Where do we stand with mCRPC?
Dr Neal Shore – Carolina Urologic Research Center, Myrtle Beach, USA
Prof Neeraj Agarwal – University of Utah, Utah, United States
Dr Pasquale Rescigno – Istituto di Candiolo IRCCS (Candiolo Cancer Institute), Candiolo, Italy
Dr Friederike Schlurmann – Centre Hospitalier Universitaire de Brest, France
NS: Hi everybody, I’m Neal Shore, today’s moderator. I’m a uro-oncologist from South Carolina in the US. Really pleased to have a wonderful faculty today and this educational programme by ecancer has organised this. We’re here at ESMO 2023 in Madrid, Spain. We’re going to review some really important work that’s come out of not only ESMO here in Madrid but also cutting edge work that was reviewed at ASCO 2023 and ASCO GU. I am here with Pasquale Rescigno from Newcastle, UK, Neeraj Agarwal from Salt Lake City, Utah, and Friederike Schlurmann from Brest, France. So welcome, thanks for being here. Dr Rescigno, let me begin with you and let’s talk about an important area that is still going largely underutilised by both urologists and medical oncologists, especially in the community, and that’s the role for genetic testing, both hereditary and somatic testing. Your thoughts and what you’re teaching your residents and fellows?
PR: Thank you for the question because it’s an extremely, as you said, relevant question nowadays where we have PARP inhibitors available for metastatic CRPC patients progressing on hormonal treatment. What I suggest to my residents is always to first of all check for family history. That will already tell us if we have to trigger genomic testing on a somatic level or on a germline level. So if the patient has a strong family history I would suggest to go for the germline testing; if the patient doesn’t have family history it’s still worth it to try and see if the patient has any somatic mutation for the BRCA1 and BRCA2 genes. The other thing that I always say to these students at university is always to start the genomic sequencing from the tissue. There is a lot of debate if we should use the tissue or if we should use sequencing from ctDNA, what we call a liquid biopsy, so using blood tests. My suggestion and my advice is to start from the tissue. So what we are doing in Newcastle and in all the Northeast of the UK is to consider tissue for sequencing if the tissue is not older than five years. That’s based on the profiling data that showed that the chance to get good DNA for sequencing is better if the tissue is not older than five years. So that’s what we are doing. In case we don’t have this kind of tissue because, of course, the patient had the biopsy ten years earlier, we then suggest either a rebiopsy, if the rebiopsy is not feasible then we suggest to go for a liquid biopsy. That’s for one important reason – there is a high concordance between the results that we can get from the tissue biopsy and the liquid biopsy, they overlap 80% of the time, like was shown last year at ASCO GU, but what liquid biopsy misses is the BRCA2 loss. So, on the copy number level the results that we can get from the liquid biopsy is not optimal. Patients with BRCA loss are the ones that are going to have the best benefit from PARP inhibitors. So if we are looking for the patients that are the perfect candidates for single agent PARP inhibitor in metastatic CRPC, we should interrogate the tissue rather than the liquid biopsy and choose the liquid biopsy as a second option if we don’t have tissue.
NS: A great response, very detailed. I love that. So for all of our colleagues out there who are not testing, it’s not about if you’re going to do it, it’s when are you going to start. It’s standard of care now to check both the hereditary component for cascade family concerns but also we now have clinical utility – HRR mutations, MSI high, MLH – we have approved therapies. Neeraj, I’d love for you to comment regarding your leadership and the really remarkable results that were presented by you regarding the TALAPRO-2 trial. Then we’ll go to Dr Schlurmann and we’ll talk about PROpel. And why, to your point, Pasquale, this is actionable now. And if you’re not testing you will never know patients who could potentially benefit. But there was also the controversy about the all-comers population too. So, Neeraj.
NA: Yes, thank you for asking the question. I just would like to add one sentence to what you said, Pasquale, fantastic discussion. I think pretty much all guidelines are very clear that every single patient with metastatic prostate cancer, advanced prostate cancer, should be tested for these genomic mutations, hereditable or somatic, regardless of family history. We are testing every single patient coming our way. Now, talking about the TALAPRO-2 study, this is the study which had more than 1,000 patients in metastatic castrate resistant prostate cancer in first line. These patients could have received docetaxel chemotherapy and abiraterone. Patients were randomised to enzalutamide versus enzalutamide plus talazoparib. Radiographic progression free survival was the primary endpoint. So if we look at the first cohort of 800 patients who were recruited regardless of these somatic mutations or germline mutations, there was a clear benefit as far as radiographic progression free survival, with approximately a 35% reduction in risk of progression or death. The benefit was even more pronounced in the cohort 2 which only had HRR mutation positive patients with a 55% reduction in risk of progression and death. This benefit was not confined to patients with BRCA1 and BRCA2 mutations as we are presenting. We presented in the ASCO meeting and we are updating the data here in the 2023 ESMO meeting, that we consistently see benefit in patients beyond BRCA1 and BRCA2 mutations. Accordingly, the FDA approved the combination for patients with new mCRPC regardless of what kind of HRR mutations they have. So any HRR mutation patients are qualified currently in the United States to receive the combination of enzalutamide and talazoparib. We continue to follow up for further data before we hopefully get approval. Hopefully data will be strong enough to warrant approval in an all-comer population, but time will tell.
