Clinical and lifestyle determinants of all-cause mortality among high-risk prostate cancer patients: Findings from a multicenter longitudinal cohort, 1990-2024

Patients with high-risk prostate cancer (PCa) have substantially elevated risks of disease progression and mortality, yet outcomes remain highly variable. Emerging evidence suggests that comorbidities, obesity, and smoking contribute to PCa progression and overall survival through metabolic and inflammatory pathways. However, few studies have evaluated how these factors interact to influence mortality in high-risk PCa patients. We examined individual and combined effects of clinical and lifestyle factors on all-cause mortality in a large, longitudinal cohort of high-risk patients treated within military treatment facilities. Male patients with newly diagnosed National Comprehensive Cancer Network-defined high-risk PCa who underwent radical prostatectomy (RP), external beam radiation therapy (EBRT), and androgen deprivation therapy (ADT) were included from the Center for Prostate Disease Research Multicenter National Database (1990-2024; n=2,713). Multivariable Cox regression analyses were conducted to evaluate associations between lifestyle factors (obesity, smoking) and self-reported comorbidity conditions at enrollment and all-cause mortality across treatment groups. Median age at diagnosis was 68 years; 66% self-identified as White and 26% as African American. Overall, 44% underwent EBRT, 34% RP, and 14% ADT. During follow-up, 45% of patients died. Chronic obstructive pulmonary disease (COPD) was a strong predictor of increased all-cause mortality across all treatment groups [RP, Hazard Ratio (HR)=1.98 (1.13, 3.50); EBRT, HR=1.52 (1.09, 2.16); ADT, HR=1.65 (0.98, 2.75)]. The association was more apparent among ever smokers in RP group [HR=2.58 vs. never, HR=0.58] and among non-obese patients in RP [HR=2.21 vs. obese, HR=1.27] and EBRT [HR=1.80 vs. 1.01] groups. Hypertension and diabetes were also marginally associated with higher mortality across treatment groups, with stronger associations among ever smokers in RP [hypertension, HR=1.58 vs. 0.77; diabetes HR=1.6 vs. 0.49]. Coronary artery disease was a significant predictor of mortality among EBRT patients [HR=1.34 (1.03, 1.74)] but not in other groups. Renal insufficiency was associated with increased mortality in EBRT [HR=1.84 (1.16, 2.93)] and ADT [HR=1.38 (0.70, 2.73)], with a stronger association never smokers [EBRT, HR=8.45 vs. ever, HR=1.29]. COPD, hypertension, and diabethes were consistently associated with increased all-cause mortality in high-risk PCa patients, with modest effect modification by smoking and obesity status. These findings highlight the importance of integrated management of comorbidities and lifestyle risk factors to improve survivorship in this high-risk patients.