Association of Cumulative Proton Pump Inhibitor Use with Prostate Cancer Risk and Outcomes: A Population-Based Cohort Study

Proton pump inhibitor (PPI) use has been associated with increased prostate cancer (PCa) risk in case-control and cohort studies of men with a negative prostate biopsy. We estimated the association of cumulative PPI use with PCa diagnosis and outcomes in a biopsy-naïve cohort of men using provincewide-linked administrative data from Ontario, Canada, including men ≥66 years with no prior PCa diagnosis, biopsy, or treatment and no PPI/H2-blocker prescriptions within the year preceding study inclusion (January 2003-December 2018). The primary outcome was time to PCa diagnosis. Associations were evaluated using univariable/multivariable logistic regression models with complementary log-log-modeling. Median follow-up was 9.2 years (n=559,425), and 30.2% had any PPI use during follow-up. Annual PPI use increased from 2.4% (2003) to 13.8% (2019). Cumulative PPI use was associated with lower PCa diagnosis rates (hazard ratio [HR] for highest user quintile versus non-users: 0.75, 95% confidence interval [CI]: 0.71-0.79). Following adjustment for the frequency of general practitioner visits and PSA tests in the preceding two years, PPI use was no longer associated with PCa diagnosis (HR: 0.99, 95% CI: 0.93-1.05). No association was observed between PPI use and rates of clinically significant or high-grade PCa (HRs: 0.99 and 1.04, respectively). Cumulative PPI use was associated with up to 17% lower rates of a first androgen deprivation therapy prescription or bilateral orchiectomy. Cumulative PPI use was not associated with PCa diagnosis rates, including clinically significant and high-grade PCa. These findings do not support an independent association between PPI use and PCa risk.