NS: Yes. So that’s a really great segue for Dr Schlurmann to talk to us about two other correlative trials, big global trials. So we had the wonderful work of TALAPRO-2 but maybe you’d like to comment about PROpel and MAGNITUDE and how there may be some nuanced differences in the ultimate approvals. Then I want to get back to the controversy about the all-comers versus the specific HRR mutation and even selecting out on BRCA alone.
FS: Yes, PROpel and MAGNITUDE are two studies that could seem to be the same but they’re really different. The trial design is not the same at all. MAGNITUDE was designed as a trial for patients who have a mutation and then there was a cohort that was put onto the trial when we saw that there might be a signal even for patients that don’t have any mutation. So that was a really small cohort that was added to the study with a futility analysis that was wanted from the FDA really soon – after 16 months or roundabout. This cohort was negative, it was a futility analysis so they stopped this cohort, there was too much toxicity and no signal. So we just have data today from the MAGNITUDE trial from the patients who have mutations and we had the update for this ESMO 2023. We’re really happy because it just showed that we have still the benefit, the rPFS is still positive. It showed what we already knew, so this is reassuring. The think that’s really reassuring too is that we have no other toxicity signal, we don’t have any myelodysplastic syndrome, because we were all a bit concerned about those patients that we treat with PARP inhibition that we might see that but there’s not any patient with this myelodysplastic syndrome. We have some signals about some pulmonary embolisms, this is something that I think you should survey when you put patients on PARP inhibition but it’s not something that’s not manageable. So that was really great news.
Then you have PROpel which is completely different, I think, because it’s an all comers study, blinded study. We didn’t know if the patient had a mutation. Patients were all treated with abiraterone and then we added olaparib or not. There was a testing that was done on the tumour and on ctDNA, we did both of the tests, and then the readout was done. We saw at ASCO GU, one and a half years ago, roundabout, that there was a benefit for all patients. Sure, we all see the benefit that it’s more important for BRCA1 and BRCA2 patients, that was something that we were expecting but we still see a benefit for all patients. So at this ESMO 2023 we have a subgroup analysis of the non-HRR patients to see if there is still a clinical benefit for those patients. Because, just a little reminder, primary endpoint was PFS and it was positive for the ITT population, a little bit more for the BRCA1/BRCA2 and the HRR cohort but positive for everybody. So we had a big discussion because, like I said, the delta is a little smaller for the non-mutation patients. So we were really asking ourselves do we do the right thing if we give PARP inhibition to those patients and we can see with the update that we presented here at ESMO 2023 that there is a clinically meaningful benefit for the patient. Even if they don’t have any mutation the time to subsequent therapies is prolonged, time to chemotherapy is prolonged, PSA response is a lot better with PARP inhibition. So I think there is still a role for PARP inhibition in patients that don’t have those kinds of mutations but this should not mean that we don’t have to test. We still have to test because we have so many other reasons to test. It’s important to know because we know that those patients have worse outcome so it’s really important. Then you have all the family history side that you have to explore. So still the message to oncologists, urologists, to still test but I think it’s really good news that we still can give those combos to patients that are not mutated because we still have some patients where we have a hard time to get a result because we don’t have tissue, we don’t have access to circulating DNA and things like that. So it's still good news for those patients when we cannot get the results because we have this clinical meaningful benefit to do that. I think it’s still good news.
