Cardiometabolic health’s influence on outcomes in men with localized high-risk prostate cancer (HRPCa) treated with pre-operative ADT ± AR pathway inhibition (ARPI).

Abstract

225 Background: Cardiometabolic health (CMH) has a complex and divergent association with clinical outcomes in men with prostate cancer (PCa), exemplified by the differential impact of metabolic agents like metformin across disease states (e.g., active surveillance vs. metastatic). Increased adiposity is linked to higher risks of recurrence and lethal disease in localized PCa but may also enhance response to androgen receptor pathway inhibition (ARPI) in metastatic castration-resistant PCa (mCRPC), suggesting the need to study adiposity and prostate cancer in a stage-specific manner. Here, we investigated how baseline and treatment-induced changes in adiposity and lipid metabolites relate to clinical outcomes in men with localized high-risk PCa (HRPCa) treated with pre-operative androgen deprivation therapy (ADT) ± ARPI. Methods: Men with localized HRPCa who received 3–6 months of pre-operative ADT ± ARPI across three investigator-initiated clinical trials were included if baseline L3 vertebral computed tomography (CT) imaging was available. Body composition was quantified using an AI-assisted segmentation tool on CT scans obtained before treatment and at radical prostatectomy (RP). Fasted plasma lipid metabolites were profiled at both time points via LC/MS. Pathologic response was defined as ≤T2N0 disease, and PSA progression-free survival (PFS) as the time from RP to PSA ≥0.2 ng/mL or initiation of adjuvant/salvage radiotherapy if PSA remained <0.2 ng/mL. Results: Among 104 men (median age 63 years, baseline PSA 12.7 ng/mL), 77% had Gleason grade group 4–5 and 45% had clinical T3–4 disease. At radical prostatectomy, lower visceral adipose tissue (VATi; p = 0.002) and subcutaneous adipose tissue (SATi; p = 0.004) were significantly associated with higher rates of pathologic response. Conversely, greater adiposity measures at the time of RP were associated with an increased hazard of PSA progression (VATi HR 1.09, p = 0.04; SATi HR 1.14, p = 0.03). Intrapatient decreases in lipid metabolites, particularly acylcarnitines (p < 0.01), ceramides (p = 0.001), and triacylglycerols (p = 0.03), were observed among pathologic responders compared with non-responders, suggesting favorable metabolic adaptation during therapy. Conclusions: In men with localized HRPCa, elevated adiposity and intrapatient lipid metabolite changes in select pathways were associated with inferior clinical outcomes following pre-operative ADT ± ARPI. These findings demonstrate that specific features of CMH exert multifaceted effects on prostate cancer outcomes and warrant further investigation into CMH as a modifiable factor in PCa management.