Mehmet Asim Bilen: Thank you so much, Dr. Agarwal. It's always great to be here with you and discuss some of our recent data, and always great to see you also.
Neeraj Agarwal: And you continue to present a lot of data in different meetings. Congratulations for all your successes. Tell us more about the recent real-world experience you published on apalutamide in patients with metastatic hormone-sensitive prostate cancer.
Mehmet Asim Bilen: Yeah, thank you so much, Dr. Agarwal. Yeah, this is a team effort that we put together, and I'm glad to share some of our recent data, which, as you said, published recently, overall survival with apalutamide versus enzalutamide in metastatic castration-sensitive prostate cancer. You are a prostate cancer expert, you know all these trials very well, and you are the lead investigator for TITAN trial, which is a phase 3 trial, apalutamide plus ADT versus ADT alone. And as you know, after this trial, we start using apalutamide in our patients with metastatic hormone-sensitive prostate cancer, and also the same population like we had ARCHES data bring enzalutamide and we have LATITUDE data bring abiraterone.
And again, all these studies prolong overall survival in this patient population. And I think, as a medical oncologist, we all feel that we have great options, great tools like for our patients with metastatic hormone-sensitive prostate cancer, but the gap is there is really no head-to-head comparison with all these drugs. And sometimes, choosing which one we're going to prescribe is always a challenge. And we also know we are not going to have any prospective head-to-head clinical trial. Because of this reason, I think real-world comparison can be quite helpful to give us some data, generate some data to help our day-to-day clinical practice is the main reason for these analyses. Again, our objective is compare the proportion of ARPI-naive patients surviving by two years who received apalutamide versus enzalutamide was the objective of this data.
And what we use in this analysis, Dr. Agarwal, we use FDA guidance for real-world evidence. As you know, this is a evolving territory. We are using real-world evidence. I think we're going to use more and more in the near future. And recently, FDA put a guidance how we ensure there is a methodological rigor in those studies, which I think is very, very important because we don't want garbage in and garbage out. We really want a trustworthy data. Because of this reason, I'm very happy that FDA put some methodological guidance not only for academia, but also industry, and also not only FDA. There is a number of institutions, like Duke and others, also put some guidance document to make sure we have a good methodology in this real-world evidence. And this is what we use in this publication. We use the FDA guidance best practices. And because of this reason, hopefully we make this study as robust as possible for the readers and for the audience.
And what are the key elements for a good real-world evidence? We need to have a study design. We need to have the hypothesis, and we need to define the outcome, even before we did the analysis. And data source is very important. We need to make sure the data is as reliable as possible. We try to minimize any biases, and we also need to make sure the data is reproducible and archived. And when we need to reanalyze, we need to make sure the data is available. And also, just like anything else, I think analytical plan is very, very important, including sample size, a statistical estimation and endpoints. And all of those need to be set stone before you do the analysis. I think that make a real-world evidence all together.
And in this publication, we use two unique source in terms of data. One of them is Precision Point Specialty Analytics, which is an EMR-based data coming from urology practices. As we know, a lot of patient with prostate cancer treated urology practices in real-world. And this database give us all the clinical information, like your PSA, castration resistant date, and all the demographics, and so on and so forth. And in addition to that, we also use KRD, which is an insurance claim, because we want to make sure the drug is prescribed, but also paid and patient receive it. Because of this reason, having two data source is very important. And the other advantage for KRD, they have a robust overall survival data, which is getting from the EMR, but not only EMR, from national state government data, public listing, or arbitrary data, because that's very, very important in real-world study since our endpoint is overall survival.
And the study period is between 2018 to 2023. This is the time both of the drug was FDA-approved, not only enzalutamide, but also apalutamide. And we have a pretty large cohort, initially 20,000 patient. But after then, we dissected the patient population that is applicable in this analysis, metastatic hormone-sensitive, no other ARPI, no other chemotherapy usage. And ultimately, we have close to 2,000 patient in each cohort which was analyzed for this publication, and the outcome is, again, two-year overall survival.
And this is the baseline characteristics. I think one of the advantage for real-world evidence, since you have a large cohort of patient, you are able to match, and we use propensity score matching to control known biases as much as possible. As you see in this table, like age, race, index years, the percent of de novo prostate cancer, the PSA, Gleason score, Charlson Comorbidity Index, those are all matched. Try to make the cohorts as similar as possible was used in this analysis.
And ultimately, this is the primary endpoint for the analysis, like OS comparison. The blue line is apalutamide. The black line is enzalutamide. And as you see, the patient who received apalutamide by 24 months post-index have a better survival, a 23% reduction of death in apalutamide cohort. And when we look at all available data, still, apalutamide have better survival than enzalutamide with the HR of 0.77 and the p-value is 0.008. We had a median follow-up of close to two years. And then, hopefully, when the data is mature, we can reanalyze in this cohort of patient.
