Frailty and comorbidity surpass probable sarcopenia in predicting survival of mCRPC patients treated with first-line ARPIs: a comprehensive geriatric analysis.

PURPOSE: To evaluate the impact of probable sarcopenia on overall survival (OS), toxicity, and quality of life (QoL) in metastatic castration-resistant prostate cancer (mCRPC) patients receiving androgen receptor pathway inhibitors (ARPIs), adjusting for geriatric and inflammatory markers. METHODS: We retrospectively analyzed 213 mCRPC patients treated with first-line abiraterone or enzalutamide. Probable sarcopenia (low muscle mass) was defined as SMI < 40.8 cm²/m². Geriatric (G8), comorbidity (CIRS-G), and inflammatory markers were assessed. Primary endpoints were OS and grade ≥ 3 toxicity. RESULTS: Patients with probable sarcopenia (n = 93) had shorter median OS (12.7 vs. 24.7 months; p < 0.001) and increased univariable mortality risk (HR = 2.17, p < 0.001). Despite similar 3-month PSA50 responses (86.0% vs. 85.8%, p = 1.000), the prognostic impact of low muscle mass attenuated in multivariable analysis (HR = 1.05, p = 0.783). Instead, frailty (G8: HR = 0.85, p < 0.001) and comorbidities (CIRS-G: HR = 1.21, p < 0.001) independently predicted mortality. A CART model identified a high-risk phenotype (CIRS-G > 8.5, NLR > 3.35, albumin ≤ 3.35 g/dL) experiencing 98% grade ≥ 3 toxicity. Furthermore, probable sarcopenia was associated with significantly faster QoL deterioration. CONCLUSION: Mortality associated with low muscle mass in mCRPC is primarily driven by physiological frailty and comorbidities. Integrating geriatric and inflammatory assessments refines clinical risk stratification and anticipates severe toxicity. External validation is warranted.