Integrating cardiometabolic health with AR pathway modulation and prostate cancer

BACKGROUND: Altered lipid metabolism, adiposity, and androgens have been linked to cardiac disease and prostate cancer. Adiposity increases risk of recurrence for prostate cancer and may enhance response to androgen receptor pathway inhibition (ARPI). We evaluated whether adiposity and circulating lipid metabolites are associated with response to pre-operative ADT +/- ARPI in localized high-risk prostate cancer (HRPCa). METHODS: We performed a post hoc analysis of 104 men with localized HRPCa treated with 3–6 months of preoperative ADT +/- ARPI across three trials. Body composition was quantified from L3 CT imaging at baseline and at radical prostatectomy (RP; end-of-treatment [EOT] n=56). Plasma lipid metabolites were profiled by UPLC-MS at baseline (n=60) and in paired baseline/EOT samples (n=59). Pathologic response was defined as ≤ T2N0 at RP. PSA progression-free survival (PFS) was defined as time from RP to PSA ≥ 0.2 ng/mL or initiation of radiotherapy. RESULTS: Median age was 63 years, 76.9% had Gleason grade group 4-5, and 43.7% had clinical T3-4 disease. At RP, lower visceral (VATi, p=0.002) and subcutaneous adiposity (SATi, p=0.004) were associated with pathologic response. Increasing adiposity at RP was associated with PSA progression (per 10-unit increase: VATi HR 1.09, p=0.04; SATi HR 1.14, p=0.03). In paired analyses (n=59), pathologic responders demonstrated decreases (p<0.05) in diacylglycerols and polyunsaturated fatty acyl chain-containing triacylglycerols (PUFA-TAGs) and elevations in ceramide species. Non-responders exhibited (p<0.05) increases (p<0.05) in PUFA-TAGs and glycerophospholipids with reductions in lysophosphatidylcholine species, long-chain acylcarnitine, and cholesterol. CONCLUSIONS: Higher post-treatment adiposity and intrapatient changes in lipid metabolite pathways were associated with inferior outcomes after pre-operative hormone therapy, supporting a stage-dependent link between cardiometabolic health and prostate cancer that warrants further elucidation.