Alicia Morgans: Hello. I am so excited to be right here right now with Professor Karim Fizazi, who’s becoming a member of me from Gustave Roussy and who additionally joined me at ASCO 2024 the place he gave up to date information on survival, in addition to high quality of life information from the PSMAfore trial. Thanks a lot for being right here with me right now, Karim.
Karim Fizazi: Thanks very a lot, Alicia. This can be a presentation that I made on behalf of my co-workers concerning the standard of life and ache information in PSMAfore, which is a part three trial for lutetium PSMA and castration-resistant illness. I assume now most likely everyone is conscious of the mechanisms of motion of lutetium PSMA. Principally, PSMA is a transmembrane protein, largely overexpressed by prostate most cancers cells, particularly in sufferers with superior illness. A ligand is injected intravenously. It goes to and binds to the protein. And since the ligand is certain to a radioisotope referred to as lutetium, most cancers cells are hopefully being focused by this therapy. So we already know that lutetium PSMA works within the illness due to VISION, which was reported three years in the past. General survival was improved and in addition high quality of life was improved within the lutetium PSMA arm.
So mainly PSMAfore is the second part 3 trial of lutetium PSMA within the illness. This time in much less superior phases, males have castration-resistant illness, metastasis. They’ve exhausted one AR pathway inhibitor, however they have not seen any chemotherapy. And they’re really not candidates for rapid Taxanes therapy, principally as a result of their illness is plus or minus indolent and since they haven’t any or gentle signs. So actually a inhabitants of males that we’re all seeing and in whom we do not essentially need to go for Taxanes not less than instantly. So these sufferers after settlement had been randomized in a one-to-one trend to obtain both lutetium PSMA for as much as six cycles or a second AR pathway inhibitor, abiraterone or enzalutamide, relying on what they obtained as first therapy. The first endpoint was radiographic progression-free survival. This was proven to be considerably improved already greater than six months in the past, with a transparent profit, roughly 60% discount within the threat of radiographic development or loss of life.
General survival is a secondary endpoint. Really, the 2 therapies are related to comparable total survival. We confirmed up to date evaluation at ASCO, with a hazard ratio of 0.98, however actually the objective of this presentation was to deal with high quality of life. We used the FACT-P questionnaire, which is sort of particular to prostate most cancers, and we confirmed roughly 40% discount within the threat of degradation in high quality of life favoring the lutetium PSMA arm. We discovered comparable information when utilizing the EQ-5D-5L questionnaire, which is extra generic. And as you’ll be able to see by the form of the curves, the standard of life deterioration can also be prevented by lutetium PSMA use. I feel what’s fascinating is that numerous elements, numerous domains of high quality of life had been considerably improved by lutetium PSMA.
For instance, this was true for bodily well-being, as it’s possible you’ll anticipate, as that is straight measuring signs associated to most cancers development, but additionally purposeful well-being was improved and emotional well-being was additionally improved. Maybe as a result of emotionally sufferers do not prefer to know that they’ve most cancers development both by PSA, by imaging, or by signs. Solely social and household well-being was comparable in each arms and once more, that is most likely measuring completely completely different elements of high quality of life. Concerning ache, additionally excellent news, we noticed time to worsening in ache depth being improved considerably by lutetium PSMA with roughly a 30% discount within the threat.
And this was additionally proven when it comes to time to worsening in ache interference with regular life, in addition to time to disease-related ache. So making an attempt to focus extra on most cancers ache versus another causes of ache or therapy for one thing else. So all elements of ache look like improved considerably favoring lutetium PSMA. We additionally checked out unwanted effects, which usually can impression negatively on high quality of life equivalent to high-grade anemia or fatigue. And as you’ll be able to see, there isn’t any actual adverse impression of lutetium PSMA. This was actually comparable throughout the board. So in conclusion, I feel we have now now a transparent demonstration that the early use of lutetium PSMA within the illness, in males who’ve progressed after a primary AR pathway inhibitor can actually get pleasure from a greater time earlier than most cancers develops development. And that is true in all elements of development, together with in fact PSA development, which is dramatically improved by lutetium PSMA, but additionally imaging-based development, which is a registration endpoint.
And naturally, this is essential when it goes to discussing with the well being authorities, however perhaps much more clinically necessary, are these information concerning high quality of life and time to deterioration in high quality of life as assessed by the FACT-P or EQ-5D-5L questionnaires. And ultimately on the finish of the day, time to deterioration is an clearly crucial medical endpoint. Once more, security was not likely a problem with lutetium PSMA on this trial and total survival seems to be comparable, understanding that this was achieved in a context the place about 80% of sufferers from the management arm really crossed over to lutetium PSMA. In different phrases, for these males, we had been actually evaluating rapid lutetium PSMA versus lutetium PSMA six months down the street.
So actually it’s possible you’ll not anticipate a distinction in total survival in such a context. However I feel we have now a very good case now to debate with the well being authorities and the payers, to hopefully have lutetium PSMA authorised on this indication. Once more, it is a actually unmet want in mCRPC. Many sufferers both will not be rapid candidates for chemotherapy simply because the illness is indolent or they do not need chemotherapy, and all of us see these circumstances. Or lastly, we additionally deal with some weak sufferers who simply can’t tolerate chemotherapy at energetic doses. So we have now to handle all these populations and I feel lutetium PSMA is an excellent choice primarily based on this information for these males.
Alicia Morgans: Effectively, thanks a lot, Karim. I feel it is actually thrilling actually to the general survival replace after which additionally to see this high quality of life information. I would love to listen to your ideas on the general survival information and the way it seems to be like we’re honing in additional exactly on that time estimate. And now it has moved under one. What’s your tackle this when it comes to the utility of this therapy and the earlier thought that maybe it might be inflicting hurt if the purpose estimate was above one? Does this transformation now with the brand new estimate?
