Treatment sequencing for patients with mCRPC

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Published: 17 Feb 2023
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Prof Axel Merseburger and Prof Stéphane Oudard

Prof Axel Merseburger (University Hospital Schleswig-Holstein, Lübeck, Germany) and Prof Stéphane Oudard (Georges Pompidou Hospital, Paris, France) discuss sequencing for patients with mCRPC.

Prof Oudard talks about the post-hoc analysis of the SPARTAN phase III trial. This study investigated the efficacy of subsequent treatments in patients who progressed to mCRPC following treatment with apalutamide for nonmetastatic castration-resistant prostate cancer (nmCRPC).

Prof Merseburger then mentions the CABASTY trial and discusses the clinical implications of the results from this trial with Prof Oudard. This trial was important because it investigated the optimum dosage for cabazitaxel with lesser toxicity than before.

They also discuss testing HRR mutations in a metastatic setting and the treatment options for mCRPC when it progresses from nmCRPC.

Efficacy of subsequent treatments in patients who progressed to mCRPC following treatment with apalutamide for nmCRPC: A posthoc analysis of the SPARTAN phase III trial
Testing for HRR mutations
Biology and prgonosis of classical mCRPC versus derived mCRPC
Sequence of therapies in practice for mCRPC
Immunotherapy for mCRPC
Olaparib as a maintenance therapy post-taxane for patients having a BRCA1/2 mutation
This programme is supported by an unrestricted educational grant from Janssen.

ASCO GU 2023

Treatment sequencing for patients with mCRPC

Prof Axel Merseburger – University Hospital Schleswig-Holstein, Lübeck, Germany

Prof Stéphane Oudard – Georges Pompidou Hospital, Paris, France

AM:   Dear colleagues, welcome to this ecancer edition from the ASCO GU conference in beautiful San Francisco. I’m sitting here with Stéphane Oudard from also beautiful France, welcome. Welcome, nice meeting you again.

SO:   Yes, hello Axel.

AM:   So I’ve learned a lot since we met last time in Paris at the ESMO conference where you presented the CABASTY data, but we will come to that. This time I learned again a lot from you presenting. I think this was a post hoc analysis from the SPARTAN trial, if I remember correctly. This was apalutamide in non-metastatic CRPC and the question was what happens after progression to mCRPC. So can you tell us about the presentation you have here at ASCO GU?

SO:   Yes, of course. The meaning of this study was to see for those patients becoming mCRPC what to do next after apalutamide. We took all the patients who progressed on apalutamide in this study, around more than 300 patients, and we wanted to see what was a choice of clinicians in daily practice. The main choice was abiraterone because the drug was given by Janssen and also clinicians could give either chemotherapy, enzalutamide or other drugs as well. We found that, in fact, in terms of rPFS and OS the data were comparable between the drugs. Saying that, this stage of the disease was much earlier on compared to patients having metastatic CRPC at a later stage and you can go from one hormonal therapy, apalutamide, to abiraterone, so you change your class of drugs from a drug inhibiting the AR pathway to a drug below the level of testosterone. Abiraterone seems to work as well as chemotherapy. So it’s good news for clinicians, reassuring the clinician that they can use, at this stage again, either hormonal therapy or chemotherapy.

AM:   That’s a very strong message and a very important question we ask each other in everyday clinical life. We’ve learned from mHSPC studies like the TITAN trial that the sequence apalutamide, enzalutamide and so on doesn’t really make sense. So after one NHD it’s not really guideline practice to give another NHD. But here in non-metastatic CRPC you have shown that either docetaxel, mode of action change, or apalutamide followed by abiraterone is possible, is that correct?

SO:   Yes, that’s true. Maybe at this stage of the disease the underlying mechanisms of resistance are maybe less active, less aggressive, so maybe leaving a time to go for another hormonal therapy which is maybe not the case, as you say, in the TITAN trial where maybe after apalutamide in the hormone sensitive metastatic situation, going to the hormone resistant situation, maybe it’s not fair to go for another hormonal therapy.

