Karim Fizazi: Thank you, Tanya. My pleasure.
Tanya Dorff: You are part of this very helpful and informative educational session. In prostate cancer landscape, now clinicians are faced with many choices and navigating decision-making is increasingly complex. So you're focusing on the castration-resistant population.
So let's start with a very basic question. When a patient has been on their ADT-ARPI doublet and is now starting to progress, how do you know when they're really castration-resistant, so to speak, and ready for a new line of therapy?
Karim Fizazi: Sure. And that's very important to remind colleagues that they need to demonstrate that their patients are experiencing not only progression based on either PSA or imaging and more rarely at the stage clinically, but that they are actually castrated, meaning that they need to double-check the testosterone level because in some patients we all know testosterone is not any longer at a castrated level for whatever reasons, either patients forgot their injections or their pills, or there was an issue with the injection and the testosterone is rising, which explains why the PSA is rising and that's not a castration-resistant prostate cancer. The solution is simply use ADT again and double-check. So that's very important again.
And then if you are sure that your patient has castration-resistant disease, I guess this next step is to not only do the clinical assessment that we are probably all doing, comorbidities, symptoms, drug-drug interaction, geriatric assessment, all those things, but also order imaging, and you may argue whether this is conventional imaging versus PSMA-PET. There are pros and cons, obviously. But also, I think nowadays we need to order an NGS analysis for these patients, of course, if available and not too expensive, but that's really important for decision-making, at least in my practice in the last years.
Tanya Dorff: Yes. I think that NGS has been something we've been thinking about in CRPC because of things like PARP inhibitors. Now people are maybe doing it earlier. Do you see a role for repeat testing or confirming what kind of testing had been done?
Karim Fizazi: I think ideally the answer is yes, because it's true that some targets or some alterations occur very early in the course of prostate cancer, meaning that you don't necessarily need to repeat and repeat and repeat if you have a first idea, but some others are in different scenarios. And for example, BRCA alterations are mostly early events. There are a few acquired events for BRCA, but if you take androgen receptor alterations, they are clearly appearing while on AR-targeting pressure.
So more and more, for example, I think we will look at AR mutations. I suspect that some, what I tend to call the third-generation AR-targeting might be more active in patients with AR mutations or Opevesostat, maybe the AR degraders. So that will be important to figure out for decision-making.
Tanya Dorff: So you put patients into three very practical and helpful buckets: genomically informative, slow progression, and then aggressive rapid progression. So let's start with that genomically informative bucket.
Karim Fizazi: Yeah. I really think those three buckets are helpful clinically for the colleagues to better understand what we should discuss. First one indeed would be, yes, NGS is informative. You have a target. It can be BRCA, it can be PALB2, it can be anything that we know is predicting for PARP inhibitor benefit. And again, if you don't have access to PARP inhibitors, some of the colleagues worldwide don't necessarily have access to PARP inhibitors, in those scenarios, a platinum could be a good option and it's cheaper. Of course, you also have the rare scenario of a patient with MSI-high or dMMR two, 3% of the cases, and here you go. You have a very good reason to go for immunotherapy. Of course, again, if available, but the data clearly support benefit from IOs in this situations.
AR mutations, hopefully in the coming future, will be also informative, and we just saw data, recent data from the STAMPEDE group indicating that PTEN deficiency might predict for taxane efficacy. I recognize that this was shown mostly in the hormone-sensitive space, but who knows if this is also true and within validation in the CRPC space. That could be a very good tool or parameter to take into account when it comes to decide whether I should go for docetaxel or cabazitaxel, for example. So this is with the first bucket where the NGS basically helps you.
Then second situation, NGS is not helpful, but then the pace of the progression is a slow one. So basically slowly rising PSA, patient might be anxious of course, but mostly not clinically symptomatic, no clinical deterioration, no lab issues, et cetera, et cetera. In this scenario, taxane, which was historically the main treatment for these men with CRPC, is not necessarily what you want to start with, at least immediately. I would still speak about it with patients also to prepare them because eventually we might go to that. But I think now we have some other options.
Obviously, if a patient has not received an AR pathway inhibitor, and those patients still exist, that's an obvious answer, given what we know from abiraterone and enzalutamide in this space. So that would be a clear choice to me. But in the scenario when the patient has exhausted one AR pathway inhibitor, I think we should avoid switching to the other RP. It mostly doesn't work. At APCCC a month ago, the vote from the experts was about 90% against recommending it. So that I think is something important to know from a colleague's perspective.
