Mingrui Huang, Jiahui Yang, Heng Guo, Cong Huang, Yingli Fu, Liqun Zhou
Circulating tumor DNA (ctDNA) has emerged as a novel detection technique that provides molecular profiles without invasive procedures. This study assessed the prognostic value of ctDNA-based androgen receptor (AR) gene alterations in metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide and abiraterone. A comprehensive search was conducted in PubMed, Embase, and the Cochrane Library from January 2016 to April 2025. Studies investigating the prognostic value of AR alterations in ctDNA in mCRPC were included. Hazard ratios of overall and progression-free survival were extracted. The overall meta-analysis and subgroup exploration stratified by ctDNA sampling time, research type, prior androgen receptor inhibitor (ARI) use, detection method, and AR alteration type were performed using Review Manager, Stata, and R software. Twenty-five studies were included in the meta-analysis. The presence of AR gene alterations in ctDNA was significantly associated with worse overall survival (HR = 1.99, 95% CI, 1.61-2.46, P < .001) and progression-free survival (HR = 2.37, 95% CI, 1.81-3.10, P < .001). Subgroup analyses showed that these associations were observed across different ctDNA detection methods and sampling-time categories. Among patients with prior exposure to next-generation AR-targeted therapies, the association with OS was attenuated and was not statistically significant (HR = 1.58, 95% CI, 0.96-2.62, P = .07), whereas the association with PFS remained significant (HR = 2.00, 95% CI, 1.16-3.46, P = .01). Significant between-study heterogeneity was observed. ctDNA-detected AR gene alterations are associated with inferior OS and PFS in patients with mCRPC treated with novel hormonal therapies, supporting their potential role as prognostic biomarkers. However, the available evidence does not establish treatment-predictive utility, because the included analyses do not demonstrate that AR status modifies the relative benefit of one therapy compared with another. Interpretation should consider sampling timing, alteration type, prior and subsequent treatment exposure, substantial between-study heterogeneity, and potential publication bias. Prospective biomarker-stratified studies are needed to determine whether ctDNA AR alterations predict differential benefit from specific therapies.