Prostate cancer updates: Advances in precision medicine and PARP inhibitors

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Published: 2 Oct 2019
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Prof Karim Fizazi, Dr Joaquin Mateo, Dr Shahneen Sandhu and Prof Bertrand Tombal

Prof Karim Fizazi (Institut Gustave Roussy, Paris, France) chairs a session with Dr Joaquin Mateo (Vall d’Hebron Institute of Oncology, Barcelona, Spain), Dr Shahneen Sandhu (Peter MacCallum Cancer, Melbourne, Australia) and Prof Bertrand Tombal (Université catholique de Louvain, Brussels, Belgium) on the key developments in prostate cancer that were presented at ESMO 2019.

Prof Tombal provides a summary of the RADICALS trial which investigated the role of radiation therapy in patients with localised disease or biochemical failure.

The panel then discuss the results from the SPARTAN and STAMPEDE trials and question whether docetaxel and androgen receptor targeted agents should be both used upfront.

Dr Sandhu provides an overview of the PROfound trial, in which patients experienced an increased progression-free survival with olaparib. She also describes the results of this study as a game changer for precision medicine.

The panel conclude by discussing the use of PARP inhibitors in the treatment of prostate cancer and share their experiences with using these agents in the clinic.

This programme has been supported by an unrestricted educational grant from AstraZeneca.

 

KF: Hello, I’m Karim Fizazi, medical oncologist from Gustave Roussy in Villejuif, France. I’m here in Barcelona for the ESMO 2019 meeting which was really exciting with lots of good news for all the patients, especially for men with prostate cancer. So I’m sitting here together with esteemed colleagues from all over the world. I have Shahneen Sandhu from Australia, I have Dr Bertrand Tombal from Belgium and the local guy is Dr Joaguin Mateo from here, Barcelona. So what I propose, you guys, is that we review the main data that we saw here at the congress, maybe starting with localised disease and then continuing the patient journey as the disease progresses. I think it’s fair to say that even if it’s a medical oncologist congress we saw very important data regarding men with localised disease or biochemical failure post-prostatectomy, especially the role of radiation therapy. Bertrand, can you summarise this to us please?

BT: Yes, a very important question. You remember ten years ago three trials that showed that adjuvant radiotherapy is better than no radiotherapy if you’ve got abnormal pathological features that are positive margin, pT3 disease, high Gleason and also, to some extent, seminal vesicle invasion. Never tested the possibility of doing radiotherapy when the PSA is rising - millions of discussions around that, thousands of papers, no consensus. And now we can say next week now we have a consensus. One large trial which is RADICAL, a UK-based trial, randomised patients to immediate adjuvant versus delayed salvage but at very low PSA levels, 0.2, very important. A meta-analysis, pre-planned meta-analysis like we like to do now, with the French GETUG trial and Tasmanian radiotherapy group from Australia and New Zealand. Now the case is clear, it’s clearly delay treatment. It doesn’t seem to have a different effect. Toxicity is the same but the difference is that you save up to 60% of the patients. Okay, we’re treating maybe more aggressive patients so in the end we may save a little bit less radiotherapy on modern patients but still my view is that the case is done. If the patient has an undetectable PSA, no involvement of the lymph node, we should monitor the PSA and intervene rapidly. The question remains should we use hormones or not. It’s still an open discussion but that’s left to everybody’s own perception.

KF: So the new standard of care is salvage radiation therapy. But let’s carry on. Okay, let’s say that all the patients had actually received salvage radiation therapy, PSA is rising, let’s say that we’re deciding to use androgen deprivation therapy and this is also something debated at the moment but many people are doing it, for good or bad. The patient is now progressing on ADT also with normal bone scan and a normal CT scan. So this is an M0 CRPC man. I think we show here the data from an updated analysis in the SPARTAN trial.

SS: Yes, the SPARTAN study, as you highlighted, was for a subset of patients with non-metastatic but castration resistant prostate cancer. They were randomised to apalutamide and ADT versus ADT and placebo. Essentially that study had previously reported out a metastatic free survival benefit. Here at ESMO we saw an update on the overall survival data which certainly with additional follow-up showed an improvement of survival of 25%. It didn’t quite meet the p-value based on the O’Brien-Fleming criteria but nonetheless in the right direction. So we wait for more data as it emerges.

KF: And actually you’re right, we should have more data from the two other trials, PROSPER and ARAMIS.

SS: Correct.

KF: So in, say, one or two years from now we will know whether clearly there’s an overall survival benefit with these drugs.

