The Uromigos Episode 177: ENZAMET Study Assesses Enzalutamide in Prostate Cancer

During the 2022 Annual Meeting of the American Society of Clinical Oncology (ASCO), 3-year follow-up data were presented from the ENZAMET (Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer) trial by Ian Davis, MB BS, PhD, medical oncologist and Professor of Medicine and Head of Eastern Health Clinical School, Monash University and Eastern Health, Melbourne, Australia.¹ The new data reconfirmed findings of overall survival (OS) benefit with enzalutamide added to testosterone suppression in metastatic hormone-sensitive prostate cancer (mHSPC) from an interim analysis reported in 2019.²

Thomas Powles, MBBS, MD, (Barts Cancer Centre, London, UK) and Brian Rini, MD (Vanderbilt University, Nashville, TN) invited Dr Davis to review the ENZAMET trial and discuss the implications of the latest analysis. Dr Davis is co-chair of ENZAMET, along with Christopher Sweeney, MBBS (Dana-Farber Cancer Institute, Boston), and chair of the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Ltd (ANZUP), the primary sponsor of ENZAMET.

First Analysis of ENZAMET

ENZAMET is an ongoing phase 3, randomized, open-label study in patients with mHSPC who were first treated with testosterone suppression. “It was a very simple question when the study began,” Dr Davis explained, “Could we improve outcomes, particularly overall survival by adding enzalutamide 160 mg/day upfront compared to a standard nonsteroidal antiandrogen drug such as bicalutamide, nilutamide, or flutamide?” A total of 1125 men were entered into the trial at 83 sites in Australia, New Zealand, Canada, UK, and Ireland between March 2014 and March 2017.

At the first interim analysis in February 2019, after 235 deaths and a median follow-up of 34 months, enzalutamide was shown to significantly improve OS. “At that time, we had a hazard ratio for death of 0.67 for patients on the enzalutamide arm, which was very exciting,” Dr Davis recalled. This finding aligned with data already reported from the CHAARTED³ and STAMPEDE⁴ trials, for docetaxel, and from the STAMPEDE⁵ and LATITUDE⁶ trials, for abiraterone, he noted. Improved radiographic progression-free survival (rPFS) was reported with enzalutamide in the ARCHES trial⁷ and significantly longer OS and rPFS with apalutamide in the TITAN trial.⁸

ENZAMET differed from these two trials, however, in that docetaxel was allowed at investigative discretion. “We opened ENZAMET at the beginning of 2014, just before the CHAARTED data were presented,” Dr Davis explained. “Then after the CHAARTED results came out, literally overnight in Australia, people were filling up prescription pads with docetaxel. So our study was dead in the water unless we amended it very rapidly to allow docetaxel.” Docetaxel use was not randomized in ENZAMET, but it was stratified. Overall about 45% of patients on the study received concurrent docetaxel.

“There was lot of interest about whether the triplet therapy would be of additional benefit compared with testosterone suppression plus enzalutamide alone,” Dr Davis recalled. “We really wanted to answer this question, but that would have made it a much larger study and we didn’t have the resources to do that,” he admitted. A compromise was reached by allowing docetaxel at investigator discretion and about 45% of patients overall eventually received docetaxel, predominantly those with high-volume disease compared with those with low-volume disease. “We believe that this was probably related to clinical factors that led the investigators to conclude this was something that these participants should receive,” Dr Davis said. The question of whether patients with low volume disease were less suitable for docetaxel remained controversial.

Updated Data Reconfirms Findings

The updated ENZAMET survival data reconfirmed the earlier findings. After a median of 68 months of follow up, the benefit of enzalutamide persisted, with a hazard ratio for OS of 0.70 (95%CI 0.58 to 0.84), still statistically significant (P<0.001). The estimated median survival was 73 months for the control group and not reached for the enzalutamide group, and 5-year survival was 57% and 67%, respectively. The control group “did very well,” Dr Davis noted. “It’s gratifying that this does represent the best international standard of care for the outcomes of the control group, and even with that, we’re still seeing the benefit of enzalutamide as the alternative,” he remarked.

