Zhu D, Srivastava A, Agalliu I et al: Finasteride Use and Risk of Bladder Cancer in a Multiethnic Population. J Urol 2021; 206: 15.

Introduction

Bladder cancer (BCa) is the fifth most common cause of cancer among men in the U.S., and is the eighth most common cause of cancer-related death.¹ While not classically thought of as an endocrine-driven malignancy, there is increasing evidence that androgen receptor (AR) signaling is associated with BCa development.² Five α-reductase inhibitors (5ARIs) inhibit the production of dihydrotestosterone and down-regulate AR-dependent pathways.³

Clinical and epidemiological studies have demonstrated that 5ARIs can reduce BCa incidence.⁴ More specifically, in an analysis of the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening cohort study, the authors reported that the use of the selective type II 5ARI finasteride was associated with a reduced incidence of BCa (HR 0.63, 95% CI: 0.49–0.82, p=0.0004).⁵ However, the PLCO and other similar studies were conducted in majority nonHispanic White (NHW) or East Asian populations.^6,7 Given that AR expression can vary among benign prostatic hyperplasia (BPH) patients of different races, there is a need to assess whether this finding is present among the Hispanic or nonHispanic Black (NHB) populations.⁸ Therefore, we sought to examine associations between finasteride use and BCa risk among a multiracial population.⁹

Materials and Methods

Using queries to our institutional database, we collected the records of all men diagnosed with BPH from 2000 through 2016 at our institution. We then identified who was prescribed finasteride, and followed all patients who developed BCa. Finasteride was offered to men whose BPH symptoms were not controlled by alpha blocker alone, or in symptomatic men with enlarged prostates on imaging. We used multivariate competing risks regression models adjusted for age and smoking to estimate the hazard ratios for BCa development among all men and stratified by race/ethnicity.

Results

We identified 42,406 men with BPH, of whom 27.7% were NHB, 27.7% were NHW, and 14.8% were Hispanic. Finasteride was prescribed in 13.4% of patients (see table). During the followup period, 1.5% of patients who took finasteride developed BCa, while 2.1% of patients who did not use finasteride developed BCa (p=0.003). The median time from BPH diagnosis or finasteride initiation to BCa diagnosis for all patients was 26.4 months (inter-quartile range: 7.4-66.9).

Figure. Cumulative risk of bladder cancer by finasteride use among all patients (A) and stratified by race/ethnicity (B through E).

The cumulative incidence of BCa by finasteride is reported in the figure. The risk of BCa was lower among finasteride users vs nonusers, with a HR of 0.65 (95% CI: 0.51–0.80, p <0.0001) after adjusting for age, race/ethnicity, and smoking history. When we stratified the data by race/ethnicity, we found that NHW men (HR 0.61, 95% CI: 0.43–0.86, p=0.005) and Hispanic men (HR 0.44, 95% CI: 0.21–0.90, p=0.026) who took finasteride had lower cumulative risks of BCa compared to men of the same race/ethnicity who did not take finasteride. However, among NHB men there was no association between finasteride use and risk of BCa (HR 1.01, 95% CI: 0.67–1.51, p=0.964).

Discussion

Men who took finasteride had a lower risk of developing BCa compared to men who did not. When we stratified the results by race/ethnicity, we found that NHW and Hispanic men who took finasteride had a lower risk of developing BCa compared to finasteride nonusers. However, NHB men who took finasteride did not experience a lower risk of developing BCa compared to finasteride nonusers.

Our results further confirm the findings of the PLCO cancer screening trial, which reported that 5ARIs were associated with a lower risk of developing bladder cancer in a population that was 90% Caucasian.⁵ This finding was also reported in another large study of 10,720 Finnish men, which showed that treatment with 5ARIs prior to BCa diagnosis was associated with a 26% decreased risk of BCa incidence (HR 0.84, 95% CI: 0.73–0.97) and a 33% reduction in risk of fatal BCa (HR 0.77, 95% CI: 0.68–0.88).⁶ Similar findings were also reported in East Asian populations.⁷

To our knowledge, our study is the first to explore this relationship within Hispanic and NHB men.⁹ We demonstrated that while Hispanic men experience a similar reduction in risk compared to NHW men, NHB men do not. A possible explanation for this observation might be the structural variations in the AR across different races. Studies have shown an inverse relationship between AR CAG and GGN repeat length and AR activity.¹⁰ NHB men have a higher incidence of and greater mortality from prostate cancer than NHW men and, on average, a smaller number of repeats at AR CAG and GGN.¹¹ We hypothesize that since NHB men are more likely to harbor polymorphisms in AR, it causes their AR to become active independent of dihydrotestosterone binding. However, these results need to be further investigated through randomized clinical trials with genetic profiling.

Conclusions

Our study confirms previous findings from other authors that men who are on finasteride have a lower incidence of BCa, but only in NHW and Hispanic men. Further work is needed to confirm these findings and elucidate their mechanisms.