Bobby Liaw, MD, reviews the study design and results of the phase 3 ENZAMET study and discusses an ongoing trial in mCSPC, ARASENS.
Neal Shore, MD, FACS: Bobby, let me turn it over to you. Maybe you can tell our colleagues how ENZAMET was nuanced but different from ARCHES. In ARCHES, 18% of patients had prior docetaxel. In TITAN, 11% of patients had prior docetaxel. Review now for us ENZAMET and the ARASENS trial, which is pending a readout in the near term, hopefully in 2022.
Bobby Liaw, MD: You set me up really well. ENZAMET was also a phase 3 study in the CSPC [castration-sensitive prostate cancer] setting looking at enzalutamide plus ADT [androgen deprivation therapy]. But the control arm was looking at ADT plus 1 of the first-generation AR [androgen receptor] antagonists, whether it’s bicalutamide, nilutamide, or flutamide. But flutamide was by far the most popular 1. Trial design was similar to the ARCHES and TITAN studies, and people were randomized 1:1 to either arm, their stratification, according to the volume of disease based on the CHAARTED criteria.
The disease on this trial didn’t have to be de novo metastatic. It also allowed people with metachronous disease to come on for enrollment, and I’ll get into that a little later. The primary end point of study overall survival [OS]. The secondary end point was PSA [prostate-specific antigen] progression-free survival. Because data for early docetaxel came out midaccrual, the study changed its protocol to allow patients to receive docetaxel up to 6 cycles at the patient’s preference and at the investigator’s discretion. Roughly 45% of patients received docetaxel on this study.
As far as the top-line data, ENZAMET showed that the addition of enzalutamide to ADT was significantly associated with significant overall survival benefit to the tune of a hazard ratio of 0.67. Median OS was not reached in either group, but when we looked at 3-year overall survival, it was 80%. In the enzalutamide arm, it was 72% of the standard care arm. That’s the 1 including bicalutamide. Secondary end point of progression-free survival also strongly favored enzalutamide. These figures refer to the overall study population. When you start looking into subgroup analyses, we see differences for enzalutamide. There was a smaller effect on overall survival in patients with high-volume disease, those planned for early docetaxel, and those on antiresorptive bone therapy.
These subgroup analyses are limited. The amount of follow-up has been not quite as long. We didn’t have as many deaths for the overall survival cohort. But when you look at the same subgroup analyses in the United States using the secondary end point of PFS, you start to see a much more consistent benefit with the addition of enzalutamide in the high-volume patients in those who receive docetaxel.
I mentioned that it also allowed folks with metachronous metastases to enroll. About 28% of enrolled men had metachronous disease. It’s important to note because these patients tend to have a better prognosis compared with men with de novo metastatic disease. It’s important to note that these men with metachronous recurrence tend to have a lower burden of disease upon metastatic recurrence. But when we look at folks who had metachronous metastatic disease, regardless of disease volume, there was still a clear OS benefit in favor of the enzalutamide. When you look at the folks who had metachronous low-volume disease, the hazard ratio was even more attractive. It was about 0.4. This tells us that with all the controversy with the low-balling disease with docetaxel, it shows that enzalutamide has a strong stance with the improvement of overall survival in patients across the board.
Neal Shore, MD, FACS: This ARASENS trial that’s completed is potentially going to read out some time in 2022. It’s taking low- and high-volume patients with mCSPC [metastatic castration-sensitive prostate cancer], and they’re both arms will get ADT plus darolutamide, which is only right now approved in nmCRPC [nonmetastatic castration-resistance prostate cancer]. We’ll get to that. It’s an AR pathway inhibitor. There are some clear molecular differences with the other 2 approved drugs in mCSPC. But then patients will be randomized to receive docetaxel up front or not.
What do you think about that? That’s triplet comparing with couplet. There’s a graveyard of combination taxane treatments in mCRPC [metastatic castration-resistance prostate cancer]. This is different, though. This is the mCSPC population. I’m curious about your thoughts, Bobby. What are you doing…for a patient who has mCSPC. Maybe they have great performance status. They’ve got liver metastasesor maybe an enormous amount of bone disease. And you decide, “You know what? Let’s go with ADT-docetaxel up front.” When do you think about adding the ARPI [AR pathway inhibition]? Do you do it when they’re sensitive before ARASENS data come out? We have the ENZAMET data. We’ll talk about some other recent data from PEACE-1. But what are you going to do with that patient who says, “Doc, am I getting everything I can?” I’m really fascinated by how you’re handling that now.
Bobby Liaw, MD: As you mentioned, it’s starting to examine triplet regimen in men with metastatic hormone-sensitive prostate cancer. Data are still forthcoming, but I believe they’ve completed the study, and the primary end point was overall survival. It’s a very exciting study. Trying to read the future, I’d like to say that we’re going to see some very positive results out of that study. The reason I say that is because you had mentioned the PEACE-1 study data, which just came out at ESMO [European Society for Medical Oncology Annual Meeting].
They basically found that by incorporating a triplet regimen in the PEACE-1 study, it was a standard-of-care ADT plus docetaxel plus abiraterone. The combination of the triplet regimen was associated with a significant reduction in risk of death in patients with high-volume disease, to the tune of 25% risk reduction. Those are very convincing data. Whereas combination therapy with docetaxel plus drug X has not been the best strategy in castration-resistant disease. Especially for high-volume disease, we’re going to see that the data from ARASENS will show that it’s also comparable. The story is going to have to unfold a little longer for low-volume disease before we have a great sense of where that goes.
Neal Shore, MD, FACS: Great. Thank you.
Transcript Edited for Clarity