Skeletal muscle index as a prognostic and predictive biomarker in de novo hormone sensitive prostate cancer: An exploratory analysis of the STAMPEDE trials.

Abstract

173 Background: Sarcopenia is common in advanced prostate cancer and worsened by androgen deprivation therapy (ADT). Routine staging CT scans provide an opportunity to screen for sarcopenia. The STAMPEDE trials have demonstrated treatment intensification beyond ADT improve cancer outcomes; however, benefits are heterogeneous. This study investigates CT-derived skeletal muscle index (SMI), a validated marker of total muscle mass, as a prognostic and predictive biomarker in the STAMPEDE docetaxel and ARPI trials. Methods: Men with newly diagnosed non-metastatic high-risk (M0) and metastatic (M1) hormone-sensitive prostate cancer (HSPC) with available staging CT imaging in the STAMPEDE docetaxel or ARPI trials were included. These trials compared standard of care (SOC) with addition of docetaxel ± zoledronic acid (ZA) or abiraterone acetate with prednisolone (AAP) ± enzalutamide (Enz). SMI (cm²/m²) was calculated as mean muscle area divided by height squared. Outcomes were overall survival (OS) in M1 patients and metastasis-free survival (MFS) in M0. Prognostic utility of SMI was evaluated in Kaplan–Meier analyses and Cox regression models. Predictive value was assessed by comparing hazard ratios of the treatment effect in Cox models for high vs low SMI cohorts. Likelihood ratio tests were used to identify treatment-SMI interactions. Continuous predictive effects were examined using multivariable fractional polynomial interaction (MFPI) models. Results: 2,267 patients (1,578 M1, 689 M0) met inclusion criteria. The median SMI was 47.2cm²/m² (IQR 42-52) in M1 patients and 48.2cm²/m² (IQR 44-54) in M0. SMI and CHAARTED burden were identified as independent prognostic biomarkers in M1 patients, with a 10 cm²/m² increase in SMI associated with a 15% reduction in risk of death (HR 0.85, 95% CI 0.79–0.92, p<0.001). SMI was not an independent prognostic biomarker in M0 patients. SMI was identified as an independent predictive biomarker of MFS benefit upon addition of AAP±Enz in M0 patients; high SMI cohorts had greater MFS benefit from addition of AAP±Enz compared with the low SMI cohort (HR 0.44 [0.3-0.66] vs 0.59 [0.38-0.91]). Likelihood ratio tests confirmed that adding a treatment-SMI interaction improved prediction of treatment benefit (χ²: 4.67, p=0.03). MFPI modelling demonstrated a significant MFS benefit with addition of AAP±Enz in M0 patients (χ²=9.95, p=0.006) with increasing SMI, however this benefit was observed in the range of 41-63 cm 2 /m 2 only. 20% of our cohort lay outside this range (13% lower, 7% higher) and did not observe MFS benefit from addition of AAP±Enz to SOC. Conclusions: SMI is an independent prognostic biomarker in trial patients with de novo metastatic HSPC. SMI is predictive of improved MFS with addition of AAP±Enz to SOC in M0 disease. Further research is required to validate our findings in real-world cohorts.