Overall Survival Outcomes in ENZAMET (ANZUP 1304), Trial of Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer - Ian Davis

July 19, 2022

Ian Davis joins Alicia Morgans in discussing the overall survival (OS) outcomes in ENZAMET (ANZUP 1304), an international, cooperative group randomized phase three cooperative group, open label study, looking at the addition of enzalutamide, for patients with metastatic hormone-sensitive prostate cancer, commencing therapy. At this year's ASCO meeting, Ian Davis presented the updated OS findings from the prespecified analysis triggered to occur after 470 deaths. The first planned interim analysis of ENZAMET, with 243 deaths after a median follow-up of 34 months, revealed a clinically meaningful OS (OS) benefit in mHSPC with the addition of enzalutamide to the standard of care. 


Professor Ian Davis, MB, BS, Ph.D., FRAC, P FAChPM, Professor of Medicine, Monash University and Eastern Health, and Head of the Eastern Health Clinical School (EHCS)

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

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Alicia Morgans: Hi, I'm so excited to be at ASCO 2022, where I have the opportunity to speak with Dr. Ian Davis, who's presenting some information from ENZAMET, some updated data. Thank you so much for being here.

Ian Davis: Thanks Alicia. Great to see you.

Alicia Morgans: Great to see you too, finally back in three dimensions.

Ian Davis: Oh yeah.

Alicia Morgans: Yes.

Ian Davis: It's been a long time.

Alicia Morgans: It has been a long time, and it's also been a long time since we've really been able to dig into the ENZAMET data, which of course was presented previously by Chris, and then you had a New England Journal paper on this. What did you present at ASCO 2022?

Ian Davis: Well, last time I was here was in 2019. That's when we presented the interim analysis of ENZAMET. ENZAMET is a randomized phase three cooperative group study, open label study, looking at the addition of Enzalutamide, so testosterone suppression, for patients with metastatic hormone-sensitive prostate cancer, commencing therapy. It's a very simple design. Everybody got testosterone suppression, of course, open label study, one-to-one randomization, half the patient's got Enzalutamide, half got an active control with an older generation non-steroidal anti-androgen. About 45% of the participants on the study also received concurrent Docetaxel, which is one of the distinctive points of the trial at the time.

What we presented in 2019 last time I was at ASCO was the result of the interim analysis after 50% of the planned events. At that point, we showed that there was a benefit for overall survival in favor of Enzalutamide for the overall study cohort, with the hazard ratio of 0.67, and three year landmark survivals of 72% for the control arm and 80% in the Enzalutamide arm. There was a lot of interest at the time about the triplet combination of ADT plus Enzalutamide plus Docetaxel. What we found was that when we looked at overall survival, there was no evidence that addition of Enzalutamide to patients for whom a decision had already been made to have Docetaxel was of any additional benefit in terms of overall survival. But, we did see a very strong signal in terms of PSA progression-free survival and clinical progression-free survival, with hazard ratios of around about 0.4. That was the interim analysis. It was a positive study. It led to registration of the agent around the world, and has altered practice.

We're now at ASCO 2022, and we presented the data for the pre-planned 470 event analysis for ENZAMET with a median follow up now of 68 months. This is really very mature data. The top level message out of the study was that the survival benefit is maintained. The hazard ratio, now at 68 months, median follow up is 0.70, so very similar to what it was three years ago when we presented the interim analysis. The five year, now, landmark survivals are 57% for the control arm and 67% for the Enzalutamide arm. The benefit of Enzalutamide has been sustained.

We're also now in a position where we can look at some longer term data and start to do a few exploratory analyses, breaking down the findings by subgroups of interest. We predefined for this analysis two binary variables that were linked to prognosis. One is the timing of diagnosis of metastatic disease, whether it was synchronous de novo presentation at the time of diagnosis, or metachronous, in other words, hormone-sensitive disease relapsing after prior therapy. The other variable was of course high or low volume disease, which has been shown to be prognostic previously.

We've now been able to show overall survival and progression-free survival capable markers for all of these subgroups. There's a few messages that have come out of that. Firstly, it's very clear that testosterone suppression alone is insufficient, even for the most favorable risk group. We see a clear benefit with the addition of Enzalutamide in that group of patients, and that's perhaps, looking at the survival curves, perhaps the most striking effect of Enzalutamide is in that group. I'll actually just stop here for a moment and say these are exploratory analyses. We deliberately have not performed any statistical comparisons, so we are basically eyeballing these curves and trying to learn what sort of lessons we can take out of that.

We've also shown that the group of patients that are at highest risk, so these are patients with high volume synchronous de novo presentation, also benefit from Enzalutamide. Although, the magnitude of that benefit probably is a little bit less than in the more favorable groups. In this highest group of patients, you see a benefit from Enzalutamide or Docetaxel or the combination of the three together. That's now mature information for all of these subgroups. What we take out of this, basically, is that Enzalutamide is clearly an active treatment, so is Docetaxel in selected subgroups. Although, the benefit of adding Docetaxel really seems to be more pronounced in the highest risk subgroups.

If I were thinking about a clinical message to take out of this, it might be that if you're thinking about using triplet therapy, it might be best to think about concentrating on the patients with the highest risk disease. In other words, high volume de novo synchronous metastatic disease. Those are the patients that were destined to do worst, and where Docetaxel is most likely to be of benefit. If anything, we're probably seeing the strongest survival signal of the triplet in that group. These are speculative findings, but this is consistent with what we know with the biology, and it's consistent with what we've seen in other clinical trials.

