Ian D. Davis, MBBS, PhD, dives into subgroup data from the ENZAMET trial of enzalutamide in mHSPC at ASCO 2022

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Ian D. Davis, MBBS, PhD, Professor of Medicine and Director of Eastern Health Clinical School at Monash University and Eastern Health in Melbourne, Australia, spoke with CancerNetwork® to 2022 Annual Meeting of the American Society for Clinical Oncology (ASCO) on predefined subgroup data analyzed in the Phase 3 ENZAMET trial (NCT02446405), which investigated the use of enzalutamide (Xtandi) versus standard antiandrogen therapy as first-line treatment for patients with hormone-sensitive metastatic prostate cancer. Pre-specified subgroups analyzed included those who were treated with docetaxel (n=503), had high volume disease (n=602), and had de novo synchronous metastatic disease (n=683).

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The material follow-up of enzalutamide allowed us to do some exploratory analyzes of subgroups. We initially stratified patients by high and low volume disease, but we also considered an alternative prognostic grouping, namely where patients had synchronous metastatic disease, de novo metastatic disease, or metachronous presentation. Patients who fare best are those with low-volume or metachronous disease and those who fare worst usually have synchronous high-volume disease.

I did some exploratory analyzes — and we were very careful not to over-interpret them because they’re not formal statistical analyzes — but we were able to get several take-home messages. First, suppressing testosterone by itself is not enough. If a patient is fit to receive something, then they should receive something else in addition to testosterone suppression. We show that enzalutamide is a good choice for this. We also showed that enzalutamide is active in all the subgroups we tested. There was particular interest in whether the suppressive triplet of testosterone plus enzalutamide plus docetaxel would be of added benefit. We did not show a benefit of triple therapy for overall survival in the interim analysis, although there was a strong signal for progression-free survival. At this more mature update with a median follow-up of 68 months, again the impression is that the survival benefit is similar whether you [received] enzalutamide alone or docetaxel with a standard antiandrogen or enzalutamide plus docetaxel, with the possible exception of most-at-risk patients, or those with high-volume synchronous presentation. There is a suggestion that these patients might do better if we offered them triple therapy right away. However, the study was not designed to answer this question. These are exploratory analyzes and generation of hypotheses.

Enzalutamide is a good option to consider as an add-on to testosterone suppression, regardless of risk group. We can be confident that this benefit is now maintained up to a median follow-up of 68 months in this study. We can also take some comfort in the fact that we do not necessarily need to offer triple therapy to every patient. Our study was not designed to definitively answer this question, but the results seem similar for doublet therapies compared to triplet therapies across the board. One option might be to consider offering dual therapy and reserving one of the drugs for later development of metastatic castration-resistant disease. That said, there are patients who we fear are not destined to do well on treatment, so it would be entirely reasonable to offer triple therapy to these patients, and that would be consistent with the findings of d other studies like PEACE1 [NCT01957436] and ARASENS [NCT02799602].

Reference

Davis ID, Martin AJ, Zielinski RR, et al. Updated overall survival results in ENZAMET (ANZUP 1304), an international collaborative group trial of enzalutamide in metastatic hormone-responsive prostate cancer (mHSPC). J Clin Oncol. 2022;40(supplement 17):LBA5004. doi:10.1200/JCO.2022.40.17_suppl.LBA5004

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