you see once again the same benefit and that the biggest difference is driven essentially by pain. Once again, if you look in term of PSA response, objective response and pain response, this is absolutely clear and statistically significant and always in favor of cabazitaxel.

Interestingly enough, this is something we tend to forget, but that symptomatic skeletal event or something very important and a very important comorbidity in this patient at that stage of the disease and you see that we see exactly the same trend. Following the paper by the group of Kim Chi, there has been discussion around the fact that actually the sequence, abiraterone after enzalutamide performed slightly better than the sequence enzalutamide after abiraterone. And so it was important for us to show that whether you have started with enza or abi, you've got the same benefit. So there is no sequence better than the other one. It's clearly enza, docetaxel, rapid PSA progression that sequence.

This slide is very important, why? Because what it shows is that actually 33% of the patients have received cabazitaxel after being randomised to abi or enza. So clearly highlighting that people recognize the value, adding some crossover which actually do not impair the OS result. So clearly, it is not about the efficacy of cabazitaxel that it's really about the timing of cabazitaxel that starting it at the third time is really what has to be done in these aggressive patients. So that's a very important piece of information. Safety is in line with what we know from the drug. Once again, very interestingly if you stick to definition in term of definition of greatly adverse events or serious adverse event, it's always interesting to notice that in terms of amount of adverse event, percentage of adverse event, it is the same. You understand however very easily that we are not speaking about the same adverse event and there are a little bit more adverse events leading to treatment discontinuation. That is, however very interesting. They were more adverse even leading to death in the cabazitaxel arm than in the abi and enza. It was 5.6 to 11.3.

To be honest however, the adjudication of the cause of death is always something extremely complicated to do. If you look at what are the cause of death due to adverse event, you say that you have a mixed of everything and it's always very difficult to say whether these deaths are really coming from the toxicity of the drug or from the progression of the disease. And you see that clearly that has been a confounding factor in the attribution of risk of that in the favor of abiraterone or enzalutamide we need to keep that in mind. As for the adverse event definition, clearly infection, febrile neutropenia are quite low, but GCSF was used prophylactically in every patient. That is very important. It's not the case in every country, but the side effect profile is in line with what we know.

So in conclusion, this is seen in the first randomized compound trial in the third-line setting in the very combination we see today who has been receiving enzalutamide or abiraterone at an early stage, have been receiving chemotherapy as by mean of docetaxel and are no progressing. So the trial methods objective, primary objective, it more than double geographic progression versus abi or enza. It could increase the risk of death by 36% versus abi or enzalutamide on the secondary endpoint, always favor cabazitaxel PSA, PFS, tumor and pain response and time to SSE. The rPFS with cabazitaxel remained superior regardless of the abiraterone and the sequence. And clearly that is supporting the use of cabazitaxel over a second line of ACTA in this setting and as mentioned by Thom, kindly due for a more detailed, the paper is available in the New England Journal of Medicine. Thank you very much for your attention.

Thomas Keane: That was superb, Bertrand. And there's a couple of questions that I would like to ask you. Number one, what's your feeling on the analysis for the ARV seven mutation on the genomic tests that are currently available? Do you know when they're going to play a role or not?

Bertrand Tombal: We have collected a cell. We have collected that information for each patient. We had a partnership with Epic for this, so this is presently analyzed and this will come for publication very rapidly.

Thomas Keane: Okay. Great. That-

Bertrand Tombal: We have collected the data because we had, as you know, Johann de Bono in the steering committee. He was in charge of the PR component and for us it was really... We really should thank Sanofi, which really has invested massively in the TR component and made that... is making that data available for academic research. So, but that takes time. It depended on the primary endpoint, but that will be available in a few months.

Thomas Keane: Great. Second question, there may be a temptation for people to move cabazitaxel earlier in the sequence of treatment. What's your view of that?

Bertrand Tombal: So that one of a very important message is to keep that in line of the different studies. So there is the... So if you think about cabazitaxel, cabazitaxel was... If you look at in vitro, it's effective in docetaxel resistant cells.

If your patient has not received docetaxel yet, there is no difference between docetaxel and cabazitaxel. That is the beauty of that drug. So they can move it early, but it should not replace docetaxel. Still, the standard first-line is docetaxel. We've got the first FIRSTANA trial that showed basically, no difference between docetaxel and cabazitaxel when it's used first-line.

So today, the standard sequence is still docetaxel and one of the AR pathway inhibitor. Now whether you use... And we've got newly diagnosed patients, now whether you use enza, apa, darolutamide and docetaxel, the sequence at that stage seems to have very limited difference. But cabazitaxel still maybe use earlier but still, it is a third-line drug, after one of these two agents.

Now, there is a caveat and the limitation to that, these are the patients who are progressing on docetaxel. So, if you decide to give docetaxel to a patient with newly diagnosed high volume cancer, and the patient is progressing very rapidly on docetaxel that we know already, that they have a poor response rate towards ACTA and should go to cabazitaxel. But except these very aggressive phenotype, cabazitaxel is a third-line drug.

Thomas Keane: Okay. That's very clear. And then again, my feeling from reading the literature is that a lot of physicians now are considering patients who have relatively low volume metastatic prostate cancer as being more suitable to try abi or enza as opposed to they're reserving docetaxel for the higher volume patients. What do you think is that strategy?

Bertrand Tombal: I must say I share their view on this. I think that as a urologist like you, we know that actually maximum androgen blockade works very well in low volume patient. I remember the Japanese trial when we were still speaking about stage D and stage C prostate cancer showing that the benefit in overall survival was mostly seen in the stage C. That's going to be the same in combination with radiotherapy. So I think that clearly and on top of that, except for the STAMPEDE data, we still have conflicting data on the whole of docetaxel in low volume and adjuvant to radiotherapy. So I fully support that approach to say, okay, low volume oligometastatic prostate cancer high risk treated with radiotherapy. We are going to move very rapidly to maximum androgen blockade like we did 20 years ago. But using a more modern drug.

Now, a consequence of that is that we are going to have to be very attentive when these patients progress because when they progress, they progress quite rapidly. So we're going to have to be prompt to start a second-line treatment. That's clearly going to have to be chemotherapy except for the precision drug [inaudible 00:20:17], that we come along the way, but we'll be restricted to very few patients, but we have to be very quick on starting docetaxel when these patients progress and then sort out who's going to need cabazitaxel. And that's going to be the kind of a rapid, drifter progression versus who may benefit from radium and things we're going to get soon drug by PSMA lutetium and things like that. But I think that I fully support the fact that many patients will receive maximum androgen blockade to start with if we have a kind of corporate responsibility that we follow the patient well and as soon as he's progressed, we give the chemotherapy at that time. That I think is going to be the key to have these patients living longer.

Thomas Keane: You're to be congratulated for a wonderful piece of work. And thank you very much for presenting it here.

Bertrand Tombal: Thank you.