In terms of the strengths of the study, this was an academic led study. It included all of the various prognostic subgroups contemporaneously, and it was randomized against an active control with best current standard of care. As I said, 45% of patients received Docetaxel. If you had high volume disease, over 70% of patients received Docetaxel. This is shown, in fact, in our data by the fact that the control arm has done extraordinarily well. The outcomes for our control group are right up there with the best contemporary series for the active. We're confident that we treated our patients well across the board.

What other lessons can be taken out of this? I think when people are looking at the Kaplan-Meier curves, there are a few traps that you could potentially fall into. One is, in particular, in relation to Docetaxel. Docetaxel use was not randomized. We stratified for the use of Docetaxel, but the decision to use Docetaxel was made at investigator discretion. There was something about this particular patient that made someone say, "I think this person should get Docetaxel." Perhaps it was that they had high volume disease, or they were younger, or a feeling in the waters. We don't know. But, our data showed that, that group probably has the worst prognosis, and therefore, when we're looking at the benefits of treatment in that group, we have to consider that it's related to both the effects of Docetaxel, but also the underlying clinical factors that lead to that decision to use Docetaxel in the first place. I would caution people to be careful about making direct comparisons, and again, as we heard in my presentation, we were very careful not to draw statistical comparisons between those groups.

Bottom line messages, Enzalutamide continues to be active. The magnitude of the benefit is very similar in terms of absolute terms, and also the hazard ratio. We're still seeing a benefit in progression free survival. In fact, the curves, if anything are more spread. We can see perhaps the greatest benefit of Enzalutamide in the lowest risk group of patients, where we know testosterone suppression alone is insufficient therapy. We would hypothesize that if we are going to use triplet therapy, it might be best concentrated in that patient with the highest risk disease.

Alicia Morgans: Congratulations. What a wonderful amount of information you gained from this trial, which of course includes so many different subpopulations, so I also appreciate that you caution us to think about those subgroups as hypothesis generating in a lot of ways, but they can help guide our clinical decision making, maybe not in an absolute way, but in a guide kind of a way, so really, really important. Just to reiterate, there was a population of patients that received Docetaxel, and among the population that received Docetaxel in our 2019 data, we did not see that there was a clear benefit to adding Enzalutamide in that population. In terms of overall survival, it was not yet mature data.

Ian Davis: Correct.

Alicia Morgans: In your data, when we added Enzalutamide to the Docetaxel treated patients, we saw a benefit in terms of survival as compared to patients receiving ADT, Docetaxel, and Nilutamide, Flutamide, or Bicalutamide.

Ian Davis: We saw benefits of comparable magnitude in patients who received Enzalutamide or Docetaxel with the standard anti-androgen, or the combination of Enzalutamide, Docetaxel. There doesn't really seem to be any benefit across the board in using triplet therapy. But, when we dig down into the exploratory subgroups, it looks like perhaps there might be a suggestion, if there is going to be any benefit, it might be in that highest risk group of patients, high volume synchronous disease.

Alicia Morgans: But, so interesting, because of course, that was the group that we really saw in piece one that seemed to have the most benefit, again, a subgroup analysis in the high volume patients, but all patients in piece one were de novo metastatic-

Ian Davis: That's right.

Alicia Morgans: Or synchronous, as we call in the ENZAMET trial. Then in ARASENS, a majority of those patients were de novo metastatic and high volume.

Ian Davis: That's right.

Alicia Morgans: Or at least, we presume they were high volume.

Ian Davis: Yeah.

Alicia Morgans: Volume has not yet been reported. This seems consistent with our other trials.

Ian Davis: That's right. That's a good point you make. People are going to be tempted to make direct comparisons between the studies. The study populations were not the same. We had a mix of prognostic groups, whereas both piece one and ARASENS were arguably weighted towards higher risk patients. Of course, ARASENS, the baseline treatment was ADT plus Docetaxel, so we don't have a direct comparison, or Derolutamide plus ADT versus ADT alone or against the standard anti-androgen. This is the closest we've come in that respect. There are a few other limitations to this study. Obviously, the Docetaxel use was not randomized. Most importantly, the study was not powered for these subgroup analyses to undergo formal statistical analyses. These exploratory findings and our hypotheses are just that, hypothesis generating. We hope that this will help people to guide selection of treatment for their patients.

Alicia Morgans: I think it absolutely will. It really does, as you said, reiterate the message that ADT alone, it's not an option for these patients anymore, which I think is also one of the most important messages that we've heard pretty consistently over the last few years. From your perspective, is that a message that rings true?

Ian Davis: Yes. I think that's a very good summary.

Alicia Morgans: Yeah, wonderful. Well, congratulations to you and your team. Is there anything else you'd like to share or to sum up the data in terms of the clinical implications?

Ian Davis: Well, I think summed up the data, but what I really would like to do is to express my thanks to everybody who participated. Of course, the patients and the people that support them. This trial was led by ANZUP Cancer Trials Group. It was sponsored through the University of Sydney and the NHMIC Clinical Trials Center. We've been able to build a wonderful international collaboration here with great support from Cancer Trials Island, who coordinated the study in the UK and Ireland, the Canadian Cancer Trials Group, and also sites in the United States, and ends up through Australia and New Zealand. A wonderful team and great fun to work with, and we're looking forward to more studies with this great global initiative.

Alicia Morgans: Wonderful. Well, I do congratulate you. I thank the patients, and I really do say that ANZUP is a phenomenal group, and I can't imagine another group taking on such a challenge as the ENZAMET trial and really giving us such a wonderful amount of information that is just so meaningful in itself, but also generates so many other questions for us to continue to pursue. Thank you and your team for such wonderful work.

Ian Davis: Thanks so much.