Risks associated with the combination of Darolutamide and Docetaxel in interstitial lung disease : a pharmacovigilance study based on the FAERS database

Darolutamide plus docetaxel is a first-line treatment-intensification regimen for metastatic hormone-sensitive prostate cancer, but whether it has a distinctive pulmonary safety signal remains unclear. We analyzed FAERS reports for darolutamide + docetaxel, enzalutamide + docetaxel, and abiraterone + docetaxel using disproportionality analyses at the system organ class and preferred-term levels, comparative reporting odds ratios (RORs), age subgroup and time-to-onset analyses, and multi-model drug-drug interaction assessment. Network pharmacology, pathway enrichment, protein-protein interaction analysis, molecular docking, and molecular dynamics simulation were used to explore potential mechanisms. The three combinations included 555, 519, and 421 reports, respectively. Respiratory, thoracic and mediastinal disorders were more prominent for darolutamide + docetaxel (N = 120; ROR = 2.62), and interstitial lung disease (ILD) was the most distinctive respiratory preferred term (N = 37; ROR = 31.30, 95% CI 22.42-43.70). Comparative RORs for ILD were 22.66 versus darolutamide alone and 13.31 versus docetaxel alone. Darolutamide x docetaxel showed positive interaction signals for ILD and Core_ILD, whereas enzalutamide x docetaxel and abiraterone x docetaxel did not show the same ILD-directed synergy. Mechanistic analyses highlighted xenobiotic response, apoptosis, gap junction, calcium signaling, GPCR/cAMP pathways, and hub genes including MYC, TP53, KRAS, ATM, PIK3CA, PTEN, CCND1, and BRCA1. These findings do not establish incidence or causality but support darolutamide + docetaxel-related ILD as a pharmacovigilance cue requiring priority validation.