Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so delighted to have here with me today a friend and colleague, Dr. Cora Sternberg, who is a Full Professor of Medicine and a medical oncologist at Weill Cornell University. She's also the Clinical Director of the Englander Institute for Precision Medicine, as well as being the PI of the PROSPER trial, the study that looked at enzalutamide in men with nonmetastatic CRPC and recently reported an updated analysis, including overall survival data. Thank you so much for being here with us today, Dr. Sternberg.

Cora Sternberg: It's a pleasure to be here as always. So in terms of patients with nonmetastatic castration-resistant prostate cancer, just back in 2018, if you looked at all the guidelines, it was clearly stated that one should never treat these patients outside of a clinical trial. And many patients do develop nonmetastatic castration-resistant prostate cancer because they are considered to be elderly, for one reason or another, they're treated with androgen deprivation therapy, or they've had radiation and androgen deprivation therapy, or not had a prostatectomy or had one. And they can develop nonmetastatic CRPC as defined by bone scan and CT scans.

And what we know from earlier trials was that there's a relationship between PSA doubling time and risk, for example, bone metastases or death. And the shorter the PSA doubling time, the higher the risk, so that in patients with a doubling time of less than 10 months, or specifically less than six months, they have a very high chance of developing bone metastases or death. And so, therefore, the PROSPER trial was designed with this knowledge. And patients with nonmetastatic CRPC on androgen deprivation therapy and a rising PSA, despite having castration levels of testosterone and a PSA doubling time of less than 10 months, but also baseline PSA of greater than equal to two nanograms per ml, 1400 of these patients were randomized in a double-blind period on two to one to receive either enzalutamide, 160 milligrams a day, plus ADT versus placebo and ADT. And the primary endpoint of this study was metastasis-free survival, and metastasis-free survival was reported back in 2018 at GU ASCO and published in the New England Journal of Medicine. And we did find a 71% reduction in metastasis-free survival.

At the time of that publication and presentation, there were amendments made to the study, and a crossover was allowed for all the patients on the placebo group who had not progressed, and they were allowed to cross over to enzalutamide. And what we showed even back then, again, I told you, a 71% reduction in metastasis-free survival, a huge difference in PSA progression, and also a very large difference of the time to the first neoplastic agent.

What we did in this study and in the New England Journal now was to update the data and looking at the time to the first use of a subsequent antineoplastic therapy, there was, again, a huge difference, a hazard ratio of 0.29. The median was 66.7 months on the enzalutamide arm as compared to 19 months on the placebo arm, in which they received a subsequent neoplastic therapy. And what was really remarkable was the overall survival analysis. We were thinking that metastasis-free survival was important. The FDA had approved enzalutamide for this indication for metastasis-free survival, but the overall survival analysis showed a statistically significant 27% reduction in the risk of death, which meant that the median in months was 67 months as compared to 56 months on placebo. And that's an 11-month difference with a hazard ratio of 0.73. And this was with approximately 48 months of median follow-up.

And if we looked at the overall survival in all the prespecified subgroups, the benefit was consistent across all of the prespecified subgroups, including performance status, the PSA doubling time, if it was less than or more than six months, their Gleason score, their baseline LDH and hemoglobin as well.

And you had asked me of something about subsequent antineoplastic therapy. Well, it's true that in the New England Journal article, we did have a slide explaining that the placebo group, 65% got a subsequent neoplastic therapy and 33% in the enzalutamide group, but this is within the study itself. And within this study itself, the placebo group got primarily abiraterone acetate, which was 59% and the enzalutamide group 67% got docetaxel chemotherapy. But if you add in the other 87 patients who didn't progress and who did cross over to active therapy with enzalutamide, then 84% in the placebo group actually received a subsequent, or at least one, antineoplastic therapy after discontinuing treatment. It was 84%. So, I think there was a little bit confusion about that, and we have it in the footnote of table one in the New England Journal article.

Alicia Morgans: Yeah, I think that's really important to emphasize that, as you said, that having these subsequent therapies in the control arm was really important in understanding that survival data. Because we know that there have been trials that have failed when patients who have had actually not as early diseases, nonmetastatic CRPC, even in the metastatic CRPC setting, who have received subsequent therapies after an initial treatment that was presumed to work because the magnitude of benefit may not have been as strong, but in this nonmetastatic CRPC setting, I think it's really important to recognize that not only was metastasis-free survival improved, but the long-term overall survival was improved, suggesting that this window of opportunity could potentially be capitalized upon. And if we do wait for effective treatments to begin later, we may be missing some of the benefits that we could reap if we do it earlier. What do you think?