AM:   But surely there is also the theory, and I remember ESMO 2019 there was a poster by Kim Chi showing that apalutamide treated patients had less AR alterations so you could give potentially apalutamide afterwards. So a lot going on in the mCRPC situation, we have learned. We have touched on the PARP inhibitors a lot here at ecancer already and a lot of discussion on whether or not we should test or not, the next step. So what do you do in France in your centre of expertise? Do you still test HRR mutations or do you go right into the combination approved now?

SO:   We do test our patients in the metastatic setting because we know that at this stage of the disease those patients are not curable by any treatment so far. So we do it as soon as possible at the metastatic stage, especially for aggressive – patients having metastatic hormone sensitive cancer – because we know for those patients having a Gleason score of 8 or 10, whatever, that they are going to have a short response to first therapy even though you go for intensive treatment with ADT plus hormonal therapy or the triplet. We know that if you do that quite early on you have better results regarding the tumour tissue and so that’s why we do it quite rapidly.

AM:   And do you think the mCRPC out of your trial you presented here, deriving out of non-metastatic CRPC, is it the same prognosis or the same disease than the classical mCRPC after ADT failure in metastatic disease or after doublet or triplet therapy when it comes to mCRPC? Is this the same or is it a different biology, those non-metastatic CRPC coming towards the metastatic CRPC?

SO:   I think it’s really different. We are speaking from patients having de novo metastatic disease to patients having a localised disease and then moving into rising PSA and metastatic stage. So it’s different patient populations, maybe less aggressive. So that’s why maybe in the SPARTAN study we could go from one hormonal therapy, apalutamide, to abiraterone which is maybe not the case, as you say, in the TITAN, or whatever, study. So I think based on that we need to have a specific strategy in order of sequencing treatment for our patients.

AM:   I understand. Having you here as one of the world experts in mCRPC, what’s your sequence in your practice in Paris? For example, you have a doublet like, let’s say apalutamide or enzalutamide and ADT and it comes to progression, or you even have a triplet with abiraterone or darolutamide and ADT and chemotherapy and then you have the situation of mCRPC. So what’s your next sequence? Does it depend on patient factors, does it depend on the tumour aggressiveness or Gleason? What’s your recipe on the next step?

SO:   We had a very nice presentation from Silke yesterday about the different situations according to monotherapy, doublet, triplet. For instance, if you have a patient having ADT plus hormonal therapy plus chemotherapy you don’t have so many choices later on so you need to check for HRR mutation to see if he can go for PARP inhibitor, for instance. You can go also for cabazitaxel, and we will speak about that later on, and also you could choose lutetium-PSMA.

AM:   What’s the role in France with lutetium, is it approved and you use it on a daily basis or is nuclear medicine offered?

SO:   It’s only in clinical trials that we can do it and we don’t have access so far to radium-223.

AM:   Okay. Yes, as you said, Silke Gillessen really had a superb presentation on this topic, mCRPC, and we used to say first line, second line, third line. I think this has changed, we had maybe pre-treated patients with docetaxel, pre-treated with NHT. So there’s a lot of mixing around and you really need to identify the patients that are at risk of dying and then treatment intensification really makes sense on the one side in mHSPC but surely also in mCRPC. There was always this discussion on what’s better, lutetium or cabazitaxel, post-docetaxel. I always thought it’s good when looking at the VISION trial and the TheraP trial you probably better tend towards lutetium. But then you showed us the CABASTY trial at ESMO and let me just interview you on this CABASTY trial because I think it’s very important and it cues in very well in the ASCO GU data we saw yesterday here in San Francisco.

SO:   Yes, thank you. The CABASTY trial was to evaluate different schedules of cabazitaxel because you know cabazitaxel at the standard regime of 25mg/m2 is associated with a high rate of neutropenia and neutropenia complications so far. A lot of clinicians don’t want to go for cabazitaxel due to the side effects and we are facing an elderly patient population. So we need to adapt the schedule and the dose for cabazitaxel. So we tried to compare the standard regime to 16mg/m2 every two weeks with GCSF for those patients. We found out that we can really decrease the rate of neutropenia and neutropenia complications for those patients. In other words it means that you have a safe therapy for those patients, even for a very elderly patient population up to 80 years or 85 years. It’s associated with the same outcome in terms of PSA response or PFS and OS. So I would say that it’s a new drug for our patients because it’s safe, you need to give GCSF, you need, of course, to follow those patients but you can be reassured about the toxicity and the tolerability of the drug as compared to hormonal therapy.

