Enzalutamide shows improved relative efficacy over darolutamide in mHSPC

Findings from a matching-adjusted indirect comparison (MAIC) analysis showed that enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) significantly extended radiographic progression-free survival (rPFS) and time to castration resistance compared with darolutamide (Nubeqa) plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC).¹

The study included data from the phase 3 ARCHES (NCT02677896; enzalutamide + ADT) and ARANOTE (NCT04736199; darolutamide + ADT) trials.

“In the absence of direct head-to-head trials, MAIC analyses offer a valid method for data comparison, minimizing biases derived from differences in study designs and populations,” explained lead author Andrew J. Armstrong, MD, MSc, of Duke Cancer Institute in Durham, North Carolina. “Applying this method to the ARCHES and ARANOTE phase 3 trials showed that for patients with mHSPC, enzalutamide in combination with androgen deprivation therapy slowed disease progression or death compared to darolutamide plus ADT and extended the time to castration resistance. The differences in efficacy were statistically significant."

Specifically, in the intent-to-treat (ITT) populations, enzalutamide plus ADT was associated with a 46% lower risk of radiographic progression or death (HR, 0.54; 95% CI, 0.32 to 0.93; P = .03) and a 43% lower risk of progression to castration resistance (HR, 0.57; 95% CI, 0.34 to 0.94; P = .03) compared with darolutamide plus ADT.

These trends were also observed among patients who had not received prior docetaxel. In these patients, enzalutamide plus ADT was shown to significantly prolong rPFS (HR, 0.47; 95% CI, 0.26 to 0.84; P = .01) and the time to castration resistance (HR, 0.46; 95% CI, 0.27 to 0.79; P = .01) compared with darolutamide plus ADT.

There was also a trend toward improvement in the time to prostate-specific antigen (PSA) progression in the enzalutamide plus ADT arm, though this difference did not reach statistical significance (HR, 0.61; 95% CI, 0.29 to 1.30; P = .20). This finding was consistent with what was seen in the docetaxel-naïve population (HR, 0.48; 95% CI, 0.21 to 1.10; P = .08).

Data also favored the combination of enzalutamide plus ADT over darolutamide plus ADT in the time to initiation of new antineoplastic therapy in both the ITT population (HR, 0.65; 95% CI, 0.34 to 1.24; P = .19) and the docetaxel-naïve population (HR, 0.57; 95% CI, 0.28 to 1.17; P = .13), though the differences did not achieve statistical significance.

In total, the ARCHES trial enrolled 1150 patients who were randomly assigned 1:1 to receive enzalutamide plus ADT (n = 574) or to placebo plus ADT (n = 576). The median follow-up was 14.4 months.

The ARANOTE trial enrolled 669 patients who were randomly assigned 1:1 to receive darolutamide plus ADT (n = 446) or placebo plus ADT (n = 223). The median follow-up was 25.3 months.

All patients in the ARANOTE trial were docetaxel naïve. In the ARCHES trial, 17.9% of patients in the enzalutamide plus ADT arm and 17.7% of patients in the placebo plus ADT arm had prior docetaxel exposure. Further, a higher percentage of patients were Asian in the ARANOTE trial vs the ARCHES trial (31.2% vs 13.5%, respectively), which the authors considered to be a “potential effect modifier.”

There were also differences between the 2 studies in terms of the regions of investigational sites and disease characteristics such as the distribution of ECOG Performance Scores and baseline PSA levels.

“This is the first MAIC study to compare efficacy outcomes of combining ADT with enzalutamide or darolutamide for patients with mHSPC,” the authors concluded. “As multiple ARPI options are currently available, the findings from this study, along with other patient factors, will help guide treatment decisions for management of mHSPC.”

REFERENCE
1. Armstrong AJ, Pandya BJ, Bhadauria HS, et al. Matching-adjusted indirect comparison of enzalutamide versus darolutamide doublet in mHSPC. Future Oncol. 2025:1-11. doi:10.1080/14796694.2025.2526324