Genetic ancestry–concordant ceramide metabolism and response to androgen receptor pathway inhibition in metastatic castration‐resistant prostate cancer

BACKGROUND: The authors observed differences in response between Black and White patients with metastatic castration-resistant prostate cancer (mCRPC) who were treated prospectively with androgen receptor pathway inhibition (ARPI) in the Abi Race and PANTHER studies. In addition, genetic ancestry-related single nucleotide variants in ceramide metabolism genes were associated with the time to prostate-specific antigen progression in the Abi Race study. For this report, the authors analyzed ceramide metabolites and their association with response to ARPI treatment in the Abi Race and PANTHER studies. METHODS: Fasting serum levels were obtained from 22 Black patients and 22 White patients in the Abi Race trial and from 28 Black patients and 37 White patients in the PANTHER trial who were evaluable pretreatment and on treatment. After metabolomic profiling using the Biocrates MxP Quant 500 Kit and liquid chromatography/tandem mass spectrometry quantification of sphingolipids, differences in ceramide metabolites by race and timepoint and associations of ceramide metabolites with outcomes were evaluated. RESULTS: Pretreatment total ceramide levels were lower among Black patients compared with White patients who had mCRPC. Among pretreatment ceramide levels, Black patients had higher C24:C16 ceramide ratios compared with White patients. During ARPI treatment, Black patients had lower C24:C16 ceramide ratios, whereas the majority of C24:C16 ceramide ratios were higher during treatment among White patients. Ceramide metabolites were associated with the time to prostate-specific antigen progression, radiographic progression-free survival, and overall survival among Black and White patients with mCRPC who received ARPI, with higher expression of the ceremide Cer(d18:1/20:0) associated with shorter radiographic progression-free survival and worse overall survival among Black patients who received treatment with apalutamide and abiraterone. CONCLUSIONS: This study identified genetic ancestry-concordant ceramide metabolites that were associated with outcomes in patients with mCRPC who received treatment with ARPI from the Abi Race and PANTHER studies (ClinicalTrials.gov identifiers NCT01940276 and NCT03098836, respectively).