NS: Yes, great comments so thanks for summarising really quickly very complicated but important global phase III trials that are changing the landscape. Yes, absolutely you have to test. If you’re not testing, start testing tomorrow and because of all of the reasons, Pasquale, that you brought out which were so important. Then we have these three really game-changing trials, TALAPRO-2, MAGNITUDE and PROpel. And there’s controversy and we have a lot of our colleagues who have said, ‘In the all comers I’m not comfortable yet.’ We see different regulatory approvals around the world so it’s still a little bit confusing to some of our colleagues. Of course, when you add one therapy to another there clearly is going to be some more toxicity but, again, it has to do, in my mind, about patient choice and one’s risk seeking, risk aversion and having a full understanding of the data. So thank you all for bringing that up. Let’s switch over to some other really important aspects of pre-chemotherapy mCRPC. We had the ground-breaking presentation a year or so ago of the first PSMA radioligand therapy in the VISION trial. Here at ESMO we have the FORE trial which is clearly showing now a hazard ratio of 0.41 and about a six months median delay in rPFS, so quite a big deal. It’s a Presidential address being presented here at ESMO. Your thoughts, maybe let me start with you, Pasquale, regarding the implications of taking radioligand therapy prior to chemotherapy. And then also the panel even think about your thoughts on where will that go into earlier disease states within prostate cancer.
PR: There is just advantage in having a new treatment in prostate cancer, it doesn’t matter if this happens in early stage or later stage as long as the treatment works, that’s a general rule I guess. So I think everyone is happy when we have a new treatment. Also, looking at this ESMO, there are a lot of new treatments. Bladder cancer came up with new treatments after many years of domain of chemotherapy so having something new in prostate cancer where we haven’t had, really, many new drugs in the last few years, it’s extremely important. So I would favour the use of lutetium or any other radioligand that works, even in early stage.
NS: So, Neeraj, how does a novel therapeutic, a novel mechanism of action, radioligand therapies, how does that change the multidisciplinary structure in your institution and how will that ultimately affect MDT in the community? And maybe you can answer that globally outside of academic centres.
NA: So we are privileged to be working in an NCR-designated comprehensive cancer centre where everybody is housed within the same building or the same complex. So we don’t have to send the patients to somewhere else to get treated with Pluvicto or lutetium therapy. There are going to be challenges in the real world where patients have to travel hours sometimes to get access to these therapies. There will be real work which will need to be done to allow those patients to access. As you have done a lot of work from the perspective of access to care, this is a global issue including in the US, many patients are not able to have access. So working on education, working on improving access to patients, not only from the perspective of funding for the drug but even funding for the transportation to these cancer centres sometimes. Many patients don’t have the social structure, social support, to do that. So those are the issues which come up with every therapy which requires patients to travel long distances. So those things will need to be worked upon.
NS: I love that you brought that up, this whole notion about access to care and social determinants of health and how we can all do better. As physicians we’re globalists when it comes to healthcare, we don’t care what’s on your passport – if you’ve got cancer you want to get treated. So I really appreciate that you brought that up. Friederike, your thoughts on how the globalisation of healthcare, but there are clear regional differences, how is MDT working and evolving in France?
FS: I’m in a really lucky position, I’m in the university hospital so I have access to lutetium-PSMA, I have nuclear medicine colleagues that are really involved in this treatment and they’re really motivated to do everything that works. But we can still see that we have patients travelling for a couple of hours to get the treatment and so this is sometimes difficult for oncologists to send the patients to my clinic because they know it’s a lot of time. We have reimbursement in France, we’re really happy, we can have the reimbursement for travel, this is not a problem, but it’s a big country and we only have the right for now to do this treatment in university hospitals or anti-cancer centres. So we don’t have that many. So the problem for us right now is just to absorb all of those patients because, like you said, lutetium-PSMA and all the other PSMAs are going to be used earlier and earlier in prostate cancer and even we have the studies in mHSPC that are running. So we can see this huge amount of patients who are going to come and then we have to see how we can observe that in the university hospital. This is really a challenge for us because we have the challenge of the product, is the product available, and we had a lot of problems with that for a long time. Then we have the problem that we have to have the person who is going to do it, who is going to inject it. Because this is in nuclear medicine where it’s done and they have to get used to those treatments too. They don’t know our prostate cancer patients for now because they saw them just to do the PSMA-PET but they never treated those patients. So they have to learn a little bit with us and we have to help them how to treat those patients, what adverse events you can expect, how you can do that. So we have to learn to work together with those nuclear medicine colleagues. That is really a challenge but it’s really super-interesting and I’m really happy to be in that field because it’s changing so quickly and we have so many new colleagues that work with us. So it’s really a multidisciplinary team but it’s challenging, that’s for sure.
NS: You raise great points. When you look at those typical diagrams of the MDT we keep adding new spokes and it’s good because we’re making advances in our therapeutics and our biomarkers and precision-based healthcare. So very, very important but, of course, it doesn’t go anywhere unless we can get access for our patients. So, in our closing minutes maybe I’ll just take an opportunity to ask you what you’re all most interested in going forward. Some great work coming out of the world of combination therapy, of PARP inhibitors and AR pathway inhibitor drugs, genetic testing. It’s now you’ve got to start testing. Then, of course, radioligand therapy. But what else is on the horizon? Maybe I’ll start with you, Neeraj, because I think you’ve been doing some really cutting edge things with different combinations. Maybe the CONTACT-02 you’d like to talk about?
