Association of Treatment With 5α-Reductase Inhibitors With Time to Diagnosis and Mortality in Prostate Cancer

Abstract

Importance: 5α-Reductase inhibitors (5-ARIs), commonly used to treat benign prostatic hyperplasia, reduce serum prostate-specific antigen (PSA) concentrations by 50%. The association of 5-ARIs with detection of prostate cancer in a PSA-screened population remains unclear.

Objective: To test the hypothesis that prediagnostic 5-ARI use is associated with a delayed diagnosis, more advanced disease at diagnosis, and higher risk of prostate cancer-specific mortality and all-cause mortality than use of other or no PSA-decreasing drugs.

Design, setting, and participants: This population-based cohort study linked the Veterans Affairs Informatics and Computing Infrastructure with the National Death Index to obtain patient records for 80 875 men with American Joint Committee on Cancer stage I-IV prostate cancer diagnosed from January 1, 2001, to December 31, 2015. Patients were followed up until death or December 31, 2017. Data analysis was performed from March 2018 to May 2018.

Exposures: Prediagnostic 5-ARI use.

Main outcomes and measures: The primary outcome was prostate cancer-specific mortality (PCSM). Secondary outcomes included time from first elevated PSA (defined as PSA≥4 ng/mL) to diagnostic prostate biopsy, cancer grade and stage at time of diagnosis, and all-cause mortality (ACM). Prostate-specific antigen levels for 5-ARI users were adjusted by doubling the value, consistent with previous clinical trials.

Results: Median (interquartile range [IQR]) age at diagnosis was 66 (61-72) years; median [IQR] follow-up was 5.90 (3.50-8.80) years. Median time from first adjusted elevated PSA to diagnosis was significantly greater for 5-ARI users than 5-ARI nonusers (3.60 [95% CI, 1.79-6.09] years vs 1.40 [95% CI, 0.38-3.27] years; P < .001) among patients with known prostate biopsy date. Median adjusted PSA at time of biopsy was significantly higher for 5-ARI users than 5-ARI non-users (13.5 ng/mL vs 6.4 ng/mL; P < .001). Patients treated with 5-ARI were more likely to have Gleason grade 8 or higher (25.2% vs 17.0%; P < .001), clinical stage T3 or higher (4.7% vs 2.9%; P < .001), node-positive (3.0% vs 1.7%; P < .001), and metastatic (6.7% vs 2.9%; P < .001) disease than 5-ARI nonusers. In a multivariable regression, patients who took 5-ARI had higher prostate cancer-specific (subdistribution hazard ratio [SHR], 1.39; 95% CI, 1.27-1.52; P < .001) and all-cause (HR, 1.10; 95% CI, 1.05-1.15; P < .001) mortality.

Conclusions and relevance: Results of this study demonstrate that prediagnostic use of 5-ARIs was associated with delayed diagnosis and worse cancer-specific outcomes in men with prostate cancer. These data highlight a continued need to raise awareness of 5-ARI-induced PSA suppression, establish clear guidelines for early prostate cancer detection, and motivate systems-based practices to facilitate optimal care for men who use 5-ARIs.

Figure 1.. Percentage of Prostate Cancer Diagnoses by Time From Elevated Prostate-Specific Antigen (PSA) Levels to Biopsy

Adjusted PSA for 5α-reductase inhibitor (5-ARI) users was calculated by multiplying the PSA by 2, per the REDUCE trial, to account for PSA suppression by 5α-reductase inhibitors.¹⁰

Figure 2.. Unadjusted Cumulative Prostate Cancer–Specific Mortality and All-Cause Mortality

α-Blocker refers to patients who took α-blockers and were not exposed to 5α-reductase inhibitors (5-ARIs). 5-ARI refers to 5-ARI users who may or may not have also taken α-blockers. Neither refers to patients who were not exposed to either 5-ARIs or α-blockers.