ESMO 2024: Optimising the personalisation of prostate cancer treatment

Prof Alison Birtle – Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK

Dr Pasquale Rescigno – Newcastle University, Newcastle, UK

Prof Gunhild von Amsberg – Martini Clinic, Hamburg, Germany

Dr Alejo Rodríguez-Vida – Hospital del Mar, Barcelona, Spain

AB:   Hello and welcome to this special broadcast from ESMO 2024 on behalf of ecancer. What we’re going to talk about today are two separate aspects – we’re going to talk about a symposium that was held two days ago looking particularly about personalisation of care in GU medicine and we’re going to look at what the panel think are the most effective and interesting highlights of the meeting so far in the prostate field. So I’m really thrilled to welcome such an illustrious faculty today, so could I ask you all, starting from Alejo, could you all introduce yourselves please?

ARV: Hi, hello everyone. My name is Alejo Rodriguez-Vida, I’m a medical oncologist, a consultant, here in Barcelona at Hospital del Mar.

PR:    My name is Pasquale Rescigno, I’m a senior lecturer at Newcastle University, UK.

GVA: Hi, my name is Gunhild von Amsberg, I’m located at the Martini Clinic in Hamburg, Germany and I’m a medical oncologist.

AB:   And I’m Alison Birtle and I’m a consultant clinical oncologist in Preston in the northwest of England. So welcome to you all. Alejo, I’m going to start with you because you shared the platform with me on Friday night. We were lucky enough to be together. Could you tell me what you were talking about on Friday night?

ARV: Yes, thank you for that question. Actually the most important part of the meeting was discussing about metastatic hormone sensitive prostate cancer and intensification therapy for patients. We discussed about the importance of balancing efficacy and quality of life when deciding the best treatment for our patients. As you all know, we now have several treatment options to offer to our patients in the metastatic hormone sensitive prostate cancer. So we can go to a doublet with docetaxel, we can also choose among the different doublets with new hormonal agents such as apalutamide or enzalutamide, and finally we have the third option of a triplet therapy which is obviously combining these two mechanisms of actions. Because we do not have any head-to-head comparisons between these two last options we have to really individualise every patient when we are deciding what is the best treatment for them. It’s important that we remember that prostate cancer is a very heterogeneous disease and we have patients with very different characteristics and we have to look upon those in order to decide what is the best treatment. We know there are many variables that are very important because they have prognostic impact in prostate cancer, such as the volume of disease. We know that patients with high volume of disease have maybe poorer prognoses than patients with low volume disease and, likewise, we know that patients that were diagnosed with de novo metastatic prostate cancer also have more aggressive disease. Therefore we can look upon those variables in order to decide what is the best treatment option. We know that doublets with new hormonal agents such as apalutamide and enzalutamide are active in all the subgroups of patients and therefore it’s a valid option for every patient we see in the clinic. We see that triplet options are also good but we know that the major part of the benefit for the triplet therapy is driven in the subgroup of patients with more aggressive disease such as the de novo high volume disease. Therefore we have to use these variables in order to decide what is the best treatment.

AB:   Yes, the idea of with great power comes great responsibility now that we have a number of options. So you had really two key take-home messages about things that we shouldn’t do now in this disease space.

ARV: Absolutely. There are two things I think we should be avoiding: using ADT alone now we know that ADT alone is a suboptimal treatment of the past; we have several treatment options that have demonstrated that adding something else on top of ADT really makes a massive impact in overall survival, either a doublet with RC or a triplet therapy, and therefore ADT alone should be abandoned also as a suboptimal treatment of the past. On the other hand, we also know that the doublet with docetaxel, as in the CHAARTED trial, is also inferior to triplet and is also probably inferior to doublet with new hormonal agents, as we have seen in several meta-analyses. So in my opinion the backbone therapy for patients with mHSPC should be a doublet with RC and then we have to individualise what patient needs to have this docetaxel added on top of that.