And overall, our conclusion is patients with metastatic castration-sensitive prostate cancer in this real-world analysis, if they receive apalutamide, they have 23% less likely to die by two years compared to enzalutamide, and we also see similar overall survival. If you look at the phase 3 TITAN trial in this cohort of patient, versus TITAN trial, apalutamide might have a similar survival, which also gave us some relief and comfort because we don't want to have a two different survival in two different cohort of patient, and I think this is the first head-to-head real-world comparison. Because of this reason, hopefully, it will be helpful for clinicians and doctors who are treating patients with prostate cancer.
But any other real-world study, Dr. Agarwal, of course, there is some limitations which I always want to highlight. Because at the end, this is a retrospective data and miscoding and misclassification can be possible, and that led some biases, like in the study population. Although we have a very robust database, but this is still always a possibility. And also, as I mentioned earlier, the data has come from urology practices, and we know prostate cancer not only treated urology. Hopefully, we have other databases, and also databases having patients from oncology practices, and that make the study even more robust in the future. We use KRD to capture as much as overall survival as possible, but there is always some missing survival in real-world data. That's always a limitation. And also, we use regression analysis, try to balance all these confounding factors, but there is always some unknown confounders that can affect the survival. And last but not least, we have a two-year median follow-up. Hopefully, once those databases are becoming more and more mature, we have some additional follow-ups that make comparison even more robust and more applicable.
I think those are my quick summary, Dr. Agarwal, and happy to help, happy to answer if you have any questions.
Neeraj Agarwal: Congratulations, Asim, for doing this analysis. Real-world data always help. Please tell us more about the guidance by the FDA for our audience, how it is different from just picking up real-world data randomly and comparing the two drugs. So, what is different following this FDA guidance?
Mehmet Asim Bilen: Yeah. No, that's a great question, Dr. Agarwal. Again, the FDA document, I think, is quite helpful because you have to have a protocol ready, and that protocol have your study design, your statistical methodology, your endpoints, your sample size, and all of those need to be planned before you analyze the data. I think that's one of the highlights of the guidance.
Neeraj Agarwal: Like we do for clinical trials?
Mehmet Asim Bilen: Exactly, like we do for prospective clinical trial. Another important thing also, whatever your data is, you need to publish. That's also one of the requirements for the guidance. Even if it's a positive data, negative data, you still need to publish, and you also need to archive all your database and your analytical plan, and so on and so forth, which I think make this kind of studies more trustworthy. Of course, this is a process. More of us do those kind of analyses and then discuss, and then make it even better and better. And in addition to that, our databases are also getting more robust, like if you are using AI and other technology, and also give us more trustworthy databases. And ultimately, I think those guidance really make things better down the road.
Neeraj Agarwal: And I see that these are large number of patients in both sides, and these are mostly from urology practices. So, in your opinion, how this population could have differed from the medical oncology practices? Because we know our urology colleagues treat large number of patients with metastatic hormone-sensitive or castration-sensitive prostate cancer.
Mehmet Asim Bilen: Yeah. No, that's really important, Dr. Agarwal. Yeah, that's the trend in real world because, most of the time, our urology colleagues diagnose those patient and then continue. I think because of the practice setting, they tend to use more doublets than triplets. Because of this reason, for this kind of analysis, I think it's not a problem because we are comparing doublet versus doublet. But if you want to compare a triplet versus another triplet, I think you may need more medical oncology-based data since there is not much chemotherapy administration in urology practices. I think overall, this is still important database, and I think those data is also coming from area of excellence, like our urology colleagues treat prostate cancer in all these drugs. Because of this reason, I think overall, it's applicable and is generalizable at the end of the day.
Neeraj Agarwal: And I agree with you. If you look at the real-world databases, even Flatiron, we have looked into the use of triplet. Use of chemotherapy remains very low, actually, in the real-world patient population. Until very recently, it was about 10% of all patients with metastatic hormone-sensitive prostate cancer treated with ADT plus ARPI, plus a chemotherapy, like docetaxel, which is the only approved chemotherapy right now. So I think from that perspective, these data do reflect the practices across urology and medical oncology in my view, if you look at the use of doublet, which was used in majority of patients. Any final comments for our audience today? Would you be able to summarize these data for our audience who are listening to us today?
Mehmet Asim Bilen: Perfect. Thank you so much again, Dr. Agarwal, for highlighting our work. It's always great to discuss with you. I think in this analysis, we see better overall survival in patients who receive apalutamide versus enzalutamide in metastatic hormone-sensitive setting. I think overall, real-world evidence become more and more, and we're going to hear more and more real-world evidence in the future. And as a field, as a group, we discuss and make those studies more robust. And I think this will also help our patients to get the information quick and early and give us some evidence-based therapy selection. Because of this reason, I think overall, things are heading on the right direction.
Neeraj Agarwal: Thank you, Asim, for taking the time to discuss your data with us today.
Mehmet Asim Bilen: Thank you so much, really appreciate it.