PSMAfore Trial: Lutetium PSMA's Impact on mCRPC Quality of Life - Karim Fizazi

July 2, 2024

Alicia Morgans interviews Karim Fizazi about the updated survival and quality of life data from the PSMAfore trial. The study compares lutetium PSMA to second-line AR pathway inhibitors in metastatic castration-resistant prostate cancer patients who have progressed after one AR pathway inhibitor. Dr. Fizazi discusses the trial's findings, highlighting a significant improvement in radiographic progression-free survival and quality of life with lutetium PSMA. The updated overall survival data shows no detrimental effect, with a hazard ratio of 0.98. The quality of life improvements are observed across multiple domains, including physical, functional, and emotional well-being, as well as pain reduction. Dr. Fizazi emphasizes the importance of these findings for patients who may not be immediate candidates for chemotherapy. He concludes that lutetium PSMA offers a promising option for this patient population, addressing an unmet need in mCRPC treatment.


Karim Fizazi, MD, PhD, Head of the Department of Cancer Medicine, Institute Gustave Roussy (IGR), Villejuif, France, Professor in Oncology, University of Paris, Paris, France

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA

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Alicia Morgans: Hi. I'm so excited to be here today with Professor Karim Fizazi, who is joining me from Gustave Roussy and who also joined me at ASCO 2024 where he gave updated data on survival, as well as quality of life data from the PSMAfore trial. Thank you so much for being here with me today, Karim.

Karim Fizazi: Thank you very much, Alicia. This is a presentation that I made on behalf of my co-workers regarding the quality of life and pain data in PSMAfore, which is a phase three trial for lutetium PSMA and castration-resistant disease. I guess now probably everybody is aware of the mechanisms of action of lutetium PSMA. Basically, PSMA is a transmembrane protein, largely overexpressed by prostate cancer cells, especially in patients with advanced disease. A ligand is injected intravenously. It goes to and binds to the protein. And because the ligand is bound to a radioisotope called lutetium, cancer cells are hopefully being targeted by this treatment. So we already know that lutetium PSMA works in the disease thanks to VISION, which was reported three years ago. Overall survival was improved and also quality of life was improved in the lutetium PSMA arm.

So basically PSMAfore is the second phase 3 trial of lutetium PSMA in the disease. This time in less advanced stages, men have castration-resistant disease, metastasis. They have exhausted one AR pathway inhibitor, but they haven't seen any chemotherapy. And they are actually not candidates for immediate Taxanes treatment, mostly because their disease is plus or minus indolent and because they have no or mild symptoms. So really a population of men that we are all seeing and in whom we don't necessarily want to go for Taxanes at least immediately. So these patients after agreement were randomized in a one-to-one fashion to receive either lutetium PSMA for up to six cycles or a second AR pathway inhibitor, abiraterone or enzalutamide, depending on what they received as first treatment. The primary endpoint was radiographic progression-free survival. This was shown to be significantly improved already more than six months ago, with a clear benefit, approximately 60% reduction in the risk of radiographic progression or death.

Overall survival is a secondary endpoint. Actually, the two treatments are associated with similar overall survival. We showed updated analysis at ASCO, with a hazard ratio of 0.98, but really the goal of this presentation was to focus on quality of life. We used the FACT-P questionnaire, which is quite specific to prostate cancer, and we showed approximately 40% reduction in the risk of deterioration in quality of life favoring the lutetium PSMA arm. We found similar data when using the EQ-5D-5L questionnaire, which is more generic. And as you can see by the shape of the curves, the quality of life deterioration is also prevented by lutetium PSMA use. I think what is interesting is that various aspects, various domains of quality of life were significantly improved by lutetium PSMA.

For example, this was true for physical well-being, as you may expect, as this is directly measuring symptoms related to cancer progression, but also functional well-being was improved and emotional well-being was also improved. Perhaps because emotionally patients don't like to know that they have cancer progression either by PSA, by imaging, or by symptoms. Only social and family well-being was similar in both arms and again, this is probably measuring totally different aspects of quality of life. Regarding pain, also good news, we saw time to worsening in pain intensity being improved significantly by lutetium PSMA with approximately a 30% reduction in the risk.

And this was also shown in terms of time to worsening in pain interference with normal life, as well as time to disease-related pain. So trying to focus more on cancer pain versus some other causes of pain or treatment for something else. So all aspects of pain appear to be improved significantly favoring lutetium PSMA. We also looked at side effects, which typically can impact negatively on quality of life such as high-grade anemia or fatigue. And as you can see, there is no real negative impact of lutetium PSMA. This was really similar across the board. So in conclusion, I think we have now a clear demonstration that the early use of lutetium PSMA in the disease, in men who have progressed after a first AR pathway inhibitor can really enjoy a better time before cancer develops progression. And this is true in all aspects of progression, including of course PSA progression, which is dramatically improved by lutetium PSMA, but also imaging-based progression, which is a registration endpoint.

And of course, this is very important when it goes to discussing with the health authorities, but maybe even more clinically important, are those data regarding quality of life and time to deterioration in quality of life as assessed by the FACT-P or EQ-5D-5L questionnaires. And eventually at the end of the day, time to deterioration is an obviously very important clinical endpoint. Again, safety was not really an issue with lutetium PSMA in this trial and overall survival appears to be similar, understanding that this was achieved in a context where about 80% of patients from the control arm actually crossed over to lutetium PSMA. In other words, for these men, we were really comparing immediate lutetium PSMA versus lutetium PSMA six months down the road.

