Neeraj Agarwal: Thank you, Leslie. It's always a pleasure.
Leslie Ballas: Tell me a little bit about TALAPRO-2 to set the stage.
Neeraj Agarwal: Yeah. So TALAPRO-2 is a big randomized phase three trial with more than 1,000 patients. And the trial was reported first in 2023 ASCO GU meeting. And since then we have... So just to take a step back, patients with newly diagnosed metastatic castration-resistant prostate cancer were enrolled in this trial. There were two cohorts. Cohort one was about 800 patients who were unselected for HRR mutations. So they were all-comer mCRPC patient population and as expected, 20% of them had HRR mutations, but other did not. So this cohort one had HRR mutation negative patients, some were undetermined status and HRR positive patients. But then cohort two specifically focused on HRR mutation positive patients. So HRR-deficient mCRPC patient population. And all patients were randomized to Enzalutamide plus minus Talazoparib and radiographic progression-free survival was met in both cohorts in 2023.
And then overall survival was also met in both cohorts in 2025. So we reported that last year. And based on these, there are variable indications in EMA, the approval is for all-comer patient population and the FDA approval for Enzalutamide plus Talazoparib is for HRR-deficient metastatic CRPC patient population. In the AUA presentation, we focused on correlation of radiographic progression-free survival with overall survival.
Leslie Ballas: And tell me why is that an important analysis?
Neeraj Agarwal: Great point. Radiographic progression-free survival has been shown to associate, to correlate well with overall survival in multiple tumor types, including in prostate cancer in different setting. That's number one. Number two, why this is important? When we show radiographic progression-free survival and if drug gets approved based on that, and assuming there is a good correlation with overall survival, this allows a expedited approval of the drug and an early access to a potentially life-changing drug for our patients. And that is the reason why radiographic progression-free survival has become an acceptable endpoint in multiple tumor types leading to multiple FDA approvals, including in metastatic prostate cancer. We have seen the approval of drugs based on metastasis-free survival and radiographic progression-free survival. This study was important because this has not been tested in the context of HRR-deficient mCRPC in first-line in the context of a PARP inhibitor.
Leslie Ballas: And remind us the definition of radiographic progression-free survival is based on conventional imaging. Is that correct?
Neeraj Agarwal: Yes, that's a great point. So PSMA PET scan was not used in this study. This study was started in 2018. Also, the PCWG3 criteria, so Prostate Cancer Working Group three criteria were used. So they use CT scan and bone scans for assessing the composite progression. So the CT scan is standard RECIST 1.1. So you have to have increase in the number of either new lesions or increase in the size of the existing lesions to satisfy the criteria for RECIST 1.1 or the bone lesion which are not considered measurable, but they're considered evaluable. So they look at the number of new lesions. But if you use the PCWG3 criteria, which is accepted criteria for regulatory approval, that's what was used for assessing radiographic progression-free survival in the TALAPRO-2 trial.
Leslie Ballas: And so how should we sort of think about radiographic progression-free survival in an era where everyone gets PSMA?
Neeraj Agarwal: Yes. So we'll talk about it later, in a moment, but before we get there, I will just elaborate on the results-
Leslie Ballas: Please.
Neeraj Agarwal: And methodology of this project. So standardized oncologic statistical methods were use. So I'm not a statistician, but I have got to learn a bit about statistical methods which were used from the brilliant statisticians, so Spearman's P, Kendall T statistical methods were used and as I learned, they're validated tools in oncology trials. They have been used in previous trials in assessing correlation between PFS and OS and then frailty model T was used, which was unique to capture the censoring of patients. So all these complement each other basically. And the correlation coefficient of less than 0.4 was considered weak correlation and correlation coefficient of 0.4 to 0.7 was considered moderate and anything more than 0.7 was considered strong correlation.
So we looked at the different patient population in the TALAPRO-2 trial, HRR-deficient, HRR unknown, HRR non-deficient by tissue testing. This is a very robust trial where everybody got tissue testing done. A lot of patients got ctDNA testing done. So the HRR-deficient status, if they're positive, is a well established status. Now, many patients also received Abiraterone and Docetaxel chemotherapy in the castration-sensitive patients, small number of patients, but still they can create heterogeneity. So we also looked at those patient population.
So multiple patient populations were looked at when we correlated radiographic PFS with OS. We also looked at investigator assessed PFS. The primary endpoint of the trial was independent radiology assessment for rPFS, but we also looked at investigator assessed rPFS and its correlation with OS. So as you can imagine, multiple statistical methods were used, multiple populations are used. Arms were looked at separately, arms were combined, separate patient population and what we saw was consistent. There was a moderate to strong correlation between radiographic progression-free survival and overall survival, regardless of the arm, regardless of the population, overall population, subsets of population, whether they received Abiraterone, Docetaxel in the past, whether it was investigator assessed, whether it was independent radiology assessed, except one setting when Enzalutamide plus placebo was given to patients with BRCA mutation and these were relatively small number of patients, but consistent correlation between radiographic PFS, OS, moderate to strong correlation.
Leslie Ballas: How would you take these results and put it into the modern context where everyone is getting PSMA as opposed to just conventional imaging?
Neeraj Agarwal: Yes. We know the PSMA PET scan shows us presence of metastatic disease like CT and bone scans do and they show this with higher sensitivity, to keep it simple. So if somebody get PSMA PET scan today and they do not have conventional bone scan, I would suggest continuing to do PSMA PET CT scans every three months as long as we are consistent with one type of scan modality. Obviously this was not a question which was answered in the trial, but for my clinic, if I'm using PSMA PET scan, I tend to be consistent. I don't want to stick to the same scanning methodology or modality for repeat scans. If I flip like, if I go from PSMA PET scan to CT scan, scans certainly look better. Or if I'm going from CT and bone scans to PSMA PET scan, even though PSA response have been great, they look worse.
So that's the only caveat. But other than that, I think it is inevitable that we will continue to evolve as far as scanning technology is concerned. But the good thing to know is from our data that even in the context of PARP inhibitors, there is a consistent correlation of radiographic PFS with overall survival. So it gives me confidence in the design of all these ongoing trials. Number two, it encourages us to continue to advocate for this earlier endpoint rather than relying on overall survival, which with the hope that it will expedite drug approval and access to these life-changing therapies to our patients.
Leslie Ballas: Neeraj, it's always so wonderful to see you. Congratulations on this presentation. We at UroToday are so happy you joined us.
Neeraj Agarwal: Thank you so much for having me.