We have great therapies nowadays, and we shouldn’t save them for later. We have to use our best therapies as early as possible.
Dr Bárbara Vieira Lima Aguiar Melão
Dr Stephen Freedland and Dr Bárbara Vieira Lima Aguiar Melão share their expertise on how they choose from the range of available treatments, such as chemotherapy, for their patients who are progressing, why a second androgen receptor pathway inhibitor (ARPi) is not the answer, and when they would do genetic testing to identify patients for poly (ADP-ribose) polymerase (PARP) inhibitor or pembrolizumab therapy.
- [Steve] Hi, I'm Steve Freedland, urologist at Cedar-Sinai Medical Centre, Los Angeles, California, as well as the Durham VA Hospital in Durham, North Carolina. And it's my privilege and honour today, here to have as our guest, Dr. Barbara Melão. And I apologise for my poor Portuguese there, who's a urologist in Brazil, and is the Director of Oncology Department in Manaus, Brazil. So welcome to the podcast, Barbara.
- [Barbara] Oh, thank you, thank you for having me again, Steve.
- [Steve] Yeah, no, it's great to see you. And then, you know, we're talking today about metastatic castration-resistant prostate cancer, late stage prostate cancer. And, you know, it's hoped that, you know, if we do treatment right, most patients will have received an AR pathway inhibitor, what we're now calling an RP, prior to getting to that stage. Unfortunately, we know that's not always the case, and a lot of patients do get to that stage. But the challenge arises is when patients have failed an RP, whether it's prior to mCRPC or in the mCRPC setting, what do we do next? Where do we go with therapy? And are, I think for good reasons. I mean, AR is really the OG of targeted therapies, if you will, in prostate cancer. But, you know, there are options beyond that. So for that patient, you know, and I'd love to hear in your practise down in Brazil, for the patients that's failed an RP, again, whether it's either in the castrate sensitive or the castration resistance setting, and they're now looking to you, PSA is rising, bone scans progressing, what is your next therapy? Are you switching to a different one? You bringing in chemo or are patient's receptive to chemo? Lutetium, PARP sequencing. Where do we go? You know, I'd love to hear your thoughts.
- [Barbara] Well, it's a great question, Steve. Most of our patients in clinical practise are using our ARPIs in mHSPC settings. So first thing, I have a checklist on my mind when I see these patients because we know for sure now, for Corona resistance, that we should not sequence ARPI with ARPI. We don't give patients best results doing this. And in this checklist I have on my mind, we now have other therapies, a lot of other therapies in mCRPC. So we all know that advanced prostate cancer should be receive molecular testing. Now we have targeted therapies. So it's very important. The benefit in mCRPC and the greater benefit is for HR mutated patients, some therapies just like olaparib and niraparib plus abiraterone are eligible for patients with BRCA mutations. But we have talazoparib and enzalutamide, recommend for patients who didn't progress on ARPI and have HR deficient. So first of all, we have to look for molecular alterations because of the target therapies we have now. We also have chemotherapy and the features of the progression are really important. So patients with both lymph node progressions, patient with molecular alterations linked to poor prognosis such as TP53, RB1, PTEN loss, well, these patients will probably benefit more from chemotherapy. And in the mCRPC setting, we have docetaxel that is effective at ARPI. We have a cabazitaxel that is underused and it's also good in the setting after ARPI, especially for these patients with adverse pathological prognosis features. And we also have the radioligands. We just saw presented ENZA-p and data from PSMAfore. We have data from vision trials, these patients, progressing. In first line mCRPC, we have better results with the PSA positive patients. This is important. We have two well select patients for each therapy. We have targeted therapy, but we have to have the target there to better use it. So we have mutation in first line mCRPC for PSMA-positive patients. And now we have data from ENZA-p associated with enzalutamide. Perhaps we don't have data in this setting, progress on ARPI. So I would love to hear your thoughts about it. Should we sequence this way? We also have Radium-223 that was combined in Phase 3, and the combinations gave excellent results. So we have so many options there. You have the sipuleucel option. I don't have it here in Brazil. We don't have sipuleucel here. So it's an option that we just don't have. So we have to better select patients. What is the progression? Is it bone only progression? Can we use radium in combination? Is it has poor prognosis features and molecular alterations that will lead us to use chemotherapy? So, many options. We have to better select, better tailor the treatment for our patients now.