So really you may not expect a difference in overall survival in such a context. But I think we have a good case now to discuss with the health authorities and the payers, to hopefully have lutetium PSMA approved in this indication. Again, it's a really unmet need in mCRPC. Many patients either are not immediate candidates for chemotherapy just because the disease is indolent or they don't want chemotherapy, and we all see those cases. Or finally, we also treat some vulnerable patients who just cannot tolerate chemotherapy at active doses. So we have to address all these populations and I think lutetium PSMA is a very good option based on this data for these men.

Alicia Morgans: Well, thank you so much, Karim. I think it's really exciting certainly to the overall survival update and then also to see this quality of life data. I'd love to hear your thoughts on the overall survival data and how it looks like we're honing in more precisely on that point estimate. And now it has moved below one. What is your take on this in terms of the utility of this treatment and the previous thought that perhaps it could be causing harm if the point estimate was above one? Does this change now with the new estimate?

Karim Fizazi: Well, first of all, I think it's a very important finding towards the health authorities because any agency, either the FDA, EMA, or another one, hates to see a hazard ratio for overall survival with a new treatment above one. Because they're wondering whether we are harming patients. And even if it's just above, you never know. So we're putting them in a difficult situation to make a decision when they're facing such a scenario. And it's actually good that it's not anymore the case. But frankly, I think we have more package now. The package includes both VISION data and PSMAfore data. And I'm saying that because number one, from VISION, we know that this treatment when used in patients with CRPC versus a group of men who don't receive it at all, actually improves overall survival. And in VISION it was a 40% reduction in the risk of death. So this is very important.

Now, this being said, in a second phase 3 trial when used earlier, the same treatment clearly postponed progression as measured by all its aspects, clinical, biological, imaging, quality of life, everything. But in a context where we really wanted to be fair with patients and provide them with the opportunity to get access to that treatment. Especially at the time it was not fully and broadly available in the VISION indication. We actually allowed a crossover and the crossover was enormous in this trial. So again, we were comparing immediate lutetium PSMA versus lutetium PSMA tomorrow or in six months' time. And in such a scenario, you cannot really expect an improvement in overall survival. So I was sincerely not expecting it to happen given the design of the trial. And it's not shocking to me if we don't get it, again, understanding that this was met in VISION as the first phase 3 trial.

Alicia Morgans: Yeah. So I think that makes complete sense. And just to sort of round out your conversation around the package of information, certainly the quality of life data that you presented adds to that understanding and is really consistent with the quality of life data that we saw from the VISION trial as well. As you think about it, one thing that was raised as I was speaking about some of this with colleagues was that, can you really trust the quality of life data when patients were not blinded in this study? What are your thoughts there?

Karim Fizazi: I take this point, and it's a fair one. I think indeed, for example, when measuring the... They were not blinded for treatment, but they were also not solely blinded for PSA progression, for example. And when you're measuring emotional well-being, PSA plays an obvious role. None of my patients, and I guess it's the same for you, likes to have bad news when they receive their PSA values and understand that it's rising. And this is very obviously associated with emotional deterioration and anxiety. So again, this is also true in our practice. It's not only that we're not blinding a treatment in a phase 3 trial, but it's also that bad news and good news are not blinded in real life. So to me, it's not really shocking if we are also measuring that in our trials because again, at the end of the day, it's just reflecting real life.

Well, I think still... I think that the physical well-being improvements, for example, is probably more a, how should I say that, a fair measure, if you will, of a treatment effect against the cancer and the cancer progression. And again, it goes together with PSA, goes together with imaging-based PFS, and I have experience we've treated probably 30 patients in this trial. It's also quite obvious that the time to symptomatic deterioration is being postponed by this treatment again, as compared to a secondary AR pathway inhibitor. So I think it's really a true finding that was reported by those quality of life domain assessments.

Alicia Morgans: I would completely agree. And I think your point about patients not being blinded in real life is also really an important one. I think patients report what they feel. They try to be honest, they have no motivation, I think, in a trial or otherwise to pretend that they feel better or worse. And I think especially in a clinical trial, those individuals that have taken the time, made the commitment to participate are going to be very honest. If they feel worse, they're going to share that. And the degree of difference that we saw between these arms was more, I think, than one would expect to see if only those differences were related to being disappointed about being on one arm or the other. So I completely agree with you, particularly around the physical function, and I do think that this reflects as close to one could imagine the way that patients may feel and function in their daily lives as they're actually getting these treatments. So as you think about this and you want to maybe give us a quick summary, what would that be for this updated data for PSMAfore?

Karim Fizazi: Well, we knew already that the primary endpoint, which was radiographic progression-free survival, is improved significantly with a 60% reduction in the risk. Again, very important from a registrational standpoint, overall survival is not detrimental. Again, very important towards the regulatory agencies and more clinically important I think, are the new data we showed at ASCO regarding time to deterioration in quality of life and pain, probably directly measuring the benefit, the clinical benefit we're providing to the patients. And I mean, to me, this is even probably more convincing to be honest, as compared to rPFS. So I guess this convinced me that if approved, given the overall great safety of this treatment, I would be really confident to use this treatment in my next patient to come and again, try to avoid a switch to a secondary AR pathway inhibitor. That sometimes we do by default, simply because we don't have anything else to propose except going for chemotherapy.

Alicia Morgans: Wonderful. Well, as you said, it really adds to the package of information that we have on this particular agent, one that actually is quite compelling both to clinicians and to patients alike, whether it's disease control or whether it's improving quality of life. There seem to be benefits here in both settings. And so I appreciate you providing these updates and sharing your thoughts on some of these challenging questions. I appreciate your time.

Karim Fizazi: Thank you very much.