Background: In the randomized, open-label, phase 3 LITESPARK-005 (NCT04195750) study, belzutifan treatment showed superior PFS (primary endpoint; HR 0.75 [95% CI 0.63–0.90]; P<.001) and ORR (key secondary endpoint; estimated percentage-point difference 18.4 [95% CI 14.0–23.2]; P<.00001) vs everolimus in pts with advanced/metastatic clear cell RCC that progressed after prior immune checkpoint and anti-angiogenic therapies. We present PRO findings for belzutifan vs everolimus in LITESPARK-005. Methods: PROs were evaluated by FKSI-DRS and EORTC QLQ-C30 questionnaires in all randomized pts with ≥1 dose study treatment and ≥1 completed PROs assessment, administered electronically on d 1 of wk 1, 3, 5, and 9, Q4W thereafter, at treatment discontinuation, and d 30 after last dose. Time to deterioration (TTD) and least square (LS) mean change from baseline as measured by FKSI-DRS and QLQ-C30 global health status/quality of life (GHS/QoL) and physical functioning (PF) scales were prespecified as secondary endpoints. PROs were not formally statistically tested and 95% CI and P-values were nominal and descriptive. Results: As of June 13, 2023 (data cutoff date at second prespecified interim analysis), median (range) follow-up was 25.7 mo (16.8–39.1). Median (range) duration of treatment was 7.6 mo (0.1–35.8) with belzutifan vs 3.9 mo (0.0–33.2) with everolimus; 84 (22.6%) vs 18 (5.0%) pts remained on treatment. 366 of 374 pts randomized to belzutifan and 354 of 372 pts randomized to everolimus were included in the PRO analysis population. Completion rates for FKSI-DRS and QLQ-C30 were >90% at baseline and >55% at wk 17 (~4 mo) in each arm. Meaningfully longer TTD in FKSI-DRS and QLQ-C30 GHS/QoL scores were observed for belzutifan vs everolimus (Table). LS mean changes in FKSI-DRS and QLQ-C30 GHS/QoL scores suggested stability from baseline to wk 17 with belzutifan vs worsening with everolimus, and a potential greater worsening in PF scores with everolimus vs belzutifan. Conclusions: Belzutifan was associated with prolonged TTD in FKSI-DRS and EORTC QLQ-C30. Score changes from baseline to wk 17 also favored belzutifan over everolimus. Overall, PRO results indicate better disease-specific symptoms and quality of life among pts treated with belzutifan compared with everolimus. Clinical trial information: NCT04195750.