Ian D. Davis, MBBS, PhD, spoke about the subgroup analysis of the ENZAMET trial which analyzed enzalutamide in metastatic hormone-sensitive prostate cancer.
Ian D. Davis, MBBS, PhD, professor of medicine and head of the Eastern Health Clinical School at Monash University and Eastern Health in Melbourne, Australia, spoke with CancerNetwork® at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting about data for prespecified subgroups analyzed in the phase 3 ENZAMET trial (NCT02446405), which investigated the use of enzalutamide (Xtandi) vs standard antiandrogen therapy as first-line treatment for patients with metastatic hormone-sensitive prostate cancer. The prespecified subgroups analyzed included those who were treated with docetaxel (n = 503), had high volume disease (n = 602), and had synchronous de novo metastatic disease (n = 683).
The material follow-up of enzalutamide has allowed us to do some exploratory analyses of subgroups. We had initially stratified the patients by high- and low-volume disease, but we also now looked at another prognostic grouping, which is where the patients presented with synchronous metastatic disease, de novo metastatic disease, or metachronous presentation. The patients who do best are those with low-volume or metachronous disease and those who do worse typically have high-volume synchronous disease.
I’ve done some exploratory analysis—and we’ve been very careful not to overinterpret these as they are not formal statistical analyses—but we’ve been able to get several takeaway messages. Firstly, testosterone suppression by itself is not enough. If a patient is fit to receive something, then they should get something else on top of testosterone suppression. We’re showing that enzalutamide is a good choice for that. We’ve also shown that enzalutamide is active across all the subgroups that we tested. There was particular interest in whether the triplet of testosterone suppression plus enzalutamide plus docetaxel would be of additional benefit. We did not show a benefit of triplet therapy for overall survival at 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, once again the impression is that the survival benefit is similar regardless of whether you [received] enzalutamide alone or docetaxel with standard antiandrogen or enzalutamide plus docetaxel, with the possible exception for the highest risk patients, or those with high-volume synchronous presentation. There’s a suggestion that those patients may do better if we offered them triplet therapy upfront. However, the study was not designed to answer this question. These are exploratory analyses and hypothesis generating.
Enzalutamide is a good option to consider adding to testosterone suppression, regardless of risk group. We can be confident that that benefit is now sustained to a median follow-up of 68 months in this study. We can also be somewhat reassured that we need not offer triplet therapy necessarily to every patient. Our study was not designed to answer that question definitively, but the outcomes do seem similar for doublet therapies compared with triplet therapies across the board. One option might be to consider offering doublet therapy and reserve one of the drugs for later development of metastatic castration-resistant disease. Having said that, there are some patients for whom we we’re concerned that they might not be destined to do well on treatment, so it would be entirely reasonable to offer triplet therapy to those patients, and that would be consistent with the findings of other studies like PEACE1 [NCT01957436] and ARASENS [NCT02799602].
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). J Clin Oncol. 2022;40(suppl 17):LBA5004. doi:10.1200/JCO.2022.40.17_suppl.LBA5004