Treatment intensification with androgen receptor pathway inhibitors has become central to the management of metastatic hormone-sensitive prostate cancer (mHSPC). However, as patients remain on these therapies for years, longer follow-up is needed to understand whether the early survival benefits are sustained and how treatment is tolerated over time.
The latest analysis of the phase 3 ENZAMET trial provides a median follow-up of 8.1 years for patients treated with enzalutamide plus testosterone suppression compared with testosterone suppression plus a first-generation non-steroidal anti-androgen (NSAA).
The study, titled “Eight-year outcomes of testosterone suppression plus enzalutamide or a non-steroidal anti-androgen for metastatic, hormone-sensitive prostate cancer (ENZAMET; ANZUP 1304),” was published on August 17, 2026, in Annals of Oncology.
Authors: A.Y. Zhang, H. Thomas, S. Begbie, L. Cheung, K.N. Chi, S. Chowdhury, M. Frydenberg, C. Herberstein, L.G. Horvath, A.M. Joshua, N.J. Lawrence, G. Marx, J. McCaffrey, R. McDermott, R.A. McLaughlin, S.A. North, F. Parnis, W. Parulekar, D.W. Pook, M.N. Reaume, S.K. Sandhu, A. Tan, T.H. Tan, A. Thomson, F. Vera-Badillo, S.G. Williams, R.R. Zielinski, M.R. Stockler, I.D. Davis, and C.J. Sweeney.
ENZAMET With Long-Term Follow-Up
ENZAMET (ANZUP 1304; NCT02446405) is an international, open-label, randomized phase 3 trial that enrolled patients with mHSPC detected on conventional imaging. Patients were randomly assigned 1:1 to enzalutamide 160 mg daily or a first-generation NSAA, including bicalutamide, nilutamide, or flutamide, with mandatory background testosterone suppression in both groups.
Following a protocol amendment after the first 88 patients had been enrolled, early docetaxel was permitted at the treating clinician’s discretion. Docetaxel was given at 75 mg/m² every 3 weeks for up to six cycles and had to be planned before randomization. Enzalutamide or the NSAA was continued until disease progression or unacceptable toxicity.
Overall survival was the primary endpoint. Secondary endpoints included clinical progression-free survival, PSA progression-free survival, and adverse events.
A total of 1,125 patients were randomized across 83 centers, with 563 assigned to enzalutamide and 562 to the NSAA control group. Median age was 69 years, 54% had high-volume disease according to CHAARTED criteria, and 61% presented with synchronous metastatic disease. Early docetaxel was planned for 45% of patients. At the latest data cutoff on June 30, 2024, median follow-up was 8.1 years.
Survival Benefit Remains Evident at 8 Years
Median overall survival was 7.9 years with enzalutamide compared with 5.8 years with the NSAA control. At 8 years, overall survival was 50% with enzalutamide versus 40% with NSAA, corresponding to a hazard ratio for death of 0.73 (95% CI 0.63–0.86; p=0.0001).
The long-term analysis therefore shows that the survival advantage previously reported with enzalutamide was maintained with substantially longer follow-up.
Of 622 deaths recorded during the study, 468 were attributed to prostate cancer. Prostate cancer deaths were less frequent in the enzalutamide group than in the control group, with 207 versus 261 deaths, respectively. At 8 years, prostate cancer-specific survival was 61% with enzalutamide and 50% with control. Deaths attributed to causes other than prostate cancer were similar between the groups, occurring in 78 patients receiving enzalutamide and 76 receiving NSAA.
Long-term disease control also favored enzalutamide. Clinical progression-free survival at 8 years was 43% with enzalutamide compared with 20% with NSAA (HR 0.49; 95% CI 0.42–0.57; p<0.0001). PSA progression-free survival at 8 years was 40% versus 19%, respectively (HR 0.48; 95% CI 0.41–0.55; p<0.0001).