NA: Sure, there was a press release on the CONTACT-02. This is a phase III trial testing the combination of cabozantinib with atezolizumab, so a very well established tyrosine kinase inhibitor in the realm of genitourinary oncology clinics, and an immune checkpoint inhibitor atezolizumab. This combination was tested against an alternate NHT in patients who were experiencing disease progression on a prior novel hormonal therapy or an androgen receptor pathway inhibitor. One of the primary endpoints is radiographic progression free survival based on soft tissue metastasis. So it’s a very rigorously analysed, rigorously assessed progression free survival by RECIST1.1. There was a press release by the sponsors, Exelixis, that the study met the primary endpoint of radiographic progression free survival. The overall survival data is still immature and we are looking forward to the presentation in an upcoming meeting of this trial. I'm really optimistic that we will get this combination approved for our patients in the near future. Another immunotherapy I really feel excited about is the STEAP targeting bispecific antibody. We saw the presentation by Dr William Kelly. I was really enthused to see finally that a bispecific antibody is able to induce remarkable responses. So it’s a phase I trial and I’m really looking forward to the results of more advanced phases of trials.
NS: Yes, harnessing that whole bispecific milieu is so important. I think that Amgen and Dr Kelly are to be congratulated on the results so far and figuring out how to be able to develop it safely and effectively in the clinic setting. You mentioned combining cabozantinib, which is its own unique TKI, with an IO which will lead to potentially, hopefully, more life-prolonging therapies for our advanced prostate cancer patients which, make no mistake, it’s a lethal disease, especially in the resistant stage. So congratulations on leading that charge. Pasquale, your thoughts?
PR: I think that there are still a lot of things to do and discover. BRCA1 and BRCA2 were just the tip of an iceberg. We have seen that immunotherapy single agent doesn’t work in unselected patients but might work in really selected patients, like, for example the MMR cancers. We need more data on these in prostate cancer. We know that there are other targets that are extremely important; we know about the PTEN, P3I kinase and AKT/mTOR pathway. We now have some data about [?? 21:53] and now they are moving into early stages as well. So that will be interesting to see this in the next coming meetings as well. We have many more pathways to investigate – MEK signalling, RAS and RAF might be… They’re a really small proportion of patients with these alterations. The dream would be to design a clinical trial, a big basket trial, where we have drugs for every patient with this alteration.
NS: You just listed so many great pathways but I love that you did because it ties back to your plea to do the testing. If you don’t know what you’re testing for, you don’t have the mutation, the marker, to look for then you can’t design the ideal trial. So thank you for that. Fred?
FS: Yes, like you said, there are so many studies that are going to read out in the future. We have done a huge effort as the GU oncology community to do so many mHSPC trials that are almost all finished. We have trials with PARP inhibition, we have trials with cabozantinib, abemaciclib, we have so many. We have a trial coming up which is going to open really soon with a PUB1 inhibition which is going to be really selective, less toxic. This is really great news for patients, to have maybe one day, as I call them, the next generation triplet so we don’t have to maybe take the chemotherapy, which is still toxic, and that we can be a little bit more personalised. So I’m really, really, really looking forward to the readout of all of those studies that are still ongoing for some of them, some are starting. But there’s so much work still to do and I have to encourage, really, every clinician, every urologist, oncologist, to really continue to put the patients in clinical trials, to screen your patients for the clinical trials, because we do all of this screening work in the clinical trials because we don’t all have access to the screening as we would like to do. So really use those trials to at least get your patients screened and if you’re lucky you can put them in the trial and then we’ll see maybe in one or two years that we have new combos, new triplets that we can give to those patients. I think that’s really exciting.
NS: A great summary. Whether it’s PI3K/AKT, whether it is CDK4/6 inhibition, other combinations with AR pathway and PARP inhibitors, radioligand therapy, there’s just been an incredible second renaissance for all of us in mCRPC which logically translates to earlier disease states as well. So I think with that, thank you so much. This was a great discussion, we could have gone on for hours. Really again I want to thank the folks from ecancer for allowing us to talk to you from Madrid, Spain, today and ESMO 2023. Wonderful data. As Pasquale also said, we just focus on prostate, there’s a lot of great things outside of prostate as well in GU oncology. So thank you very much for listening.
