Abstract C116: Genetic ancestry concordant ceramide metabolism and response to androgen receptor pathway inhibition in metastatic castration-resistant prostate cancer

Abstract Introduction: Disparities in prostate cancer incidence, treatment outcomes, and mortality persist across races and ethnicities. Recently, we reported differences in outcomes among White and Black metastatic castration-resistant prostate cancer (mCRPC) patients treated prospectively with androgen receptor pathway inhibition (ARPI). Specifically, among mCRPC patients treated with abiraterone in the Abi Race study, we reported Black patients trended toward greater times to prostate-specific antigen (PSA) progression and PSA declines. Among mCRPC patients treated with combination apalutamide and abiraterone in the PANTHER study, we reported prolonged radiographic progression-free survival and overall survival among Black patients. In the Abi Race study, we also reported genetic ancestry-related single nucleotide polymorphisms (SNPs) in ceramide metabolism genes that associated with time to PSA progression. Given the identification of these SNPs and the known roles of ceramides in cancer biology and therapeutic response, in the present study, we analyzed ceramide metabolites and association with ARPI response in the Abi Race and PANTHER study. Methods: Fasting serum from 22 White and 22 Black patients enrolled in the Abi Race study and from 37 White and 28 Black patients enrolled in the PANTHER study was evaluable at baseline and on cycle 4, day 1 of treatment. Metabolomic profiling was done using the Biocrates MxP Quant 500 Kit. Significant differences in ceramides were determined using t-tests. Kaplan-Meier estimates for outcome for each ceramide were stratified by race and differences tested using a log-rank test. Random lasso was used to select the most important metabolites with respect to outcome. Results: Baseline total ceramide levels were higher among White mCRPC patients than among Black mCRPC patients in both studies. White mCRPC patients had lower baseline long-chain:short-chain ceramide ratios than Black mCRPC patients in both studies. White mCRPC patients experienced an increase in long-chain:short-chain ceramide ratios at cycle 4, day 1 whereas Black mCRPC patients experienced a decrease in long-chain:short-chain ceramide ratios at cycle 4, day 1 in both studies. Higher levels of Cer(d16:1/22:0) and Cer(d18:2/24:0) were associated with increased time to PSA progression among White mCRPC patients in the PANTHER study. Higher levels of Cer(d18:2/16:0) and Cer(d18:2/24:0) were associated with increased time to PSA progression among Black mCRPC patients in the Abi Race study. The ceramide metabolite class at baseline and cycle 4, day 1 influenced time to PSA progression on ARPI in mCRPC. Conclusions: Pending validation, we identified genetic ancestry concordant ceramide metabolism that associates with outcomes on treatment with ARPI in mCRPC. These results suggest that differences in total ceramide levels and chain length composition may contribute to response to ARPI in mCRPC. In addition, distinct ceramide species have potential to serve as genetic ancestry concordant predictive indicators of response to ARPI in mCRPC. Citation Format: Sean A. Piwarski, Lauren E. Howard, Morgan A. Paul, Nick Bachelder, Bonnie LaCroix, Angela Clayton, Donna Allen, Julie Kephart, Steven R. Patierno, Daniel J. George, Terry Hyslop, Jennifer A. Freedman. Genetic ancestry concordant ceramide metabolism and response to androgen receptor pathway inhibition in metastatic castration-resistant prostate cancer abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C116.