“We are now able to do some exploratory analysis looking at subgroups of prognostic significance,” Dr Davis continued. “When we looked at the patients with high or low volume disease and those with synchronous de novo metastatic disease versus those with metachronous or relapsed metastatic disease, a few messages emerged,” he said. First, “it is very clear that weak androgen deprivation therapy (testosterone suppression) as active control is not the best approach.” They also found that across the board, enzalutamide alone with testosterone suppression, or docetaxel, or in combination of both had similar outcomes. “That leads to the question of whether the docetaxel might be needed, and I think raises the hypothesis that the greatest benefits of triple therapy might be limited to those patients with the poorest prognosis disease, especially those with synchronous and high volume disease,” Dr Davis suggested. “So if you’ve got low volume disease, you probably don’t need docetaxel.”

Learning from New Data

Asked by Dr Powles whether ENZAMET has changed thinking, Dr Davis referred to the more recent results of the PEACE-1 and ARASENS trials.^9,10 The ARASENS data strongly suggested that all patients should be getting triple therapy, he comments. “But we have to remember that ARASENS was a different, very high-risk population, with around 86% of patients having synchronous metastases and 65% visceral metastases, and it was considered necessary for them all to get docetaxel. The ENZAMET population contained a mix of prognostic groups and more closely reflected the spectrum of patients that come through our clinic,” he pointed out.

“What ENZAMET suggests to us is that we know what not to do, which is testosterone suppression by itself in a patient who’s fit to get anything,” he asserted. “Metachronous low volume disease is the group that does best and should still have intensification of testosterone suppression but probably does not need to have triple therapy. High volume disease is probably the subset where triple therapy should be considered most seriously.”

ENZAMET hasn’t answered the clinical question of who needs docetaxel; Dr Rini pointed out “That is still the biggest gap in this area, and as a statistical purist and clinical trialist, I would say that’s the study that we need,” Dr Davis replied. “On the other hand, ENZAMET now has a median 68 months of follow up and the data are very mature, and there are some very clear messages about how well addition of enzalutamide only is doing compared with the other study groups,” he said. “We know that the addition of enzalutamide gives very good results, comparable to those in patients who’ve received docetaxel or the triplet. If you’re going to choose any subgroup to receive triplet therapy, you could probably use these data to justify giving it to those at highest risk,” he concluded.

Linda Brookes, MSc is a freelance medical writer/editor based in New York and London.

References

1. Davis ID, Martin AJ, Zielinski RR, et al; ENZAMET investigators. Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol. 2022;40(suppl 17):Abstract LBA5004. DOI: 10.1200/JCO.2022.40.17_suppl.LBA5004
2. Davis ID, Martin AJ, Stockler MR, et al; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. DOI: 10.1056/NEJMoa1903835
3. Sweeney CJ, Chen Y-H, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. DOI: 10.1056/NEJMoa1503747
4. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177. DOI: 10.1016/S0140-6736(15)01037-5
5. James ND, de Bono JS, Spears MR, et al; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377(4):338-351. DOI: 10.1056/NEJMoa1702900
6. Fizazi K, Tran N, Fein L, et al; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. DOI: 10.1056/NEJMoa1704174
7. Armstrong AJ , Szmulewitz RZ, Petrylak DP, et al. ARCHES: A randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986. DOI: 10.1200/JCO.19.00799
8. Chi KN, Agarwal N, Bjartell A, et al; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13–24. DOI: 10.1056/ NEJMoa1903307
9. Smith MR, Hussain M, Saad F, et al; ARASENS Trial Investigators. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. DOI: 10.1056/NEJMoa2119115
10. Fizazi F, Foulon S, Carles J, et al; PEACE-1 Investigators. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022;399(10336):1695-1707: DOI: 10.1016/S0140-6736(22)00367-1