Abstract Background: PANTHER is a multicenter prospective trial of Black and White cohorts of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with open label Apa and AA +P. We previously reported the 24-month radiographic progression-free survival (rPFS) for Black and White men were 61% (95% CI 49, 78) and 38% (95% CI 27, 54), while the 36-month overall survival (OS) rates were 68% (95% CI 55, 83) and 50% (95% CI 37, 66), respectively. In contrast, a similarly designed prospective study in mCRPC pts treated with AA + P (Abi Race) demonstrated no clear differences in rPFS or OS. We explored baseline and on treatment hormonal levels associated with race in PANTHER, and Abi Race, and their association with treatment outcomes. Methods: We measured levels of AA and its metabolites as well as androgens using LC/MS-MS in available serum samples obtained at baseline and at 4 weeks of therapy from 161 of the 193 pts enrolled in PANTHER (n=86) and in Abi Race (n=75). Samples were batched and all sera assessed contemporaneously. Median levels for each hormone were calculated combining both study populations and used as a cut point. Cox proportional hazard models were used to calculate the hazard ratio (HR) for rPFS and OS associated with above or below median in the overall populations and stratified by race. Results: Median baseline DHEAS was 49 mg/dl, with Black pts demonstrating a slightly higher median level (52 mg/dl; range 7-248) than White pts (42 mg/dl; 4-220). Baseline DHEAS levels below the median demonstrated a non-significant trend towards shorter outcomes in Abi Race: rPFS (HR 1.22, 95% CI 0.70, 2.15) and OS (HR 1.20; 95% CI 0.66, 2.18), and in PANTHER: rPFS (HR 1.54, 95% 0.87, 2.73) and OS (HR 1.14; 95% CI 0.67,1.95). When evaluated by race and DHEAS levels, pts in Abi Race demonstrated no clear association with outcomes. In contrast, Black pts with elevated DHEAS levels in PANTHER demonstrated the greatest rPFS and OS, with significant differences in HRs compared to White pts, for rPFS (Black men, ≤ median HR 1.81, 95% CI 0.67, 4.85; White men, median HR 2.65, 95% CI 1.08, 6.50; White men, ≤ median HR 3.67, 95% CI 1.51, 8.95), p=0.018 and for OS (Black men, ≤ median HR 1.46, 95% CI 0.61, 3.51; White men, median HR 2.43, 95% CI 1.12, 5.27; White men, ≤ median HR 2.20, 95% CI 1.00, 4.86), p=0.086. Similar trends in on-treatment DHEAS levels as well as other relevant hormones and outcomes were seen. Conclusions: Elevated baseline DHEAS levels may have positive predictive significance for rPFS and OS in Black men treated with combination Apa and AA + P compared to White men, but not when treated with AA + P alone, but larger prospective studies are needed. If confirmed, these results support that some Black men may have higher androgen signaling dependent biology of mCRPC, characterized, in part, by elevated DHEAS levels and may disproportionately benefit from combined androgen signaling pathway inhibition. Drug support and funding for Abi Race and PANTHER were provided by Janssen Scientific Affairs, LLC. Citation Format: Daniel J. George, Lauren E. Howard, Susan Halabi, Terry Hyslop, Bonnie LaCroix, Julia Hurrelbrink, Julie Kephart, Julie Rasmussen, Marco A. Reyes-Martinez, Kellie Shobe, Steven Gray, Monika Anand, Steven R. Patierno, Andrew J. Armstrong, R Bruce Montgomery, Elahe A. Mostaghel, Jennifer A. Freedman. Serum dehydroepiandrosterone sulfate (DHEAS) and race associated with longer survival in patients (pts) treated with apalutamide (Apa) and abiraterone acetate (AA) plus prednisone (P) in the PANTHER study 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 C117.
George et al. (Thu,) studied this question.