Karim Fizazi: Effectively, to start with, I feel it is a vital discovering in the direction of the well being authorities as a result of any company, both the FDA, EMA, or one other one, hates to see a hazard ratio for total survival with a brand new therapy above one. As a result of they’re questioning whether or not we’re harming sufferers. And even when it is simply above, you by no means know. So we’re placing them in a troublesome state of affairs to decide once they’re going through such a situation. And it is really good that it isn’t anymore the case. However frankly, I feel we have now extra package deal now. The package deal contains each VISION information and PSMAfore information. And I am saying that as a result of primary, from VISION, we all know that this therapy when utilized in sufferers with CRPC versus a bunch of males who do not obtain it in any respect, really improves total survival. And in VISION it was a 40% discount within the threat of loss of life. So this is essential.
Now, this being stated, in a second part 3 trial when used earlier, the identical therapy clearly postponed development as measured by all its elements, medical, organic, imaging, high quality of life, every part. However in a context the place we actually wished to be honest with sufferers and supply them with the chance to get entry to that therapy. Particularly on the time it was not totally and broadly accessible within the VISION indication. We really allowed a crossover and the crossover was huge on this trial. So once more, we had been evaluating rapid lutetium PSMA versus lutetium PSMA tomorrow or in six months’ time. And in such a situation, you can not actually anticipate an enchancment in total survival. So I used to be sincerely not anticipating it to occur given the design of the trial. And it isn’t stunning to me if we do not get it, once more, understanding that this was met in VISION as the primary part 3 trial.
Alicia Morgans: Yeah. So I feel that makes full sense. And simply to kind of spherical out your dialog across the package deal of knowledge, actually the standard of life information that you just introduced provides to that understanding and is absolutely in line with the standard of life information that we noticed from the VISION trial as effectively. As you consider it, one factor that was raised as I used to be talking about a few of this with colleagues was that, can you actually belief the standard of life information when sufferers weren’t blinded on this research? What are your ideas there?
Karim Fizazi: I take this level, and it is a honest one. I feel certainly, for instance, when measuring the… They weren’t blinded for therapy, however they had been additionally not solely blinded for PSA development, for instance. And while you’re measuring emotional well-being, PSA performs an apparent function. None of my sufferers, and I assume it is the identical for you, likes to have unhealthy information once they obtain their PSA values and perceive that it is rising. And that is very clearly related to emotional deterioration and nervousness. So once more, that is additionally true in our follow. It isn’t solely that we’re not blinding a therapy in a part 3 trial, but it surely’s additionally that unhealthy information and excellent news will not be blinded in actual life. So to me, it is not likely stunning if we’re additionally measuring that in our trials as a result of once more, on the finish of the day, it is simply reflecting actual life.
Effectively, I feel nonetheless… I feel that the bodily well-being enhancements, for instance, might be extra a, how ought to I say that, a good measure, if you’ll, of a therapy impact in opposition to the most cancers and the most cancers development. And once more, it goes along with PSA, goes along with imaging-based PFS, and I’ve expertise we have handled most likely 30 sufferers on this trial. It is also fairly apparent that the time to symptomatic deterioration is being postponed by this therapy once more, as in comparison with a secondary AR pathway inhibitor. So I feel it is actually a real discovering that was reported by these high quality of life area assessments.
Alicia Morgans: I might utterly agree. And I feel your level about sufferers not being blinded in actual life can also be actually an necessary one. I feel sufferers report what they really feel. They attempt to be trustworthy, they haven’t any motivation, I feel, in a trial or in any other case to faux that they really feel higher or worse. And I feel particularly in a medical trial, these people which have taken the time, made the dedication to take part are going to be very trustworthy. In the event that they really feel worse, they will share that. And the diploma of distinction that we noticed between these arms was extra, I feel, than one would anticipate to see if solely these variations had been associated to being upset about being on one arm or the opposite. So I utterly agree with you, notably across the bodily perform, and I do assume that this displays as shut to at least one may think about the best way that sufferers could really feel and performance of their every day lives as they’re really getting these therapies. In order you consider this and also you need to perhaps give us a fast abstract, what would that be for this up to date information for PSMAfore?
Karim Fizazi: Effectively, we knew already that the first endpoint, which was radiographic progression-free survival, is improved considerably with a 60% discount within the threat. Once more, crucial from a registrational standpoint, total survival isn’t detrimental. Once more, crucial in the direction of the regulatory companies and extra clinically necessary I feel, are the brand new information we confirmed at ASCO concerning time to deterioration in high quality of life and ache, most likely straight measuring the profit, the medical profit we’re offering to the sufferers. And I imply, to me, that is even most likely extra convincing to be trustworthy, as in comparison with rPFS. So I assume this satisfied me that if authorised, given the general nice security of this therapy, I might be actually assured to make use of this therapy in my subsequent affected person to come back and once more, attempt to keep away from a swap to a secondary AR pathway inhibitor. That generally we do by default, just because we do not have the rest to suggest besides going for chemotherapy.
Alicia Morgans: Fantastic. Effectively, as you stated, it actually provides to the package deal of knowledge that we have now on this specific agent, one that really is sort of compelling each to clinicians and to sufferers alike, whether or not it is illness management or whether or not it is enhancing high quality of life. There appear to be advantages right here in each settings. And so I recognize you offering these updates and sharing your ideas on a few of these difficult questions. I recognize your time.
Karim Fizazi: Thanks very a lot.