SS: Yes.

KF: And it’s fair to say that it really goes to the good direction. Good news again for all the patients. Now, another very important setting of the disease is obviously that of de novo metastatic disease. This is responsible for perhaps half of the deaths in all countries besides patients who are relapsing after local treatment. Until, say, five years ago we had nothing but ADT to propose to these gentlemen and the field has changed dramatically. We saw data, again updated data from STAMPEDE, regarding two questions – docetaxel and the role of radiation. Maybe let’s start with the docetaxel question. Can you summarise this for us, please?

JM: Over the last few years we have had tonnes of data of what to do in metastatic hormone naïve prostate cancer beyond ADT. This study was actually an update of the STAMPEDE study of the docetaxel arm, the STAMPEDE study, that showed that previous data is consistent with what they are seeing now. So basically they get a 20% benefit in overall survival if you use docetaxel early, six doses of docetaxel, and then continue with ADT. The super-analysis that they performed was looking into whether they can identify groups that benefit more or less depending on the burden of disease of the patient at the beginning. This is because other studies looking at the same strategy have shown that maybe patients with more metastatic disease benefit the most from docetaxel. Actually in STAMPEDE the docetaxel arm didn’t seem to bother too much about whether patients have more or less burden of disease. I think there is something interesting that needs to be pointed out, and the authors pointed that out, that the population of the docetaxel arm in the STAMPEDE study was different to other studies that have reported in the last few years because it was enriched for patients that had de novo metastatic disease compared to relapsed after several years. Who knows, maybe there is something in the biology of these patients that may explain the different behaviour. However, it’s good that we have so many new options for patients with hormone naïve metastatic prostate cancer but we’re still in a transition period until we understand who should receive what.

KF: Yes, we’re definitely missing a biomarker, that’s really for sure. But what do you think regarding the debate as to whether we should use docetaxel or next generation hormonal agents? Regardless of access, because this is obviously very important in our countries, but let’s say that we have access to both. What do you think we should use for most patients? What are your opinions?

SS: I personally would favour a novel AR targeted agent. You have to take in patients’ preferences, quality of life, a whole range of other things as well. Some people may opt to have six doses of docetaxel and be done with it. But the data around, although there isn’t head to head data comparing novel AR targeted agents versus docetaxel, certainly it is compelling, the data on up front AR targeted agents in this setting. So that would be my perspective but the personal preference of the individual also comes into it.

KF: Very reasonable. Bertrand, what do you think?

BT: At least in my area the economy of it is very important also so clearly what we learn is you need at least one line of both. You need docetaxel and you need one of these two agents. So when we speak to patients you say it’s not about one or the other, it’s about do you want to start with this one or do you want to start with that one. Then you have patients who start with the hormone hoping that they never need hormone therapy; we know that’s never going to happen. Then you have patients who say, ‘I’d better get chemo now.’ We’re trying to understand could we predict the response of the patient? No. But I think one of the problems of this debate is we tend to forget that we should tell the patient, ‘You’re going to need both.’

KF: That’s right. And actually eventually we might use both up front.

BT: At the same time.

KF: Yes, probably not now because we don’t have level one evidence for that. But eventually with the ENZAMET updated analysis, PEACE-1 and ARASENS we’ll see, maybe we will. But let’s focus on these men with castration sensitive metastatic disease. We also saw updated data from STAMPEDE regarding the local treatment with radiation question. What do you think, Bertrand?

BT: Yes, that’s another monster of the Loch Ness that you know that for every urology meeting you had millions of discussions – should we treat patients with positive lymph nodes? Then came PET-PSMA – should we treat patients with oligometastatic? No, the UKS put the bar very high at one stage because they clearly showed that up to three metastases on a bone scan CT scan you got a benefit.

KF: From local treatment.

BT: So all these discussions now have become a little bit obsolete and we should now focus on other discussions which to me are important. When you use radiotherapy should it be a doublet? Do you have to add also abiraterone, enzalutamide, apalutamide? We don’t know. They might get registration in that setting, we don’t know.

KF: Correct.

BT: The second is do we have to treat the oligometastatic deposits. But, as for the guidelines, we should consider that up to three metastases you have to have the primary treated and we should focus on the next questions which are more important.

KF: I agree. Okay, fine. Let’s carry on. Patients progressing with castration resistant disease and they now have a metastasis. So we’ve been using AR-targeting and taxane or docetaxel for a long time now but I think we saw very important data at this congress and perhaps for the first time we are aiming towards precision medicine for patients with HRD or DDR positive cancers with the PROfound trial. Shahneen, can you explain to us?

