The ENZAMET trial (NCT02446405) has revealed that enzalutamide, a powerful androgen receptor inhibitor, significantly prolongs survival compared to standard non-steroidal anti-androgens (NSAAs).
With a median follow-up of 98 months, this landmark study underscores the transformative impact of enzalutamide when added to testosterone suppression, with or without early docetaxel, offering hope to patients facing this aggressive disease.

From March 2014 to March 2017, the trial enrolled 1,125 men with mHSPC, randomly assigning them to receive either enzalutamide (160 mg daily, 563 patients) or an NSAA (562 patients), both combined with testosterone suppression. Approximately 45% of patients in each group also received early docetaxel chemotherapy. The primary goal was to measure overall survival (OS), with secondary outcomes including clinical progression-free survival (PFS), causes of death, and severe (grade 3–5) adverse events (AEs). A key analysis examined outcomes based on prostate-specific antigen (PSA) levels at 7 months, a critical indicator of treatment response.

As of the June 30, 2024, data cut-off, 51% of enzalutamide patients (285/563) had died compared to 60% of NSAA patients (337/562). Enzalutamide extended median OS by 25 months (95 months vs. 70 months), with 50% of patients alive at 96 months compared to 40% for NSAA, reducing the risk of death by 27% (hazard ratio 0.73, p=0.0001).

Clinical PFS was also markedly improved, with a 51% lower risk of progression or death (hazard ratio 0.49, p<0.0001). Of 622 total deaths, 468 were due to prostate cancer, with fewer in the enzalutamide group (207 vs. 261). Non-prostate cancer deaths were nearly identical (78 vs. 76), showing enzalutamide’s specific impact on cancer-related mortality.

A key finding came from the PSA analysis at 7 months. Among patients with PSA ≤0.2 ng/mL (645/1,104), only 29% of deaths were due to prostate cancer (27% for enzalutamide, 32% for NSAA), compared to 60% for those with PSA >0.2 ng/mL (58% for enzalutamide, 61% for NSAA).
Non-prostate cancer deaths were consistent at 13% in both PSA groups, highlighting that achieving a low PSA early in treatment predicts better survival.
Patients on enzalutamide received treatment for an average of 58 months, compared to 36 months for NSAA, with 33% (185/562) still on enzalutamide, 88% at the full dose.

This suggests some patients, particularly those enrolled early in 2014, may have been on treatment for nearly a decade. Severe AEs, adjusted for treatment duration, were comparable. These data confirm enzalutamide’s long-term safety, with no significant increase in toxicity despite extended use. Of course, we must consider certain limitations in the follow-up — such as which subsequent therapies were used by patients who discontinued enzalutamide, or whether any additional treatments were administered alongside enzalutamide and ADT. Nevertheless, the results remain very encouraging.

Source.