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Alicia Morgans: Hi, my name is Alicia Morgans, and I am a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, Dr. Karim Fizazi, who is a Professor of Medicine and a GU medical oncologist at Gustave Roussy in Paris, France, as well as his colleague Mihaela Aldea, who is a medical oncologist at Gustave Roussy also. Thank you both so much for being here with me today.

Karim Fizazi: Always a pleasure, Alicia. Thank you for having us with you today.

Alicia Morgans: Wonderful.

Mihaela Aldea: Thank you, Alicia.

Alicia Morgans: Thank you. So I wanted to talk with you both about a presentation that you made at ESMO 2020. It was a really interesting presentation thinking about the use of cabazitaxel in patients who have DNA repair defect alterations. And Before we really dig into that specific work and your presentation, maybe Karim, you wouldn't mind just reviewing for us what the role is of cabazitaxel in the metastatic castration-resistant prostate cancer setting.

Karim Fizazi: Sure. So cabazitaxel is a well-known drug in prostate cancer. It was developed in the 2000s, and actually, we've been using it quite broadly in the last decade based on Phase 4 evidence that overall survival is improved even in men who have failed castration, but also docetaxel chemotherapy.

Having said that, during this decade, and because also we had so many other drugs to play with, there was debate as to whether the role of cabazitaxel was still important. And this is why the CARD Phase 4 data was conducted. And versus a Phase 4 arm looking at men who have failed castration, one AR drug which is abiraterone or enzalutamide. One taxane, docetaxel. And what [inaudible] was whether we should use a second taxane or second AR drug. And data came out also at ESMO some two years ago, plus or minus and actually, it was very clear that not only cabazitaxel improves the primary endpoint over radiographic progression-free survival, but also, overall survival when compared versus the second AR drug.

And actually, it was really fun because I was sitting in the room at this time when the data was presented and just side by side, the CARD data was presented. And then right before, or right after, I can't remember, the PROFOUND data looking at olaparib in pretty much the same population of men with DDR alterations was also shown, establishing the role of olaparib, a PARP inhibitor in a vast population of men. And when we get out of the room at ESMO, everybody was happy, of course, because we had two active Phase 3 trials, and everybody was asking the question, but should we really test patients for DDR alterations and go for a olaparib? Or should we just use cabazitaxel in all comers? And this is why we felt that it was worth it, trying to better understand the role of cabazitaxel in men with DDR alterations.

Alicia Morgans: Well, thank you for that summary and for that nice memory, I also was sitting in that audience and it was so powerful because these were the presidential symposia, the main presentations, or the most exciting presentations of ESMO and you are right. I think that we saw firmly, or clearly that cabazitaxel, so firmly has this established role, particularly when compared with the second AR targeted agent, and it really improved quality of life outcomes as well. I mean, all of that was so powerful, but the question remained, how should we think about patients, this smaller population of patients who have DDR alterations and Mihaela, are you able to tell us just how did you put this study together in order to try to answer that question?

Mihaela Aldea: Yes. Thank you, Alicia. So actually we wanted to investigate if cabazitaxel is active in mCRPC patients with, and without DDR defects, and we performed a retrospective multicenter study. We included 15 centers from France and Spain. We included the patients with mCRPC, who received cabazitaxel as monotherapy irrespective of their prior lines. We included those patients who already had an available DDR molecular profile. And actually, we performed two groups, patients with DDR positive tumors and patients where no DDR alterations were found in their tissue analyses. These patients were matched in a one-to-one ratio for the same molecular test and within the same institution in order to reduce the flows of retrospective studies. And in order to make the two populations more comparable.  We assessed the PSA decline in this population, radiographic progression, free survival, and overall survival. And, actually, in the end, we had 190 patients that were included, 95 patients with the DDR alterations and 95 patients without. In the NGS panel, there were various NGS panels, but we choose those patients in which the NGS panel evaluated, at least BRCA, CDK12 ATM, CHEK2, FANCM, PALB2, Ret51, and reaper alterations.

Alicia Morgans: So that is such powerful work to do, and to really make sure that the DNA repair alterations that you were assessing were actually going to be similar across all of the sites that you included, including several sites in France and in Spain as well, that in itself is a task to really be proud of undertaking. And so I love that you were able to do that, that you were able to make sure that this was a consistent assessment of these DNR repair alterations. And then, you compared actually, before we even get into the results of PSA and radiographic progression you were able to compare your populations. Then as you chose this DNA, these patients who had the alterations and those who did not, and it was interesting, I think, how these two populations really compared to each other across these sites, what did you find?

Mihaela Aldea: So actually there was a difference in terms of the median age of patients.  We found the younger patients in the DDR positive group as compared to the DDR negative group, actually, DDR positive group had the median age of 66 years and as compared to 69 in the DDR negative group. So suggesting that these patients might have more aggressive disease, but there was no difference in terms of the presence of visceral metastases between the groups or in terms of the performance status, the median PSA, or the Gleason score at the diagnosis. And also these populations are comparable in terms of prior treatments, both groups had a number two median prior lines, but in the DDR positive group, of course, these patients received a significant proportion of cases, PARP inhibitors, and carboplatin. Actually, we had nearly 45% of patients who were treated with PARP inhibitors and 38% who received carboplatin anytime in their disease evolution. Actually, in the DDR positive group, the most predominant alteration were BRCA alterations followed by ATM and CDK12. We did not have the germline status for all the patients, but for those patients where the germline analysis was available, nearly 50% of cases had germline alterations.

