Unveiling sex-based disparities in advanced renal cell carcinoma: Insights from the real-world Meet-URO33 (REGAL) study.

526 Background: Sex-related biological differences may affect cancer immunity and outcomes with immune checkpoint inhibitors (ICIs). With conflicting evidence, female sex has been associated with higher rates of sarcomatoid dedifferentiation, worse OS in metastatic RCC, higher-grade toxicities, and greater steroid use. Other analyses suggest a survival advantage for younger women compared with men, supporting a possible hormonal role with a protective effects of estrogens. Methods: Meet-URO-33 (REGAL) is a multicenter ambispective observational trial including 1560 patients with advanced RCC treated with 1st line systemic therapy after January 2021. Data from electronic medical records included demographics, histology, metastatic sites, treatment, and response according to RECIST 1.1. Clinical-pathological features, hematological parameters (including NLR), toxicities, and outcomes were compared by sex and by menopausal age cut-off (<50 vs ≥ 50 yrs). Results: Among 401 females (F) and 1159 males (M), F presented with worse baseline characteristics, such as ≥ 2 metastatic sites (35% vs 27%, p = 0.012), liver metastases (18% vs 11%, p = 0.002), and sarcomatoid variant (20.3% vs 14.5%, p = 0.025). F presented with lower BMI ≤ 25 kg/m2 (52% vs 43%, p = 0.008), and NLR <4 (73% vs 67%, p = 0.027). First-line treatment distribution (IO–TKI, IO–IO, or TKI monotherapy) was well balanced. Grade 3–4 immune related adverse events (irAEs) were significantly more frequent in F (35% vs 28%, p = 0.012), with no sex-related differences in the pattern of irAEs, but a greater need for steroids (18% vs 12%, p = 0.025). Discontinuation rates were similar in F and M (20.5% vs 19.3%, p = 0.63). No significant differences were observed for F in PFS (15.8 vs 18.5 months, p = 0.23) or OS (39.5 vs 41.9 months, p = 0.93). The presence of sarcomatoid features did not influence the sex–outcome interaction (p = 0.43 for OS, p = 0.95 for PFS). Stratifying outcomes by age, patients ≥ 50 years had similar results, but F < 50 years showed a markedly shorter PFS (8.5 vs 19.6 months, HR 2.02, p = 0.009). Conclusions: F presented with more adverse baseline features and higher severe toxicity rates, yet OS/PFS outcomes were similar, with unfavorable trends for F. The significantly worse PFS in younger F supports a possible hormonal influence, as the protective role of estrogens may vary before/after menopause. Higher steroid exposure, immune-related differences, and pharmacokinetics may also have contributed. The underrepresentation of F, consistent with other RCC trials, remains a limitation, reducing the reliability of subgroup analyses. These findings highlight the need to integrate sex and menopausal status into clinical practice and trial design. Dedicated translational research are essential to clarify biological and pharmacological mechanisms underlying sex-based disparities and to guide tailored strategies in advanced RCC. Clinical trial information: 33.