US real-world utilization and outcomes of darolutamide, enzalutamide, and apalutamide for nonmetastatic castration-resistant prostate cancer (nmCRPC): DEAR-EXT study.
Authors: George Daniel J. , Morgans Alicia K. , Khan Nasreen , Constantinovici Niculae , Ghadessi Mercedeh , Chen Guifang , Hlebec Vlasta , Xu Julie , Shore Neal D. 
Published: September 2024

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Background:
Androgen receptor inhibitors (ARIs) are recommended for nmCRPC. Darolutamide (DARO) is a structurally distinct & highly potent ARI approved for nmCRPC based on ARAMIS (phase 3). There are no prospective comparative clinical trial data for DARO vs enzalutamide (ENZA) & apalutamide (APA). DEAR (NCT05362149) compared real-world (RW) utilization, tolerability & outcomes of ARIs in 870 patients (pts) with nmCRPC. DEAR-EXT (NCT06013475) expands on DEAR with 1 y more of pt inclusion & follow-up.
Methods:
DEAR-EXT is a retrospective chart review cohort study of pts in the PPS network of US urology practices who started initial ARI for nmCRPC from 8/2019 to 3/2023. Key outcomes include time to initial ARI discontinuation, reason for discontinuation, time to metastatic CRPC (mCRPC) progression, prostate-specific antigen (PSA) response, overall survival (OS), metastasis-free survival (MFS) & treatment-emergent adverse events (TEAEs). ARI utilization & tolerability were compared using descriptive frequency statistics; time-to-event outcomes were compared using unadjusted Kaplan–Meier estimates & Cox proportional hazards models adjusted for baseline characteristics.
Results:
Of all 1375 pts meeting eligibility criteria, 565 (41%) received DARO, 609 (44%) ENZA & 201 (15%) APA. During the study, the number of pts with nmCRPC initiating ARI treatment decreased annually but the proportion starting DARO increased vs ENZA & APA. Baseline characteristics were generally similar across treatment groups; median follow-up was similar for DARO (26.2 mo), ENZA (26.2 mo) & APA (25.5 mo). Median time to discontinuation was not reached (NR; 95% CI 35.5–NR) for DARO, 27.6 mo (23.9–35.6) for ENZA & 26.8 mo (22.6–42.8) for APA. Adjusted HRs showed significant discontinuation risk reductions for DARO vs ENZA (27%) & vs APA (31%) (Table). The most frequent reasons for discontinuation were TEAEs (DARO 10%, ENZA 15%, APA 15%) & disease progression/death (15%, 19%, 18%, respectively). Adjusted HRs for mCRPC progression showed significant risk reductions for DARO vs ENZA (37%) & vs APA (28%) (Table). Times to discontinuation & mCRPC progression were similar for ENZA & APA. PSA response, OS & MFS rates were numerically higher for DARO vs ENZA & APA. TEAEs occurred in 25% of pts on DARO, 28% on ENZA & 30% on APA.
Conclusions:
These data reinforce DARO as an effective, well-tolerated treatment for nmCRPC that demonstrates potentially greater clinical benefits vs ENZA & APA in RW practice.

Clinical trial information:
NCT06013475

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HRs from adjusted Cox regression models.

HR
95% CI
P-value

Time to initial ARI discontinuation
DARO vs ENZA
0.73
0.61–0.88
0.001

DARO vs APA
0.69
0.54–0.89
0.003

ENZA vs APA
0.95
0.75–1.19
0.639

Time to mCRPC progression*
DARO vs ENZA
0.63
0.50–0.80
<0.001

DARO vs APA
0.72
0.53–0.98
0.038

ENZA vs APA
1.14
0.85–1.52
0.373

*Not adjusted for multiple testing comparisons.