Influence of body composition on the efficacy of chemotherapy in men with metastatic aggressive variant prostate cancer (AVPC).

200 Background: Higher levels of adiposity have been associated with an improved response to AR pathway inhibition (ARPI) among patients with mCPRC (PMID 39019979). However, it is unclear if the influence of adiposity was driven by disease setting (mCRPC) or was specific to ARPI. Further, it remains unclear which obesity-linked factors best predict response to therapy in this context. This study tested the hypothesis that elevated skeletal muscle will be associated with improved efficacy with cabazitaxel + carboplatin in patients with aggressive variant mCRPC, but elevated adiposity measures will not. We then explored differences in gene expression by body composition measures. Methods: This was a post-hoc analysis of NCT03263650 where patients with metastatic AVPC received 6 cycles of cabazitaxel + carboplatin before randomization 2:1 to olaparib vs observation at MD Anderson from 2017 to 2020. Body composition was measured using an AI segmentation tool at the L3 vertebra from a CT scan within 30 days prior to chemotherapy initiation. Gene set enrichment analyses (GSEA) of Hallmark pathways, stratified by skeletal muscle mass (SMMi) and subcutaneous adiposity (SATi), were performed using bulk RNA sequencing data from pre-treatment tumor biopsies of patients with AVPC enrolled in NCT02703623 to derive normalized enrichment scores (NES) for each pathway. Efficacy endpoints included progression-free survival (PFS) and overall-survival (OS). Flexible survival modeling was performed using multivariable Cox regression adjusting for ECOG and age, with body composition measures modeled as continuous variables using restricted cubic splines. Results: 95 patients were included in the efficacy analysis with a median age of 67 years (range 43-86) and most had ECOG PS ≤ 1 (88.4%). The association between SATi or visceral adiposity (VATi) and PFS or OS was inconclusive (Table 1). SMMi was associated with a trend towards improved PFS (HR 0.56, Table 1). Increased SMMi correlated with significant downregulation of the MYC (NES -2.56; adj. p-value 2.5E-09) and oxidative phosphorylation (NES -2.56; adj. p-value 2.5E-09) pathways, and to a lesser extent the DNA repair, E2F, mTORC1, and G2M checkpoint pathways. Conclusions: Among men with metastatic AVPC, adiposity was not associated with the efficacy of chemotherapy, whereas increasing skeletal muscle showed a favorable trend. These findings suggest that the impact of adiposity on outcomes in mCRPC may be specific to AR-directed therapies. Treatment response using body composition as continuous variables. Body Composition Measure PFS OS Hazard Ratio (HR) – 95% CI Body Mass Index (BMI) 0.97(0.57 – 1.67) 1.26(0.71 – 2.23) Subcutaneous Adipose Tissue Index (SATi) 0.91(0.50 – 1.66) 1.03(0.57 – 1.87) Visceral Adipose Tissue Index (VATi) 1.14(0.60 – 2.15) 0.99(0.53 – 1.84) Skeletal Muscle Mass Index (SMMi) 0.56 (0.31 – 1.02) 0.97(0.55 – 1.69)