SS: Yes, this, for me, was one of the highlights of ESMO for men with prostate cancer because it’s a game-changer. We’re starting to personalise treatment for men, as you said. We’re also learning to molecularly stratify the disease, start to take the primary tumour or metastatic deposit, sequence it, identify the genomic aberrations in the HR pathway and other DNA repair pathways that are relevant and then try to be more precise about treating those men. This is where lung cancer and breast cancer and many other cancers have gotten to and we’re just starting to have our foray in this space so it’s very exciting. The data itself is exciting in the sense that it showed an improvement in progression free survival. A significant proportion of patients that were randomised to the novel AR targeted agent were crossed over to receive abiraterone on the back of progressing and there was an improvement in survival.

KF: You mean olaparib?

SS: That’s correct. So the design of the study, essentially, was patients were randomised to olaparib or either abiraterone or enzalutamide depending on what novel AR targeted agent these patients had had before. The vast majority of patients had had prior exposure to chemotherapy in addition to one of these AR targeted agents and we saw good benefit. So that is proof of concept that we can look at a molecular target and use a drug that is effective in this space. I would say given the molecular target my expectation is we should be looking at moving these sorts of drugs earlier as a combination strategy.

KF: Fantastic. Joaquin, the two of you have been working, really, on this field for a while now so I think it’s a reward, actually, for you guys. But what do you think? Were you expecting this degree of efficacy based on the previous experience in the phase II programme with olaparib or with other drugs, with other PARP inhibitors? What do you think? Any surprise, good or bad?

JM: Obviously we’re very happy, we think this is one of the highlights of the congress but obviously I’m biased because, as you two guys, I’ve been heavily involved in this project before. It’s good news. It’s good news for patients. I wouldn’t say a surprise but clearly a reassurance that what has been observed in other studies, and actually on Sunday morning we saw preliminary data on other TOPARP inhibitor trials, that all point towards the same direction - reassuring that this strategy works. So my take home message is that we are bringing a new therapeutic option for some patients with metastatic prostate cancer. But even beyond that that the concept works, that the concept of stratifying the disease into subgroups could help to treat some patients better. It’s not perfect and we have to admit that. We still don’t know all about how to make it right. Clearly the patients with BRCA mutations benefit a lot and we think the others it may be less than clear who is benefitting more, who is benefitting less. Maybe we’ll end up having subgroups within the subgroups and that will make it a bit complex. But overall I think we can be quite confident that this is a strategy that is going to help a significant number of patients.

KF: Very nice. Bertrand, do you think all the societies will have a hard time integrating a test or not? Or, given the magnitude of the benefit, the societies should just adapt and find ways to make those tests in the academic world cheap and easy to get? What do you think?

BT: I think that there is a logistic behind that. So far everybody knew that at some point we would have to embark into actually recommending the test but always waited that we get the result. So now we’ve got the result how do we move forward? It comes with a cost. It comes with a logistic. So we’re going to have to be smart, not repeat mistakes we did. I think every country should really put in place a system to identify the patients who need a standard procedure and provide as fast as possible. But still, I remember when Iressa came on the market for lung cancer, the same company which is making olaparib realised that lung cancer doctors had no idea how to process the tissue and send it for EGFR mutation. So we don’t want to repeat that.

KF: Absolutely. So just great efficacy data with olaparib that we saw in the PROfound trial. What about the toxicity profile of the drug or, even more generally, this family of compounds? Can you explain what we see in the clinic?

SS: As a class of compounds there are a number of PARP inhibitors that are being developed in prostate cancer. So olaparib is further on in the development in terms of phase III data but there are other PARP inhibitors like niraparib and rucaparib and talazoparib. As a class of drugs they tend to have a spectrum of side effects, slightly different half-lives, slightly different PARP trapping abilities. But, broadly speaking, they tend to cause some GI toxicity, so a little bit of nausea, a little bit of early satiety, constipation or a sense of fullness in the stomach and they cause haematological toxicities. Generally speaking, they’re really quite easy to manage and these are drugs, certainly olaparib is a drug that has been around for a very long time, has been used broadly in ovarian cancer and breast cancer, now our turn to have the experience of using olaparib. We need to learn to manage some of these side effects with treatment breaks as well as dose reductions. It is important, there are some manuscripts coming out, there’s a lot of granularity detail about the dose reductions and the treatment breaks.

KF: Joaquin, is that your clinical experience also? Those two main toxicities but not big?

