Ian Davis, MBBS, PhD, FRACP, FAChPM, Eastern Health Clinical School, Monash University, Box Hill, Australia, discusses updated overall survival (OS) outcomes from the ENZAMET trial, exploring testosterone suppression plus either enzalutamide or a conventional non-steroidal anti-androgen in metastatic hormone-sensitive prostate cancer.

These updated outcomes were presented at the 2022 ASCO Annual Meeting.

Transcript:

Hi, my name's Ian Davis. I'm professor of medicine and medical oncologist based at Monash University and Eastern Health in Australia. I'm chair of ANZUP Cancer Trials Group.

It's a great pleasure to be back in Chicago for the ASCO meeting in 2022. The last time I was at ASCO was 2019 when ANZUP was presenting at the plenary session the results of the interim analysis of the ENZAMET trial. ENZAMET was an international investigator-initiated collaborative group study looking at addition of enzalutamide to testosterone suppression at the initiation of treatment for patients with metastatic hormone-sensitive prostate cancer. What we showed, at that time back in 2019 at the interim analysis after 50% of expected deaths, was that enzalutamide did improve overall survival with a hazard ratio for death of 0.67. Seventy-two percent of men were alive at 3 years in the control arm, and 80% were alive at 3 years in the enzalutamide arm. So a substantial benefit there.

There was a lot of interest at the time about whether docetaxel triplet therapy with enzalutamide and ADT would give improved overall survival outcomes. We were not able to show that at that first analysis, although there was a very strong signal in favor of the triplet for clinical and PSA progression-free survival. So for ASCO 2022, we were back in Chicago presenting the results of the planned 470 event analysis, now with a median follow-up of 68 months. What was shown at this analysis is that the benefit of addition of enzalutamide for the overall cohort is sustained, and the hazard ratio for death is 0.70. The five-year landmark survival is 57% for the control arm versus 67% for the enzalutamide arm. The median estimated survival is 73 months for the control group and not yet reached for enzalutamide. That benefit of enzalutamide now has really been confirmed to be sustained over a long period of time.

With this longer follow-up, we've taken the opportunity to do some exploratory analysis. I'll emphasize that these are exploratory, we haven't done any statistical analyses on these. We've really tried to see what the information tells us. We've broken down the outcomes by prognostic group. We know that patients with synchronous de novo presentation of metastatic disease do less well than those with metachronous later presentation, and patients with high-volume disease of course do less well than those with low-volume disease.

We've looked at those prognostic subgroups in various combinations to see what we could learn from that. The messages we took out of that were that androgen deprivation therapy alone is really not enough. That was a very clear message. Didn't matter which prognostic group we looked at, androgen deprivation therapy was the lowest curve and was brought up by addition of other therapy.

The second point we noted was that enzalutamide was active to a greater or less extent in all of the prognostic subgroups, whether you had metachronous or synchronous disease, high or low volume disease, and whether or not you were receiving docetaxel concurrently as well.

The other interesting thing that we found in terms of overall survival was that whether you added enzalutamide or docetaxel or both enzalutamide and docetaxel, the outcomes for overall survival seem to be quite similar with the possible exception of the patients at the worst risk, which are the ones with high volume synchronous presentation. They may have had a slightly better benefit from triplet therapy, but otherwise there didn't seem to be any clear signal that triple therapy was really adding anything on top of the doublet.

We hypothesized out of that, that perhaps a reasonable approach might be to reserve triplet therapy for when the clinician and the patient think that the benefit might be greatest, in other words, patients with high volume synchronous disease. For other patients, assuming they're fit to receive these treatments, any of the doublet therapies might be reasonable. When I say doublet therapy, we're talking about androgen deprivation therapy plus either enzalutamide or abiraterone or apalutamide or docetaxel. We know that all of those doublet therapies will improve survival for patients who are fit to receive them.

I guess the bottom line out of all of that, what do we take into the into clinic for next week, We can be confident that enzalutamide is active in this setting. It's active across all of the subgroups to a greater or lesser extent. It seems to have its greatest benefit in patients with low volume disease where docetaxel is not used quite so often. But we also see a benefit in patients with highest risk disease where docetaxel is frequently used.

As I said before, triplet therapy is reasonable, and we've learned that from PEACE-1 and ARASENS, but it might not be necessary to offer to every patient. It perhaps could be reserved for those at highest risk of disease, and the drug that you don't use could then be used for later castrate-resistant prostate cancer when that develops.

ENZAMET really adds to the body of knowledge that we've gained from other pivotal trials such as CHAARTED, STAMPEDE, LATITUDE, TITAN, ARCHES, PEACE-1, ARASENS, all looking at slightly different questions and all with slightly different design. ENZAMET was distinct from some of these other trials because it was an open label study. We used an active comparator, and we had in comparison to TITAN and ARCHES, we used concurrent docetaxel in about 45% of participants. It was very gratifying that our control arm did so well. The outcomes for the control arm were really comparable to other contemporary trials. So we were very confident that all the patients on our trial were getting best quality international standard treatment and even with that were able to show the benefit of adding enzalutamide across the different subgroups.

So I'd really like to acknowledge the 1125 patients and their support people who participated in this trial, which was performed at 83 centers internationally. The study was led by ANZUP Cancer Trials Group, but there was a wonderful global collaboration involving Cancer Trials Ireland, Canadian Cancer Trials Group, Dana-Farber Cancer Institute, and the NHMRC Clinical Trial Center at the University of Sydney and with study drug and support provided by Astellas.

Source:

Davis ID, Martin AJ, Zielinski RR, et al. Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). Presented at: ASCO Annual Meeting; June 3-7, 2022. Chicago, IL, and virtual. Abstract LBA5004.