Enzalutamide plus ADT continues to show durable survival benefit in mHSPC at 5 years

Five-year data from the phase 3 ARCHES trial (NCT02677896) showed that enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) continued to provide a substantial and durable benefit in overall survival (OS) vs placebo plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC).¹

The data were presented at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

At a median follow-up of 61.4 months, enzalutamide plus ADT was associated with a 30% reduction in the risk of death vs placebo plus ADT (HR, 0.7; 95% CI, 0.58 to 0.85; P = .001). The probability of survival at 5 years was 65.5% (95% CI, 61.2 to 69.5) in the treatment arm vs 53.4% (95% CI, 48.5 to 57.9) in the control arm.

The median survival was not reached in either arm. In the placebo arm adjusted for crossover, the median OS was 59.5 months (95% CI, 49.7 to NE).

Andrew J. Armstrong, MD, MSc

According to lead author Andrew J. Armstrong, MD, MSc, of the Duke Cancer Institute, who presented results on behalf of the ARCHES investigators, “[These data] represent one of the longest overall survival follow-up analyses in this hormone-sensitive setting.”

In total, the ARCHES trial enrolled 1150 patients with mHSPC who were randomly assigned 1:1 to receive 160 mg enzalutamide once daily plus ADT (n = 574) or placebo plus ADT (n = 576). Following the primary analysis of the data, 182 patients in the placebo arm crossed over to the treatment arm.

The primary end point for the trial was radiographic progression-free survival (rPFS). Key secondary end points included OS, prostate-specific antigen (PSA) PFS, time to initiation of new antineoplastic therapy, undetectable PSA rate, objective response rate, and time to deterioration in urinary symptoms.

Data were stratified by disease volume (low vs high) and prior docetaxel use for mHSPC. Across all subgroups, enzalutamide plus ADT demonstrated a survival advantage vs placebo plus ADT.

In patients with high-volume disease, the median OS at 5 years was 83.06 months (95% CI, 69.59 to NE) in the enzalutamide arm vs 47.57 months (95% CI, 40.11 to 75.66) in the placebo arm (HR, 0.70; 95% CI, 0.56 to 0.88).

Armstrong noted, “This represents a 36-month extension of overall survival for these high-volume patients that have a major unmet medical need.”

The 5-year survival rate amongst patients with high-volume disease was 58.4% with enzalutamide vs 45% with placebo.

There was a similar relative improvement in OS in patients with low-volume disease (HR, 0.71’ 95% CI, 0.49 to 1.05). At the time of data report, the median survival had not been reached in either arm. The 5-year survival rate was 76.7% in the enzalutamide arm vs 67.5% in the placebo arm.

Among patients with de novo high-volume synchronous disease, the median OS was 81.97 months in the enzalutamide arm vs 44.16 months in the placebo arm (HR, 0.71; 95% CI, 0.56 to 0.91). The median OS has not yet been reached in either arm for patients with low-volume synchronous disease (HR, 0.70; 95% CI, 0.45 to 1.07).

Armstrong also noted, “Prior docetaxel actually had one of the greatest survival benefits of any subgroup.”

In patients who had received prior docetaxel, the 5-year survival rate was 66.3% in the enzalutamide arm vs 49.8% in the placebo arm. In patients who had not received prior docetaxel, these rates were 65.4% and 54.2%, respectively.

The OS benefit with enzalutamide remained consistent across most prespecified subgroups, regardless of age, geography, ECOG performance status, and baseline PSA.

Overall, the median duration of treatment was 41.7 months in the enzalutamide arm, 13.8 months in the placebo arm, and 44.2 months in the placebo crossover arm. The incidence of treatment-emergent adverse events (TEAEs) was similar across all treatment groups.

Grade 3 to 4 TEAEs occurred in 46% of patients on enzalutamide plus ADT vs 28.4% of patients in placebo plus ADT. TEAEs associated with enzalutamide were mostly reported in the first couple of years and tended to diminish substantially over time.

TEAEs of special interest occurred in 75.9% of patients in the treatment arm vs 57.1% of patients in the control arm. The incidence of TEAEs of special interest was consistent with previously reported data from ARCHES.

No new safety signals with the combination were identified.

According to the authors, these data continue to support enzalutamide plus ADT as a standard-of-care for patients with mHSPC.

“The 5-year survival with enzalutamide and ADT in the ARCHES study shows an absolute benefit of 13% at 5 years,” Armstrong concluded during the presentation. “The [survival] benefit ranges from about 9% to 17% and was observed regardless of disease volume, prior docetaxel, and synchronous or metachronous disease. This improvement in long-term survival is accompanied by an increase in enzalutamide-related treatment-emergent adverse events, which are manageable. It does suggest the need for long-term survivorship management—exercise, bone health monitoring, blood pressure monitoring in particular—but these tend to diminish over time with good management.”

REFERENCE

1. Armstrong A, Petrylak D, Shore N, et al. ARCHES: 5-year follow-up overall survival (OS) analysis of enzalutamide (ENZA) plus androgen-deprivation therapy (ADT) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol. 2025;43(suppl 17):5005. doi:10.1200/JCO.2025.43.16_suppl.5005