Treatment with the androgen-receptor inhibitor enzalutamide plus androgen deprivation therapy led to significant survival benefits in patients with metastatic hormone-sensitive prostate cancer.
Treatment with the androgen-receptor inhibitor enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) led to significant survival benefits in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to an analysis of the phase 3 ARCHES trial (NCT02677896).
At a median follow up of 44.6 months, patients who received enzalutamide plus ADT (n = 574) had a 34% reduction in risk of death compared with patients who received placebo plus ADT (n = 576; (HR, 0.66; 95% CI, 0.53-0.81; P < .001). The median overall survival (OS) was not estimable (NE) in either group.1
In the global, double-blind ARCHES trial, adult patients with mHSPC were randomized 1:1 to enzalutamide 160 mg daily plus ADT or placebo plus ADT. The study population was stratified by disease volume and prior docetaxel use. Following the primary analysis, the trial was unblinded and crossover was permitted from the control arm to the experimental arm.2
To be eligible for the trial, patients had have an ECOG performance status of 1 or less and were permitted to have prior ADT and/or treatment with docetaxel (up to 6 cycles). Patients who were being treated with ADT and/or docetaxel and had disease progression prior to randomization were ineligible.2
The primary end point of the trial was radiographic progression-free survival (rPFS). Key secondary end points include prostate-specific antigen (PSA) progression, time to initiation of new antineoplastic therapy, overall response rate, and OS.1,2
The baseline patient characteristics were well balanced between the 2 cohorts. The median age in the enzalutamide plus ADT arm was 70 years (range, 46-92) and 70 years (range, 42-92) in the placebo arm. Most patients in both arms were White (81.2% and 79.9%, respectively), had an ECOG performance score of 0 (78.0% and 76.9%, respectively), and had high disease volume (61.7% and 64.8%, respectively).2
Additional efficacy results from the analysis showed that enzalutamide plus ADT displayed clinical benefit in terms of survival across almost all subgroups evaluated. For patients who had disease localized to soft tissue, placebo plus ADT was superior to enzalutamide plus ADT with a hazard ratio of 1.13 (95% CI, 0.48-2.69).1
In the final prespecified OS analysis, the estimated survival rates were 86%, 78%, and 71% with enzalutamide plus ADT at 24, 36, and 48 months, respectively. In the placebo arm the estimated 24-, 36-, and 48-month survival rates were 82%, 69%, and 57%, respectively.1
Investigators also reported updated rPFS data and updated data for secondary efficacy end points. The median rPFS for patients who received enzalutamide plus ADT was 49.8 months (95% CI, 47.3-NE) compared with 38.9 months (95% CI, 28.2-46.2) among patients who received placebo (HR, 0.63; 95% CI, 0.52-0.76). Treatment with enzalutamide plus ADT also had an effect on a patient’s time to next antineoplastic therapy. Specifically, the median time to next antineoplastic therapy was not reached (95% CI, NE-NE) in the enzalutamide arm vs 40.5 months (26.3-NE) in the placebo arm (HR 0.38; 95% CI, 0.31-0.48).1
To account for any possibly crossover effect, investigators performed a prespecified rank-preserving structural failure analysis. The median time to crossover from placebo to enzalutamide was 21.5 months. Of the 184 (31.9%) patients who consented to crossover 180 (31.3%) received enzalutamide. According to this analysis, the median OS was not reached (95% CI, NE-NE) with enzalutamide plus ADT vs 47.7 months (95% CI, 43.3-NE) with placebo plus ADT (HR, 0.57; 95% CI, 0.45-0.70; P < .001).
In the adjusted analysis for rPFS via investigator assessment, the median rPFS was 49.8 months (955 CI, 47.28-NE) in the enzalutamide arm vs not reached (95% CI, 23.37-NE) in the placebo arm (HR, 0.55; 95% CI, 0.44-0.67). The median time to PSA progression in this analysis was not reached (95% CI, NE-NE) in the enzalutamide arm vs 16.6 months (95% CI, 13.8-19.42) in the placebo arm (HR, 0.19; 95% CI, 0.14-0.24).1
In terms of safety, investigators reported that treatment-emergent adverse effects (TEAEs) in the enzalutamide plus ADT group were consistent with the previously known effects of long-term enzalutamide therapy. Patients in the enzalutamide plus ADT group and the placebo plus ADT group experienced TEAEs of any grade at a rate of 90.9% and 87.8%, respectively. Grade 3 or 4 TEAEs occurred at a rate of 39.2% and 27.9%, respectively. TEAEs leading to death occurred in 5.2% of patients in the experimental arm compared with 2.1% of patients in the comparator arm.1
Patients who received enzalutamide experienced a TEAEs of special interest of any grade at a rate of 72.7% vs 57.0% among patients who received placebo. Common TEAEs of special interest of any grade in the enzalutamide plus ADT group included musculoskeletal events (39.0%), fatigue (32.2%), and hypertension (14.3%). In the placebo arm, common TEAEs of special interest of any grade also consisted of musculoskeletal events (29.6%), fatigue (20.6%), and hypertension (6.8%), among others.
The study authors concluded that enzalutamide plus ADT is and effective and well-tolerated treatment option for patients with mHSPC.