AB:   And it’s awful, really, that we know certainly from the UK audits but also from around the world that often only a third of patients get anything more than ADT in metastatic hormone sensitive prostate cancer. Yet we have all of these drugs, many of which have relatively low levels of toxicity, but we’re just not optimising that patient care. As you say, people who give ADT docetaxel really should, if they’re going to give docetaxel, should only be giving it as part of triplet. That’s really in line with all the guidelines, isn’t it? So, yes, I very much enjoyed your talk on Friday and thank you for summarising that. For the rest of the panel, I’m sorry to bore you with the talk that I did but I had some new data that I was actually really excited about because PSA, we’re all usually fed up of the words PSA. When patients talk about it we go… But actually the data is really interesting. So, first of all, PSA anxiety is a real thing for patients. So there have been two studies that have looked at anxiety levels when patients have… you take out of the equation things like marital status, employment status and other factors that cause anxiety and worry about rising PSA meaning disease recurrence really affects quality of life. The second thing is the [??] as well which is where patients have after chemotherapy if their PSA isn’t falling or post-prostatectomy if their PSA isn’t falling, that again affects their anxiety and their quality of life. There have been validated tools collecting that data. But we can say to patients that actually their level of PSA and their PSA response really matters and we know this because across all studies whether it’s with ADT, an androgen receptor pathway inhibitor, ADT chemotherapy or triplet, those patients with a PSA response get better overall survival. We’ve seen it in TITAN and we’ve seen it in ARCHES in particular when we look at the RPIs. I was really interested in the TITAN data because a PSA of <0.2, better overall survival, better radiographic free survival and also better quality of life data across all validated tools. The other aspect as well was Axel Merseburger’s data – ultra-low PSA, PSA levels of <0.02, those patients did so much better. In fact, you could tell patients that if their PSA at six or seven months was at that level, <0.02, their chance of being alive at five years was 90%. Which is very strong data that we can talk to the patients about tomorrow in the clinic when I’m back. So I thought actually I’m going to take more notice of PSA from now on and my patients, as ever, have been right all along. So I’m going to now move to the highlights of the meeting and I gather that you were really interested in the Decipher data, is that right?

GVA: Yes, and it brings us back to the topic you just brought up because what we really don’t know is who needs which intensification. So we have seen this really very convincing data on the doublet treatment and we ask ourselves to whom do we need to expose to docetaxel? There are actually two trials that focus on prognostic markers in this setting and one is the Decipher test that has been carried out in the STAMPEDE trial and the other is immunostaining in the PEACE-1 trial. So maybe I’ll start with the PEACE-1 because it’s a little bit easier to understand. Here immunostaining was performed on the primary biopsy and looked actually for adenocarcinoma markers and neuroendocrine markers as well as cell cycle markers. They came up with five groups, one with a luminal high, one with a luminal weak, double negative, an amphicrine group and a neuroendocrine group. What the authors actually saw was that the patients with a neuroendocrine marker had a really worse progression free survival compared to the rest of the group, meaning that those patients may be the ones that actually need more. But actually this wasn’t predictive for the efficacy of abiraterone in this case. Maybe we need to add something new in this context. The other data was on the Decipher test that’s a 22-gene mRNA test that has actually been more performed in the localised disease so far. Within the STAMPEDE trial they looked at the docetaxel-treated patients and compared them to the control group with ADT. What they found was that the ones with the high Decipher that actually have the worst prognosis in the localised setting did react better to docetaxel than the ones with a low Decipher. That was true especially for the low volume patients; the ones with a high Decipher were the ones that actually benefitted better than the ones with the low Decipher within this trial. So that raises our hopes that we may be able to introduce new biomarker testing within the hormone sensitive setting.

AB:   That’s fascinating in itself, isn’t it, because you might expect it to be… that’s slightly counterintuitive data in terms of the volume. So that’s something where if we could just say to the patient in front of you, ‘This is your chance of response with this treatment,’ how much better is that in terms of balancing efficacy and toxicity when you can quantify that data for the patient. Thank you very much for that, I’m going to go back and have a look at that presentation later on. Pasquale, what was your favourite so far?