Early PSA Response and Long-Term Survival
The investigators also evaluated long-term outcomes according to PSA response at 7 months. A PSA level of ≤0.2 ng/mL at 7 months was achieved in 67% of patients receiving enzalutamide compared with 48% receiving NSAA. The median time to reach PSA ≤0.2 ng/mL was 2.8 months with enzalutamide and 5.5 months with control.
Patients who reached this PSA threshold had substantially better long-term outcomes irrespective of treatment assignment. Eight-year overall survival was 55% among patients with PSA ≤0.2 ng/mL at 7 months compared with 23% among those with PSA >0.2 ng/mL (p<0.001).
In multivariable analysis, PSA ≤0.2 ng/mL at 7 months remained independently associated with improved outcomes regardless of treatment allocation (HR 0.47; 95% CI 0.39–0.57). These findings support the prognostic value of an early deep PSA response in mHSPC. However, the investigators noted that the analysis of PSA ≤0.2 ng/mL at 7 months was exploratory and post hoc.
Long-Term Treatment Exposure and Safety
Treatment exposure was considerably longer with enzalutamide. Median study treatment duration was 4.8 years with enzalutamide compared with 1.9 years with NSAA.
At the latest data cutoff, 185 of 563 patients (33%) assigned to enzalutamide remained on their original treatment, compared with 79 of 562 patients (14%) in the control group. Among patients still receiving enzalutamide, 163 of 185 (88%) remained on the full starting dose of 160 mg daily without requiring long-term dose reduction or delay.
At least one grade 3–5 adverse event was reported in 73% of patients assigned to enzalutamide and 50% assigned to NSAA. Treatment-related serious adverse events occurred in 5% and 1% of patients, respectively, although treatment exposure was substantially longer with enzalutamide. Rates of serious adverse events over time were similar between the groups.
For grade 3–5 adverse events of interest reported per 100 person-years, rates with enzalutamide versus control were 2.6 versus 2.5 for cerebrovascular and cardiac disorders, 1.4 versus 0.24 for fatigue, 0.70 versus 0.24 for falls, 1.3 versus 0.72 for fractures, and 0.07 versus 0.06 for cognitive impairment.
No new safety signals were identified with extended follow-up. The investigators noted, however, that grade 3–5 falls were more frequent with enzalutamide. Baseline fall risk had not been systematically assessed, limiting interpretation of this finding.
Interpreting the Docetaxel Findings
The survival benefit of enzalutamide was observed across clinically relevant subgroups, including patients with synchronous metastatic disease and those planned to receive early docetaxel. However, ENZAMET was not designed to determine the incremental benefit of adding docetaxel to ADT plus enzalutamide.
Docetaxel was neither protocol-mandated nor standardized and was administered at investigator discretion in both high- and low-volume disease. The authors therefore emphasized that comparisons according to docetaxel use are descriptive and may reflect treatment effects, patient selection, or both.
Some of the extended subgroup analyses, including analyses according to synchronous versus metachronous metastatic disease and PSA ≤0.2 ng/mL at 7 months, were pre-specified but conducted post hoc. These analyses involved smaller patient numbers and should be interpreted cautiously.
Durable Benefit With Enzalutamide
The 8-year ENZAMET analysis provides mature evidence that the survival benefit of enzalutamide added to testosterone suppression in mHSPC persists over the long term.
At a median follow-up of 8.1 years, overall survival remained higher with enzalutamide, while clinical and PSA progression-free survival also continued to favor treatment intensification. Prostate cancer deaths were reduced without an increase in deaths from other causes.
The findings also show that, at a median follow-up of 8.1 years, approximately one-third of patients assigned to enzalutamide remained on treatment, with most of those patients continuing the full 160-mg daily dose.
According to the authors, the extended ENZAMET results provide mature evidence supporting enzalutamide-based treatment intensification as a standard-of-care approach for men with mHSPC.
The full article is available in Annals of Oncology.