Alicia Morgans: Wow. You know, that's, that's so impressive. The amount of data you were able to collect on those patients. And also very impressive to me that, so many of the patients with DNA repair alterations across these sites actually had been treated with PARP inhibitors or with carboplatin. So very interesting that there was such exposure.  As we think about the results Karim, can you tell us, did cabazitaxel work in these patients who had these DNA repair alterations,

Karim Fizazi: Right. It indeed seems to be the case. Of course, this is a retrospective analysis. We need to be cautious with the data.  But again, given the methodology we used, just really find the patients who are screened in clinical trials and match them with DDR negative patients. I think we were quite comfortable with the results and indeed the degree of efficacy, as far as we could tell by PSA decline, clinical responses, and time to progression indicates that indeed cabazitaxel seems to be an active drug in men with DDR alterations and mCRPC, which I guess is very reassuring to us because not everybody on earth has access to a PARP inhibitor. For example, carboplatin is cheaper and broadly of a label, but that's not necessarily the case for PARP inhibitor due to approval or cost or whatever reason. So knowing that cabazitaxel remains active in a vast population of men, of course, is very important.

Now, the question, I guess, we haven't completely addressed due to the methodology, but also to the number of patients we had is what actually is the activity of cabazitaxel in patients who have failed a PARP inhibitor and actually visa versa. We waited on the data, Mihaela can comment a bit more, but from the data we have, it seems that there is at least a degree of cross-resistance, whether it's true cross-resistance or just the fact that the cancer that has already progressed on one drug is more difficult to treat in general oncology. We don't know, but it seems to be the case. Again, this requires clearly more data and hopefully, we'll be able to generate more, but again, Mihaela may comment more on the efficacy data.

Mihaela Aldea: We need perspective data in order to respond to this question. The limit of this analysis was that the subgroup was very small. We evaluated only 18 patients in the post-PARP setting. So we cannot draw clear conclusions, but it was interesting to note that in the BRCA population, there were 10 patients in the post-PARP setting and neither of these patients obtained a 50% PSA decline in the post-PARP setting. But maybe because they were already in a more advanced stage after significant benefit on the PARP inhibitors, we don't know, we need more data.

Alicia Morgans: Yes. And just for the viewers who don't have a copy of the poster to really clarify this, I think it was so interesting that the responses to cabazitaxel in terms of PSA and radiographic progression actually seem to be similar among patients who had these DNA repair alterations when compared to patients who did not, but what Karim and Mihaela are really digging into is that the cabazitaxel response rates and progression time seemed to be longer in patients who had the DNA repair alterations prior to their treatment with a PARP rather than after when compared to after. But as Mihaela said, the numbers get so small that it is really difficult to draw any conclusions, but it certainly is hypothesis-generating and why this could be, maybe the diseases, as Karim said is simply more advanced, is more resistant.

Maybe there is some cross-resistance who knows, but we do know that the drug seems to work and for all of our patients or my patients, my goal is always to get as many lines of therapy into a patient as possible, because, with each line that is effective, that is more time that the patient has as long as the treatments are treating them okay. And we know that these drugs can be tolerable for patients. So very, very interesting, and important to see that the responses are strong, that they are consistent despite these DNA repair defects and more work to be done, for sure. So Karim, is there more work? Is this something of interest that you or others you think will be exploring in terms of sequencing or understanding this more thoroughly and in patients with these alterations?

Karim Fizazi: Right. I think, and this is a general thing, that we should do more and more. I mean, if I'm comparing this to the current situation and the soon situation, as compared to the situations we were living say, five years ago, we will currently, or we will soon have PARP inhibitors, likely PSMA targeting. cabazitaxel remains there. And we need to better understand whether patients can still benefit from a given treatment when we have exhausted one of them either, because in the PARP inhibitors story because they have DDR defects or say for PSMA targeting because the cancer is expressing PSMA. And I think that taxane may remain active in at least a minority of these men. But again, we need prospective data on that. And that is true for PARP inhibitor, as it will soon be hopefully with PSMA targeting. Those are the data we need to generate again because I'm like you, Alicia, I mean, this is a chronic disease. And when you have exhausted one treatment, you still want your patients to benefit from another one. So we need to try to figure out what is the best treatment to propose in those particular settings. Hopefully, we will generate these trials prospectively.

Alicia Morgans: Absolutely. Well, to both of you, then just a final question. If you had to summarize Mihaela the results of your study and give a message to the viewers, what would your message be?

Mihaela Aldea: So my message would be that cabazitaxel is definitely active in mCRPC patients irrespective of their DDR status.  Maybe the overall survival of these patients, maybe of patients with DDR alterations, maybe longer than patients with DDR negative profiles, because these patients are also treated with PARP inhibitors and carboplatin or carboplatin. We don't know if the efficacy of cabazitaxel is lower in men, previously treated with a PARP inhibitor, but this requires validation in a prospective study.

Alicia Morgans: Well, that is a great summary. We will see, what is left for Karim to put things into context for us.

Karim Fizazi: She really said everything. Maybe I may just start on a financial thing, which is that I mean, first, it is good news for the patients. We all know that BRCA2 patients, for example, have quite aggressive cancers very often. And having one more line of therapy is obviously good news. Of course, it's not a Phase 3, but the data I think is robust. And as Mihaela said, it very clearly suggests that cabazitaxel is active in these men with DDR positive cancers. And financially speaking, cabazitaxel will soon become a generic drug, which means that the costs will significantly decrease. And again, this will hopefully let much more patients worldwide get access to this agent as it is already the case for carboplatin, for example, for DDR positive cancers. And I think worldwide, this is also very good news.

Alicia Morgans: I completely agree. Well, thank you both so much for your time, for doing the work that you do, and for sharing your expertise today. I sincerely appreciate it.

Karim Fizazi: Thank you very much. Have a great day, Alicia.

Mihaela Aldea: Thank you.