AM:   And, as you said, this was also one of the take home messages of the CABASTY trial – it’s also safe in elderly men with mCRPC, older than 65. I learned a lot so it was important and I think it was a game changer. A lot of people took it back to their countries to adopt this to their [SOP]. So thanks for giving us this trial; can we expect more readout out of this trial for ASCO or is this finished or will there be more from it?

SO:   No, we are going to look at quality of life and we are going to submit for ESMO. Also we presented today some data on translational research about monocyte MDSC which seems to be correlated with outcome for those patients. So we need to find out for taxanes a predictive factor of efficacy. So we are on the way, maybe, to find something at the immunological level, MDSC level, which could predict the efficacy of cabazitaxel.

AM:   So, lastly, I would like to interview you on the topic of IO therapy. We know it’s a big development in bladder cancer, we cannot think without pembrolizumab, nivolumab in the adjuvant… it’s really integrated into the treatment in advanced metastatic urothelial cancer. So when looking at this cold tumour, like prostate cancer, especially mCRPC, we saw a presentation by Dan Petrylak today, some more on IO therapy. So what’s your take home of those multiple abstracts and multiple large trials where I know you’ve been involved also? What’s the future? Is it the future? Are we going to see… is it positive?

SO:   I’m not sure that in prostate cancer it will go through and we will have some interesting data. So far we have the negative study from Petrylak on 1,000 patients looking at pembrolizumab plus docetaxel. So the combination is not more toxic but it’s not more efficient for the patients.

AM:   Did you expect this?

SO:   No, I could for sure say that the study will be negative for those patients because we did not select the right patients for this study. We should have looked at the patients having MSI, positive MSI, which, in fact, corresponds to 1% of the patient population.

AM:   Just a small patient population, yes.

SO:   A very small patient population. And we had also some study on nivolumab plus ipilimumab compared to docetaxel and, in fact, it is really toxic for those patients. If you don’t go for a specific patient population, which is maybe tiny in prostate cancer, you won’t have great results.

AM:   And the results we’ve seen here in San Francisco at this year’s ASCO GU weren’t really convincing and not really game changing. So I’m not quite sure if we will have to continue the IO story in prostate cancer. Probably not, probably with weighting, balancing, the toxicity and also the price and the efficacy, which we haven’t seen any good results. But these were some of the take home messages from this ASCO GU on this topic of mCRPC. Is there anything I’ve missed when you fly back to Paris tomorrow, what you tell your colleagues on the topic of mCRPC? Some very exciting abstracts, I still have Silke’s presentation I will download which is very good educational-wise.

SO:   I listened to an interesting study looking at olaparib as a maintenance therapy post-taxane for those patients having a BRCA1 or 2 mutation.

AM:   They had HRR positive, as I remember.

SO:   Yes, which was around maybe 20% of the patients.

AM:   Yes.

SO:   And they found out that they can maybe delay the efficacy of chemotherapy by using olaparib alone in monotherapy. So I think it could be interesting for those patients having this target to maintain as long as we can quality of life without symptoms with a PARP inhibitor. So it could be a good way but now we are moving to a PARP inhibitor with hormonal therapy so I don’t know what is going on later on.

AM:   So in mCRPC we have lutetium, we have ADT as backbone therapy, we have chemotherapy – docetaxel, cabazitaxel, we have the PARPs, we have the combinations, so really, really a lot. Hopefully we have good guidance on what’s best for our patients. But personally I like changing the mode of action every time it comes to a progression. So exciting data here at ASCO GU. Professor Oudard, Stéphane, it was a pleasure to have you here, a pleasure to educate us on your expertise and what we have seen at ASCO GU. Thank you, thank you and have safe travel back to Paris.

SO:   Thank you Axel.

AM:   Thank you.