Significant Improvement With Continuous Enzalutamide in Men With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer – Axel Merseburger

March 25, 2022

Axel Merseburger joins Alicia Morgans to discuss the results from the PRESIDE study presented at ASCO GU 2022.  PRESIDE is a randomized, double-Blind, placebo-controlled, Phase 3b study of the efficacy and safety of continuing enzalutamide in chemotherapy-naïve, mCRPC patients treated with docetaxel plus prednisolone once they have progressed on enzalutamide.  Clinical data demonstrate that using docetaxel following progression on enzalutamide limits its effectiveness. However, continuing enzalutamide to target the androgen receptor beyond disease progression may be of clinical benefit. The objective of the PRESIDE study was to compare the efficacy of docetaxel plus enzalutamide versus docetaxel plus placebo in chemotherapy-naïve mCRPC patients who had progressed on enzalutamide. The investigators hypothesized that continued administration of enzalutamide would maintain control of responding tumor lesions and enable docetaxel to target clonal subpopulations that adopted accessory pathways of survival.  The PRESIDE study met its primary endpoint. The addition of enzalutamide to docetaxel significantly prolonged progression-free survival (PFS) (HR = 0.72, 955 CI 0.53-0.96; P = 0.027), resulting in a 1.3 month improvement in median PFS. The benefit of enzalutamide was observed across all subgroups with the greatest benefit in patients with soft tissue or visceral disease. Notably, subgroup analysis was not pre-specified. 

Biographies:

Axel Merseburger, MD, PhD, Professor of Urology, Chairman, Department of Urology, EiC “Aktuelle Urologie” University Hospital Schleswig-Holstein, Lübeck, Germany

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


Read the Full Video Transcript

Alicia Morgans: Hi. My name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I am so excited to have here with me today, Dr. Axel Merseburger, who is a Professor and Chairman of Urology in Lübeck, Germany. Thank you so much for being here with me today.

Axel Merseburger: Alicia, thanks a lot. Thanks for the invitation to meet here at ASCO GU in very lovely San Francisco.

Alicia Morgans: Wonderful. Well, I wanted to talk with you actually about the presentation that you gave at GU ASCO 2022, where you gave us some really interesting data on patients who had been treated with enzalutamide from a phase III trial where you actually added docetaxel on progression. Can you tell us a little bit about the trial and what made you put the trial together in the first place?

Axel Merseburger: Yes, thanks. So, as you said, it was a randomized phase III trial, including men patients with mCRPC, metastatic castration-resistant prostate cancer, who have progressed on enzalutamide in the mCRPC setting, and then were treated with docetaxel and prednisone. So you had one arm, placebo, docetaxel, and prednisone, and one arm, enzalutamide, docetaxel, and prednisone. The primary endpoint of this trial was progression-free survival, and as we know, important secondary endpoints like time to PSA progression, and safety, which I think it is very important when you look at combination data in advanced prostate cancer.

Alicia Morgans: Wonderful. And I agree, certainly, that toxicity data is very, very important as we think about this. And really interesting as we think about combining the enzalutamide and the docetaxel, which we've seen in some other studies, but always good to have more data. So, what did you find?

Axel Merseburger: Well, we know from metastatic prostate cancer, and 15 years ago we were discussing, you know, the Maha Hussain data of intermittent therapy. And now ADT is the backbone treatment of advanced prostate cancer. And it even goes further as we learn today, intensification not only in mHSPC makes sense like the ARASENS data, but now in PRESIDE, we could show that the therapy continuation with enzalutamide when chemotherapy CUPs comes on top of it, resulting in a statistically significant hazard ratio of 0.2 with regards to progression-free survival. So the men with advanced mCRPC had the benefit of combining enzalutamide with docetaxel and continuing the enzalutamide treatment.

Alicia Morgans: That's so fascinating, especially as you said, we are really looking at a lot of studies now that are combining these triplets of the backbone of ADT, an AR-targeted agent, and chemotherapy. And so this is a little bit of a different way of delivering that combination, but really again, suggesting that a triplet approach, these different mechanisms, may be active in our patients. And that is a really impressive progression-free survival hazard ratio.

Axel Merseburger: Agree. And I think it is also important to look at safety, once we go on and look at what clinical implications does it mean, should we continue like this in real life post-ASCO GU now? I mean a lot of therapy intensification, not only in mHSPC but now in mCRPC, is there. This is a standard in 2022. Safety-wise, PRESIDE has shown that it is safe and no new signals with regard to the combination of enzalutamide and docetaxel, as we already know from the ENZAMET trial. But now in a prospective phase III trial, we could prove, that this is safe and this could potentially prolong the overall survival of men treated with metastatic castration-resistant prostate cancer.

Alicia Morgans: Well, and to that point, are you continuing to follow these outcomes? Will you have overall survival data at some point? Or will that data become more mature over time?

Axel Merseburger: Well, this is the final analysis, and we have pre-planned this trial with PFS as a primary endpoint and secondary endpoint. So we will not have the OS, surely we will report subgroup analysis. We have biomarker analyses, which is coming, we have a lot more details in the final manuscript we are preparing right now. So exciting more data coming out of PRESIDE. But I think as of yet, and 15 years ago, when the trial was designed, PFS was the standard, surely knowing we will all want to see OS, but now looking at the other treatment options we have here, we have a clearer window with regards to comparing the two arms with PFS. And as said, the clear hazard ratio benefit of 0.71 for the combination and continuation with enzalutamide really, really supports PRESIDE data.

Alicia Morgans: And that's wonderful. So if you had to sum it up and give a message to the listeners, what would that be?

Axel Merseburger: Well, in advanced metastatic prostate cancer, and I know this is your 100% expertise, I think we are all going into the "all-in" at once. And as we learn from ARASENS, from the Titan trial, from the PRESIDE trial, from the PROpel trial, we really need to decide what is the sequence. "All-in" makes sense. In mCRPC we should continue with the enzalutamide once started and put chemotherapy on top. If this could be translated in the situation of the darolutamide trial now, or the TITAN trial with apalutamide, I don't know, but probably yes.

Alicia Morgans: It's really interesting. And since so many patients in the metastatic hormone-sensitive setting are getting combinations of ADT and one of the AR-targeted agents, it absolutely gives us food for thought as we think about what we do next. And in most cases, it's often chemotherapy. And having the ability to continue that oral agent during that addition may be a really interesting and beneficial option for us. So very interesting.

Axel Merseburger: I fully agree. And this one comment also mirrors the data we have seen with PEACE-1. I know this is mHSPC, but PRESIDE is basically a similar setting than we have in the PEACE-1 mHSPC situation. So we've also shown and seen in the PRESIDE trial that especially the men with visceral disease, with a lot of metastatic sites, had a benefit on this therapy intensification. So I think this is definitely the men that need intense treatment with a probably "all-in" indication at the beginning.

Alicia Morgans: Well, that's wonderful. And I really do look forward to seeing the subgroup analyses, the correlatives, and the breakdown, which patients benefit most. But I love the idea, the "all-in" approach. And thank you so much for sharing your data.

Axel Merseburger: Thank you, Alicia.

Alicia Morgans: And your expertise today.

Axel Merseburger: Thanks.
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