Association of prior 5-α-reductase inhibitor exposure with ICI benefit in metastatic RCC: Multicentre cohort with single-cell immune profiling.

Abstract

521 Background: Immune checkpoint inhibitors (ICIs) improve survival in metastatic renal cell carcinoma (mRCC), yet responses remain heterogeneous. Androgen-axis signalling can dampen CD8⁺ T-cell function; thus, prior exposure to 5-α-reductase inhibitors (5-ARIs; finasteride/dutasteride) may favour ICI efficacy by reshaping the tumour immune microenvironment. Methods: Design, Setting, and Participants: Multicentre retrospective cohort of 185 mRCC patients receiving ICIs (2015–2020) at three tertiary hospitals. Patients were stratified by documented continuous 5-ARI use ≥12 months before ICI initiation; propensity score matching (PSM) balanced baseline covariates. A subset of fresh tumours underwent scRNA-seq. Intervention: ICIs alone or in standard combinations; prior finasteride/dutasteride exposure as the key variable of interest. Outcome Measurements and Statistical Analysis: Primary endpoints: progression-free survival (PFS) and overall survival (OS) by Kaplan–Meier and multivariable Cox models. Secondary endpoints: objective response rate (ORR), disease control rate (DCR), time to response, duration of response, and safety. Subgroup/sensitivity analyses were pre-specified; scRNA-seq profiled immune cell states and PD-1 expression. Results: After PSM, groups were well balanced. Prior 5-ARI exposure associated with higher ORR (59.8% vs 39.8%, p=0.0075) and numerically higher DCR (87.0% vs 78.7%). Survival favoured the 5-ARI group (PFS HR 0.64, 95%CI 0.47–0.86, p=0.0085; OS HR 0.65, 95%CI 0.47–0.90, p=0.0271), with 3-year OS 31.2% vs 15.0%. Responses occurred earlier (median TTR 2.8 vs 4.05 months) and lasted longer (DoR 7.5 vs 1.8 months; both p<0.001). Grade ≥III adverse events were not increased. scRNA-seq showed reduced Tregs, lower CD8⁺ T-cell exhaustion and decreased PD-1 expression within exhausted CD8⁺ subsets among 5-ARI-exposed patients, suggesting an immunologically favourable milieu. Benefits were generally consistent across age, IMDC risk, PD-L1 status and metastatic burden. Conclusions: Pre-treatment exposure to 5-ARIs correlates with meaningfully improved ICI effectiveness and favourable immune reprogramming in mRCC. These findings support prospective trials testing androgen-axis modulation as an inexpensive, scalable adjunct to immunotherapy and warrant evaluation of 5-ARI history as a readily available clinical stratifier.