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

Educational Objective
To determine whether prediagnostic 5α-reductase inhibitor (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 compared with use of other or no drugs that decrease prostate-specific antigen (PSA).
1 Credit CME
Key Points

Question  Does prediagnostic 5α-reductase inhibitor use, with associated prostate-specific antigen suppression, lead to delayed diagnosis and increased risk of death from prostate cancer in a prostate specific antigen–screened population?

Findings  In this population-based cohort study of 80 875 men with prostate cancer, prediagnostic 5α-reductase inhibitor users had longer time from first elevated prostate-specific antigen test result to diagnosis, higher adjusted prostate-specific antigen at diagnosis, more advanced disease at diagnosis, and worse prostate cancer–specific and all-cause mortality compared with nonusers.

Meaning  Prediagnostic use of 5α-reductase inhibitors is associated with delayed prostate cancer diagnosis and increased mortality in men who underwent prostate-specific antigen screening.

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.

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Article Information

Accepted for Publication: January 26, 2019.

Corresponding Author: Brent S. Rose, MD, Department of Radiation Medicine and Applied Sciences, University of California, 9452 Medical Center Dr, Altman Clinical and Translational Research Institute Building, La Jolla, CA 92037 (bsrose@ucsd.edu).

Published Online: May 6, 2019. doi:10.1001/jamainternmed.2019.0280

Author Contributions: Mr Sarkar had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Sarkar, Parsons, Bryant, Ryan, Mundt, Murphy, Rose.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Sarkar, Mundt, Rose.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Sarkar, Bryant, Ryan, D’Amico, Mundt, Rose.

Obtained funding: Sarkar, Rose.

Administrative, technical, or material support: Sarkar, D’Amico, Mundt, Murphy, Rose.

Supervision: Sarkar, Parsons, Ryan, Kader, McKay, Nguyen, Einck, Mundt, Kane, Rose.

Conflict of Interest Disclosures: Dr McKay reported serving on the advisory board for Novartis and Janssen and receiving research funding from Bayer, Pfizer, and Genentech. Dr Nguyen reported acting as a paid consultant for Medivation, GenomeDx, Ferring, Nanobiotix, Dendreon, Augmenix, and Blue Earth and receiving grants from Astellas and Janssen for work performed outside of the current study. Dr Kane reported serving on the advisory board for Janssen and SNP Bio. No other disclosures were reported.

Funding/Support: This work was supported by the National Institutes of Health grant TL1TR001443 (Mr Sarkar and Dr Bryant).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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