- [Steve] Yeah, I think you're bringing up a good point. And I think, you know, there's days when I'm very optimistic that we're in the personalised medicine era and there's days when I'm kind of pessimistic and I look at what they're doing in lung cancer, for example, and I get envy of, if you have this mutation, it's this drug, and this mutation, it's this drug, and we're not quite there yet. But you know, you bring up some good points, you know? For the most part, after we move beyond an RP and I really don't think there's dramatic benefits to a second RP. I mean, the guidelines recommend against it. It's amazing to me. If you look at real world evidence in the US and maybe we're just behind where you are in Brazil, but at least in the US it's been very well documented. The majority of patients who get a second line, it's an RP again. And we're not really mixing up the mechanism of actions. And I think it's a shame. And I think part of it is the drugs are viewed as really well tolerated, which is great. And I think they are, not that they don't have some side effects, but patients just really are reluctant for chemo. Lutetium is only approved post chemo. So at, you know, radium is only bone only. A lot of patients don't get their genetic testing and if they do, they don't have HRD for a PARP inhibitor. So it leaves a large group of patients post RP that don't currently have a lot of great options, even though I think they exist. So I do think, you know, doing the molecular testing and if they have a BRCA2, PARPs work really well, I mean we have pretty darn good data on that. And if they have an ATM, not so much, right? So I mean, it does get, you know, very personalised. PSMA, we tend to think of as available for everyone. But you have to do a PSMA imaging test beforehand to know, you know, are they eligible? And about 15% of patients will screen fail for PSMA, which is really interesting. And what is that biology of their? But I do think, you know, doing the testing and you find that rare MSI-high tumour, we can bring in pembrolizumab. You know, it's maybe 4% of patients, but still that's, if you see enough patients you're gonna find that. And we can have really dramatic benefits. But, you know, so I do think we're getting into that personalised medicine, but I'd love to hear your thoughts on testing. And, you know, my bias is if you're waiting until they're mCRPC to be tested, it's probably late. You probably wanna do it earlier, but how early should we be testing and what are you guys doing down there in your practise and what are your thoughts on that?
- [Barbara] Well, we have two different scenarios, I guess. As early as possible, I guess, so we can better understand molecular features of the disease. But we have to be aware that since we brought and we intensify the AR signalling inhibition in early settings, it also bring us an issue with neuroendocrine differentiation. So, about, studies have shown that it, it's higher as, it was about 5% and now it's 15%, the neuroendocrine differentiation in these patients when we intensify in mHSPC. So as early as possible. But we have to be aware that the progression may be different in some patients, especially if we have neuroendocrine features. We have both masses, we have lymph nodule with no bone metastasis. I'm pretty sure we have these patients in practise. And for these patients, perhaps we should test them again because it's just not the same disease. And we know that the molecular alterations are cumulative, so they differ from stage, from in different stages. And we have to understand it better from the beginning, but we have to be aware that it might change in the course of the disease. In Brazil, the really issue is the access. We have some programmes. So it's not reimbursed, unfortunately. I have to say that. It's just not, but it's, we have the support of the industry, so we are allowed to test the patients inside programmes. So, unfortunately it's far from what it should be.
- [Steve] Yeah, no, and I think the testing is challenging. I think we're moving towards liquid biopsies, but they don't always capture everything. You have to be shedding enough tumour cells or tumour DNA. Archival tissue's, not always readily available. So there are some challenges in that sense. And I think, you know, the question we get a lot is why not just do reflex testing in every prostate cancer patient like they do in breast? You know, they'll do a HER2, ER and PR. You know, and I think people, you know, don't always appreciate that, particularly, and we see this as urologists, right? The vast majority of prostate cancer is low grade, low stage, active surveillance, cured with surgery. We're doing focal therapies now. That patients are never destined to go on to get mCRPC. So testing for all is gonna be over testing a lot of people. And in a cost effective world, it's harder and harder to justify that. But, and that's what's really incumbent upon the treating physician, the urologists, the medical oncologists, radiation oncologists, to have that in mind. And when they're starting to look bad and moving towards metastatic, to test early. And you do see, as you pointed out, you do see changes. I mean P53 mutations, RB1 loss, they occur over time. We don't actually know what to do with those tumours, right? I mean, I like your idea of chemo because that's just bad biology that's not gonna necessarily be AR driven. So I think we need to move beyond AR for those patients. But that accrues over time. I think the HRD is, seems to be more truncal. I.e., it's there at the beginning when the tumour is born. So you can go back to some of the archival tissue and get some information. But as we start to understand AR lagging, ligand-binding domains, mutations, MSI, a lot of that will accumulate over time. So, but I do think we need to be mindful of that. So the question, Barbara is, you know, we talked about once you failed an RP, we really need to move beyond that mechanism of action, right? So the first RP should be your only RP and should be your best RP, right? I mean that's really, and we've seen some interesting data between P's 3, ENZA-p, TALAPRO-2 now, that we can actually make RPs better. And particularly all of those were built upon the enzalutamide backbone. There are other combinations, you know, but these are the ones in the last year that have had new data. So what are your thoughts about, again, that patient who makes it to mCRPC, is RP naive, which we talked about is a small and perhaps shrinking group, at least in your practise, mine too, but they do exist out there in the community. How do we make that first RP really work well and maybe how do we apply that to the mHSPC setting where those trials are underway? We don't know have the answer yet, but they're certainly underway. PSMAddition, TALAPRO-3, et cetera. So what are your thoughts about the combinations now, building upon enzalutamide?
