Evaluation of toxicity profiles of next-generation androgen receptor pathway inhibitors in the geriatric population: analysis of the FAERS (FDA adverse event Reporting system) database

Abstract

206 Background: The use of next-generation ARPIs in combination with ADT has revolutionized the treatment of prostate cancer. However, toxicity data remain limited, particularly in the geriatric population. The aim of this study was to evaluate the age-related toxicity profile of ARPIs to guide personalized treatment selection. Methods: This retrospective study was conducted using data from the FAERS (2015–2025). After deduplication per FDA guidance, 14,526,785 unique reports were retained. Male prostate cancer cases aged ≥18 years in which an ARPIs —enzalutamide, apalutamide, darolutamide, abiraterone— was listed as the primary suspect drug were included (n = 33,076). Adverse events were classified using Standardised MedDRA Queries (SMQs, MedDRA v28.1), which group clinically related preferred terms into hierarchical categories. Malignancy-related SMQs were excluded to avoid indication bias. Disproportionality analyses were performed using Reporting Odds Ratios (RORs) to detect significant positive signals (lower 95% CI >1). SMQs meeting this threshold were further assessed by univariate logistic regression for age-specific risk (% of events for total population, <70 vs ≥70 years: OR, p), analyzed separately for each drug (R v4.3.1). Results: FAERS included 33,076 prostate cancer cases (enzalutamide: 19,105; abiraterone: 9,775; apalutamide: 2,981; darolutamide: 1,215).For abiraterone, hepatic disorders were less frequent in older individuals (5.6%, OR: 0.78, p=0.007), whereas hypokalaemia (3.6%, OR: 1.33, p=0.026), cardiac arrhythmias (2.6%, OR: 1.68, p = 0.001), cardiac failure (2.2%, OR: 2.32, p<0.0001), and non-infectious encephalopathy/delirium (0.4%, OR: 2.23, p=0.07) were more frequent with increasing age. For enzalutamide, gastrointestinal dysfunctions (18.4%, OR: 0.91, p=0.026) were less frequent in older men, whereas the incidence of convulsions (1.7%, OR: 1.30, p=0.068), psychotic disorders (1.1%, OR: 1.47, p = 0.029), and dementia (0.5%, OR: 33.01, p<0.001) increased with age. Apalutamide was linked to increased hypersensitivity (20.7%, OR: 1.46, p=0.001), lower hepatic disorders (3.4%, OR: 0.53, p=0.003), and a possible rise in interstitial lung disease (2.7%, OR: 1.80, p=0.064). For darolutamide, no specific toxicity was found to increase with age. Conclusions: In the geriatric population, ARPI selection should be individualized based on the toxicity profiles of the agents.