Cora Sternberg: I think you're absolutely 100% right. And not only do we have these data showing that in patients with non-metastatic CRPC, there's an improvement in survival with enzalutamide, there were two other trials, the SPARTAN trial with apalutamide, the ARAMIS trial with darolutamide. All of them had very similar entry criteria, patients with a PSA doubling time of less than 10 months. All of them had patients who had nonmetastatic CRPC. All of them were looked at with CT scans and bone scans, and they all showed very similar improvement in metastasis-free survival and in overall survival as presented at this year's ASCO. So when you have three studies with three different drugs giving you very similar results, I think that one supports the other, showing that giving these androgen receptor-targeted agents earlier on is better.

Alicia Morgans: Very important to know and to understand. And thank you for making sure that we have the data to understand that and to make those choices with our patients.

One thing I hear a lot in practice or from clinicians as we are facing kind of the great unknown in terms of molecular imaging and thinking about eventually having access to things like PSMA PET or other forms of these nuclear medicine targeted imaging techniques, folks have said, "Well, this will be a vanishing space." Certainly, Europeans have said that this is a space that we don't see in our practices because we are doing this more intensive imaging. And, importantly, I think we did see data that suggests that if we take patients who are similarly characterized as those who might be in the nonmetastatic CRPC setting in any of the trials that we have in the space, that most of those patients actually do have demonstrable disease by this more sensitive imaging technique. How would you respond to folks who are trying to understand whether this data would still be applicable to those patients who have conventional imaging, non-metastatic disease, but maybe PSMA positive disease?

Cora Sternberg: I'm not sure how long it's going to take to have PSMA PET scans all over the world that not even FDA approved yet. And we also don't know the cost yet of the PSMA scans. I like to use them in the context of the research setting now. And, for me, they're most important in patients with localized disease who have a very low PSA and rising PSA, let's say post-prostatectomy or post-ADT and radiotherapy. When you need to, especially post-prostatectomy, to understand the radiotherapy field that you might want to give, I think that this imaging is extremely important.

It's also important, as we heard in the therapy trial later on, if you want to select patients for PSMA lutetium treatment, for example, but having said that, at Weill Cornell, we do not use the PSMA scans to select patients for treatment. We do not do both PSMA scans and PET scans. But in this case, I think that what we've seen in three different studies is that treating patients earlier means that they do better. And I would not be surprised if we do more PSMA scans to your question that we won't find more micrometastatic disease, which is just more of a reason to be treating these patients earlier because we're treating the micrometastatic disease, and that's why they're living longer when they get effective treatment with an AR targeted agent earlier. So I think that if we do have the scans, we might find micrometastatic disease earlier, and then we'll still be treating them earlier. But I don't know if that will be the place exactly where these will be used, these scans.

Alicia Morgans: I think there's a lot of food for thought and a lot for us to still learn. And I appreciate hearing your thoughts and how we can kind of sort through that at this point. As we think about the newly released overall survival data from the PROSPER trial, what would your closing message or summary be to patients and to clinicians who are trying to put this new data into context?

Cora Sternberg: I think it's important to understand that in patients with nonmetastatic castration-resistant prostate cancer who have a doubling time of less than 10 months, not for everybody, but for having a PSA doubling time of less than 10 months, giving enzalutamide resulted in a 27% lower risk of death, meaning prolonging overall survival by approximately one year. And I think this is extremely important for clinicians to understand we had before approvals based on metastasis-free survival, and metastasis-free survival does correlate with overall survival in this trial and in the two other trials.

I would say the adverse events seen with enzalutamide in the PROSPER trial were consistent with what we know from the established safety profile of enzalutamide from the AFFIRM and PREVAIL trials and many other trials, and we have a long experience of using enzalutamide. And when we look at safety, also, in comparison among trials, which is always very difficult to do, you have to understand that, for example, the enzalutamide treatment duration was 34 months, and the placebo duration was 42 months. So I think it's very important to look at adverse events in terms of hundred patient years and not just look at absolute numbers because the time on treatments can be very different among the different studies, and even within a study, comparing an active agent to a placebo.

Alicia Morgans: Thank you very much. And thank you for your time and your dedication to helping us understand better how to treat these patients. Thank you again.

Cora Sternberg: Thank you so much.