But then we have other options. For example, lutetium-PSMA, the PSMAfore data is clearly one option with clear benefit in rPFS, quality of life, pain, you are improved by, or at least deterioration is prevented. We also saw recently data from the radium plus enzalutamide combination in PEACE-3. So that could be also an option if a patient has not received an RP, for example.
And then you have two options that I tend to discuss with patients also. One is irradiating an oligoprogression. Of course, we don't have level-one evidence, but that's something I would discuss with patients. And also simply the switch from prednisone to dexamethasone in patients progressing while on abiraterone, that would work in approximately 40%. It's simple, easy, cheap, and you'll know in three weeks from now whether it works or not. So in a patient who is asymptomatic and anxious with this PSA that's just starting to rise, this is something you might do and keep him on drug for a longer time. So you see, you have probably what, I don't know, five different options to discuss with patients and I think that's very important.
Tanya Dorff: And I'm curious, in these patients, let's presume the patient we're talking about, the slow progressor, does have bone metastases. Is this a juncture at which you would start to add a bone supportive agent?
Karim Fizazi: Oh, yes. I would have concluded all the conversation with that for sure because I think whatever you do, so first bucket, again, NGS is helpful. Second, in the lung cancer, NGS is not helpful. And the last one that we may speak about if you want, aggressive cancers, NGS not helpful, use bone-targeting agents. Across the board we have strong data showing that whatever you decide, a bone-targeting agent used on top of will prevent patients from developing fractures and other skeletal-related events. So that's very important.
Tanya Dorff: I just thought I would raise it there because this is maybe a group where that flies under the radar, right? Clearly someone with aggressive, symptomatic progression, we're thinking bone support. Someone maybe in the NGS category, maybe not, but here, especially if we're thinking about PEACE-3, we know how important the bone support was to the successful outcome of that trial. But these are slow progressors and maybe we forget that this is really a good opportunity to get that started.
Karim Fizazi: I do think so.
Tanya Dorff: So let's talk now then about the aggressive bucket. How do you describe that, and what are their options?
Karim Fizazi: True. Well, you have the classical aggressive scenarios: liver metastasis, bone pain terrible, patient come who was doing super well, coming back to you on pain, et cetera, clinically. But you also have some other scenarios. For example, a patient starting to deteriorate by labs, platelets are going down, hemoglobin is going down, et cetera. We should react because this is not good and it's not going to improve if we don't act rapidly.
Also in my practice, a rapidly rising PSA, even if a patient is doing well today as I'm seeing him, is really not a good prognostic factor. So if you don't intervene soon, you'll see soonish this very same patient coming back to you on pain, lying on a bed, et cetera, and maybe just too late. So in all those scenarios, and of course you may add on top of that indirectly some NGS information, PTEN is lost, P53 is out, RB is not there, et cetera, et cetera, so all those scenario-aggressive cancers, also probably dose with zero PSA but terrible disease appearing, all that is not good, as we all know.
That to me is a strong signal to speak about a taxane plus or minus platinums right now with a patient because if we don't do that, we may miss the opportunity. And some of these cancers are very taxane-sensitive, so they can actually drive an enormous benefit from those treatments.
Tanya Dorff: And what about doing a biopsy? Are you trying to get a biopsy if you see someone developing visceral metastases?
Karim Fizazi: I do. And also because in some scenarios you want to make sure your patient is actually not developing another cancer, and I saw that, and probably so did you. For example, PSA is not rising or rising just a bit, liver metastasis or some other visceral, do a biopsy and out of a sudden it's a pancreatic cancer or colorectal cancer, or kidney or whatever. So you really want to know.
On top of that, the biopsy can also help with the biology. You may repeat your NGS and find something new. So yes, I think if you can, if you have time, if this does not delay the access to treatment, then a biopsy is a good idea.
Tanya Dorff: Yeah, that's true. Sometimes it's just too logistically complex, especially maybe if patients live far away or in an underserved health system and then we just make our best gut sort of reaction to all the other clinical information.
Karim Fizazi: Agreed.
Tanya Dorff: Yeah. Well, thank you so much. I think this was a really helpful discussion.
Karim Fizazi: My pleasure, really.