JM: Correct. I think that even also compared to the trials in ovarian cancer we are seeing a bit less GI toxicity and primarily anaemia is the main problem. But it’s something that is relatively easy to manage with dose reductions and interruptions. Not that often you have a patient where you have to definitely stop treatment because of the anaemia. As a new class of drugs in the field it will require some time for us all to get used to it but I think that it’s manageable.

KF: Would you say to all our colleagues that it’s easier to manage as compared to the haematotoxicity we see with chemo, generally? What do you think?

JM: Correct, it’s different. Haematological toxicity from chemotherapy is like a [?? 18:21], right, and you know it will recover. This is something that will kick in slowly but then also with a break normally patients recover by themselves. For me the most relevant factor to predict the risk of anaemia for patients would be the burden of metastatic disease in the bones. So it’s also true that if new trials come and suggest that this drug can be used in earlier stages of the disease or earlier lines of therapy probably it will make it even easier to manage because we will have patients with less burden of bone metastatic disease.

KF: Correct. I think we’ve heard also some other good news here at the congress. Another phase III trial comparing cabazitaxel versus a second AR targeting agent, the CARD trial.  Can you briefly summarise the design and the most important findings?

JM: CARD was an international study randomising patients who have progressed on abiraterone or enzalutamide to receive either cabazitaxel or enzalutamide or abiraterone, whatever they had not received before, to see if the sequence of novel hormonal agents was better or worse than actually changing to chemo. The patients were selected in part based on the time they had had abiraterone or enzalutamide for. So patients who had very long responses were not included in this trial which may have to be taken into account when interpreting the results. But overall the results were very positive and it was shown that after progression on hormonal agents switching to chemo prolongs PFS and also overall survival of these patients. This is something that actually in many places is already happening as a standard of care because in some healthcare systems we don’t even have access to a second NHA. But in some other countries it’s not and I think that this data is very important to set the mark for the guidelines to treat these patients.

KF: I’m with you. Actually we were participating in the trial and for most patients who were candidates we thought that ethically because we had access to cabazitaxel we would not randomise. So we actually put a minority of all the potential patients in the trial just because we thought it was not ethical. Patients where you were wondering who were plus or minus fit for chemo or a long period of time on AR, so maybe a second AR might work, we randomised those ones. But actually I’m glad that we have clarity on this subject.

JM: Of course. And having said so it’s true that trials are always designed for five or six years before and so many things have happened in the field of metastatic prostate cancer but it still is very important that the data says clearly what’s best for these patients.

KF: Absolutely. Shahneen, do you use broadly cabazitaxel in Australia? Is that a confirmation or how does it work?

SS: Yes, my practice is very much like you. I think I would have been challenged to randomise those patients just because there were multiple retrospective series that had emerged that suggested that an AR targeted agent on the back of prior exposure does not make a lot of biological sense. So the bias has always been towards switching to chemotherapy. So that would have been my practice and, yes, we use a lot of cabazitaxel.

KF: Okay, very nice. And a lot of PSMA lutetium now.

SS: Yes, increasingly.

KF: You have an ongoing trial comparing the two.

SS: So actually we have an ongoing trial that has completed recruitment in a very short space of time comparing the next possible promising therapeutic agent for men with prostate cancer, so looking at lutetium PSMA versus cabazitaxel. Hopefully we’ll get a readout of that study in the next year.

KF: Fantastic. Excellent. Congratulations. Any other important message that you would like to briefly discuss regarding this ESMO? Are we done?

BT: I think the main message is that if we have active agents we should not delay their administration.

KF: So earlier is better.

BT: That really, really, really we’ve been doing AR pathway after AR pathway and we should stop unless it’s a very specific end of life situation. We need to move quicker and monitor the patient. If we have an active agent with a known target we should not hesitate.

KF: Okay, thank you. So I guess it’s fair to say that this ESMO shed some light on one, two, three different situations. The post-prostatectomy situation with positive margins we should not use postoperative radiation, we should defer that. Also for the castration sensitive metastatic setting the role of docetaxel which is, for de novo patients at least, true for both high burden and low burden but unfortunately not super-impressive with just 19% reduction in the risk of death. Also, as we just said, for CRPC pre-treated the role of cabazitaxel is getting clearer now. On top of that, and probably most important, we have some new data regarding olaparib which is really new. Again, as we said, for the first time this is personalised medicine and we were dreaming about it for basically a decade. So it’s a very important day for prostate cancer research. Okay, so having said that I would like to thank you, all three, for this really stimulating discussion. And thank you to all of you for listening to