A new study from Sarkar et al [5] suggests the 5-ARI story in prostate cancer is not over yet, however. Finasteride and dutasteride are commonly used to improve bladder outlet obstructive urinary symptoms in men with benign prostatic hyperplasia. In addition to a reduction in the size of the prostate, one of the most prominent effects of these medications is an approximate 50% reduction in the serum prostate specific antigen (PSA) concentration [6]. The appropriate PSA based screening for prostate cancer practice in men on 5-ARIs is to therefore normalize the PSA by doubling it in these men, for appropriate population based comparisons [7]. There has been speculation that this normalization is seldom done in primary care practices that pursue PSA screening in general, which may lead to delays in detection and worse outcomes for some men. Sarkar and colleagues [5] performed a retrospective cohort comparison of men in the Veterans Affairs database who were diagnosed with prostate cancer from 2001 to 2015. The cohort consisted of 80,875 men, of whom 8,587 (10.6%) had been prescribed a 5-ARI at least 1 year prior to diagnosis. The study found that men taking 5-ARIs had significantly higher rates of prostate cancer-specific (39% greater) and overall (10% greater) mortality. Interestingly, there was no difference in non-cancer related mortality. Secondary outcomes were also worse across all measures in the 5-ARI group, showing a significant delay in time to diagnosis of cancer (3.6 vs. 1.2 years), higher adjusted PSA value (13.5 vs. 6.4 ng/mL), higher grade (25.2% vs. 17% Gleason 8–10), stage (4.7% vs. 2.9% T3–4), presence of lymph nodal (3.0% vs. 1.7%), and metastatic disease (6.7% vs. 2.9%) at diagnosis.

In the absence of randomized controlled trials, these findings would raise greater concerns over the effects of 5-ARIs to directly influence the genomic behavior of prostate cancer, leading to aggressive and more lethal disease. But prior randomized controlled trials show at most a small increase in the incidence of more aggressive disease, a finding which is likely due to detection bias [3]. While this explanation is still possible based on the study's observational design, a more likely explanation is the delay in diagnosis in men taking 5-ARIs, related to the misinterpretation of their artificially lower PSA values. Although the absolute median delay in diagnosis time was only 2 years, in this cohort it was associated with a median PSA of 13.5 ng/mL, a value more than twice the median in men not taking 5-ARIs, and a significant predictor for more aggressive disease. Setting aside discussions about PSA based prostate cancer screening in general, and accepting that all major guideline-based organizations in the US, including the US Preventive Services Task Force, now recommend at least a discussion about PSA-based screening for certain aged groups, it appears imperative to address the appropriate adjustment of PSA values in men taking 5-ARIs. Further investigation into current primary care PSA screening practices appears warranted.