PR:    Talking about personalised medicine, now we know that one of the emerging… well, it’s not emerging anymore, really, but one of the established biomarkers in prostate cancer are BRCA1 and BRCA2 mutations. That’s because we have PARP inhibitors that are available in the metastatic CRPC setting in first line or second line or first line in combination with hormonal treatment. There was a beautiful educational meeting with Gerhardt Attard, Elena Castro, Silke Gillessen and they faced again the topic on how we can define and how can we identify BRCA1 and BRCA2 mutation in prostate cancer. There is a great debate about using liquid biopsies versus tissue biopsy, so sequencing from tissue, sequencing from blood, or germline – identifying these alterations in the germline. There was also an interesting abstract that was presented this year about some analysis on the MAGNITUDE trial that was testing the combination of niraparib and abiraterone in the first-line metastatic CRPC setting. So what I gathered from all this data that were presented this year, that were presented also in the last few years in ESMO and ASCO, is that definitely we should not use just germline testing because we miss the somatic mutation and that’s extremely important. Now, the debate that was discussed this year in the educational session and in the abstract that I’ve seen is can we use the liquid biopsy and sequencing from blood rather than rebiopsy the patient or getting a biopsy using an old biopsy for the prostate cancer patient. I don’t think that there is extreme certainty or a clarification. What we know is that if we use old samples, and that’s data from the PROfound, if you use old samples, older than a year or three years, the chance that we get good DNA and having sequencing report might be low. More than 30% of the time the sequencing will fail. So can we use the sequencing for blood? The concordance, and this is where the data presented in the abstract on MAGNITUDE as well, it’s quite high. So we are talking about around 80% concordance with a high positive predictive value but not that high, it’s around 70-80%, but really high negative predictive value. What the abstract on the MAGNITUDE showed quite nicely is that… they split the patients on positive on blood, positive on tissue sequencing and negative on blood but positive on tissue sequencing for the BRCA1 and BRCA2 mutation. What they saw is that the higher radiological progression free survival that was not even reached was for the patients on combination, so that received a PARP inhibitor, that were identified as BRCA mutant on tissue for which the blood was negative. I find this interesting because what this data would suggest is that there is a high concordance between the two methods and that’s for the point mutations, so missense mutation, but what you miss testing just of blood are the loss of BRCA2 because it’s difficult to identify copy number, especially because the tumour fraction in liquid biopsy might not be as high. These are the patients that derive most benefit from a PARP inhibitor. So if we don’t want to miss these patients that are around 20% of the BRCA mutant patients we should test, at least based on what we have now, we should use tissue biopsy.

AB:   Absolutely. And tissue is still the gold standard and that’s why we should test as early as possible, really, because we don’t want that tissue to degrade. Thank you so much. Alejo, back to you. I gather that you liked the PEACE-3 data?

ARV: I do. I think that the abstract on PEACE-3 is probably, in my opinion, the most important abstract in prostate cancer in ESMO this year. It was, as you all know, at the Presidential plenary session and the results were presented yesterday. PEACE-3 is a big randomised phase III trial, as you know, undertaken by the EORTC that included patients with metastatic CRPC at the first line of treatment in the CRPC setting although patients were allowed to have received prior docetaxel in the hormone sensitive setting and abiraterone. The trial randomised over 400 patients, more or less, to the control arm of enzalutamide alone or the experimental arm of enzalutamide plus six cycles of radium-223. At the beginning of the trial the administration of a bone protecting agent was just as per the investigating criteria but after more or less one third of the patients had been included there was an amendment based on the ERA-223 trial where, you would remember, there was an increased risk of bone fractures in the combination arm. There was an amendment that made it mandatory to give either denosumab or bisphosphonates to patients in order to prevent bone fractures. The results, the study is a positive trial, luckily, in the primary endpoint which is radiographic progression free survival. The impact in rPFS is statistically significant and clinically meaningful. Luckily the secondary endpoint of overall survival is also positive, although we still have to wait until the final and more mature data are presented. Interestingly, I think that’s the first important message is it’s the first trial of a combination of a hormonal agent with radium-223 that is positive in terms of efficacy compared to the ERA-223 trial. The other message that I think is very important is bone health. Because we have been doing a poor job generally speaking with preventing bone complications. What we saw in the PEACE-3 trial is that before the amendment was done there was a very high risk of bone fractures in all the treatment arms, not only in the enzalutamide monotherapy arm but also in the combination arm it was even more so. Once the amendment was done the risk of fracture was almost zero. So this points out that it’s really, really important to really give a bone protecting agent in this setting, which actually it’s already standard of care, we already know that bone protecting agents should be given to all CRPC patients with bone metastases. But obviously we weren’t doing, as I was saying, a very good job in that regard because most patients were not receiving those agents. Therefore I think it really indicates the importance of bone health in this scenario. Maybe the sad bit of this trial, as Dr Fizazi pointed out, is that maybe the trial is arriving a little bit too late where the scenario has moved, has changed, since now we are treating patients with new hormonal agents such as enzalutamide or apalutamide in the hormone sensitive setting. So very few patients will reach the CRPC setting without having had any of these drugs. Therefore the scenario is infrequent and all of us will probably not be able to use this combination much because the standard of care has changed.

AB:   Thank you. So three really important abstracts and thank you for sharing those today. Obviously much more to come from ESMO 2024 but here on day 3 of the congress these are the ones that we and my panel found the most exciting. So all that’s left for me to do is to thank you all very much for sharing those thoughts today and to thank you for watching.