- Oh, it's great question because that's what we saw in ASCO GU this year. The combinations work better. It's just like that. Enzalutamide plus mevrometostat, which is a new agent, enzalutamide plus lutetium, enzalutamide plus radiation. So we see that this target therapies associated with RP and they may better results. So these days when we have patient, a RP patients naive, so we can definitely go for a combination. We'll have to wait for the approvals. But we know now that the combination works better for this patient. PARP inhibitors with TALAPRO-2, if the patient is a PARP naive, PARP inhibitors, net TALAPRO-2, talazoparib with enzalutamide works better. So we now know that we can improve results from RPs. And it's very important for our patients, since, as you said, I don't have this data here, but in US, I think Neeraj told us that 40% of the patients are still not receiving ARPIs first line. So it will be these patients, as you said. But the great issue now is that, in my clinical practise, all of them are using, so what do I do with these combinations that are doing really well but they don't actually fit for my patients? This is my greatest issue right now. So how am I going to translate this data from my practise since my patients are usually using ARPIs? What are your thoughts about it?
- Yeah, it's an important question and I think if you have received ENZA or apalutamide and you're coming into mCRPC, I don't think there's a lot of value to adding enzalutamide. Really, you're not getting any benefit. We do see, for patients who are failing Abi, ENZA has some activity. I think it's, there's a lot of real world evidence now saying ENZA has more efficacy than ABI. It's modest, but there, but we see it. So for those patients who are failing ABI, I do think, in a combination study or combination treatment, maybe not say study, but in combination treatment, I think ENZA plus something makes sense. I wouldn't do ENZA alone because I think there's more efficacious agents. Chemo, lutetium, et cetera. But in a combination, I can live with that. We need to see the real world data on that to understand that better. But if you're failing ENZA, I think it's time to move on. You know, it's, and that's, so to me the key question is all those great combinations that we just talked about, right? Super exciting, changing the face of mCRPC. Do they work for mHSPC?
- [Barbara] Yeah.
- [Steve] And in time we'll know for some of these therapies. You know, PSMAddition is hopefully gonna be weeding out at some point in the not too distant future. TALAPRO-3. Some of the other ones are gonna be farther behind. But that's where we need to go. And then the question, you know, at that point is when you're treating earlier and earlier, do we need to, how long do you need to be on therapy? You know, if you look at the mCRPC, they're on therapy until they progress, which is, border of a couple years. But mHSPC, that could be five years. If you have an effective combination, it could be seven, could be 10 years, now, until they progress. That's a lot of therapy. And it's just hard to imagine someone needs 10 years of that therapy. So can we start to de-intensify? Intensify upfront, but then if they do well, de-intensify. And we saw that in BCR, right? Biochemical occurrence, nine months of therapy with enzalutamide. If you responded well, we stopped treatment. So as we move earlier, I do think we need to think about cumulative toxicity de-intensification. I know we're coming up here on time, but I was wondering if you had any quick thoughts on that?
- [Barbara] Yes, just a key point that I think that we have great therapies nowadays and we should not save therapies for later. That's what we have been saying. We have to use best therapies as early as possible. And well, having said that, we will probably having more combinations upfront in on early settings, as you said. And yes, the benefit will be greater and patients will be years and years in therapy, but we don't have to save better for later. So yes, well, let's see. I'm looking forward to it.
- [Steve] Correct, and I think that's, our drugs are so potent now and patients are living a long time. We actually have to think about survivorship issues in patients with metastatic cancer. I mean, that's amazing.
- Yeah.
- That's a win, right?
- Yeah.
- That we're thinking long term. The goal is to turn this into a chronic disease. I'm not sure we're gonna cure all these metastatic patients. Maybe some, but manage them like a chronic disease. It's a new era. It's an exciting era, but it's definitely a new era.
- [Barbara] Very exciting. Exactly.
- [Steve] Alright, on that note, again, Barbara, this was wonderful to chat with you, as always, certainly very enlightening and enjoyed the discussion and I hope you listening enjoyed the discussion as well. Thank you.
- [Barbara] Thank you, thank you for having me. Always great to be with you.
