Reduced Risk of Prostate Cancer With 5α-Reductase Inhibitors

Prostate cancer (PCA) and lower urinary tract symptoms (LUTS) associated with aging and benign prostatic hyperplasia are ubiquitous in aging men. PCA has a high prevalence, causes considerable morbidity when metastatic, and is the third most common cause of cancer death in men (1). LUTS adversely affects quality of life and may result in recurrent infections and urinary retention, leading to morbidity and mortality among older men.

A seminal clinical trial compared the efficacy of two medications to control symptoms and prevent progression of LUTS. In this study, while alpha blockade with doxazosin resulted in more improvement in urinary symptoms, inhibition of 5α-reductase with finasteride was found to not only improve symptoms but reduce the risk of long-term consequences of LUTS including urinary retention and the need for surgical therapy (2).

PCA is as ubiquitous as LUTS but more complex. Two opportunities for disease control are prostate-specific antigen (PSA) screening, coupled with treatment with surgery or radiation, and new pharmaceutical therapies for metastatic PCA. Each approach has challenges. Screening commonly detects disease that will not cause morbidity or mortality; if treatment is then applied, cost and side effects result without clinical benefit. If the patient is managed with active surveillance, cost is substantial, anxiety is common, and 30% to 40% of patients are ultimately treated within five to six years (3). The number needed to screen to prevent one death is approximately 718; the number needed to treat is approximately 27 (4). In the case of metastatic disease, while new therapies improve survival, treatment is morbid and expensive, and most men ultimately succumb to the disease.

In 1994, the Prostate Cancer Prevention Trial (PCPT), in response to the registration of finasteride (the first 5-α reductase inhibitor [5-ARI]) and the dramatic increase in prostate cancer detection due to PSA testing, began subject recruitment. Randomly assigning men to finasteride or placebo, integrating an end-of-study prostate biopsy to mitigate the PSA detection bias due to finasteride, centralized PSA testing, and pathology review, the study randomly assigned 18 880 subjects with a PSA of 3.0 ng/mL or less and normal digital rectal exam. The study reported results early, as the primary end point had been reached: finasteride was associated with a 24.8% reduced risk of prostate cancer (5). While seemingly a public health “home run,” the small but statistically significant increase in high-grade tumors among subjects receiving finasteride resulted in no adoption of this approach as well as a “black box warning” on the medication, a drug commonly used for LUTS.

Subsequent post hoc studies found a number of biases that provided a window into this phenomenon. Not only were the tests to detect PCA affected by finasteride (the sensitivity of PSA and digital rectal examination for detection of prostate cancer were statistically significantly improved with finasteride), but the test to diagnose prostate cancer—prostate biopsy—was similarly statistically significantly improved, likely due to the smaller prostate and improved sampling with biopsy (6–8). Several studies subsequently incorporated these findings and concluded that these biases likely explained the greater detection of high-grade disease in the study (9).

Despite these findings, finasteride is rarely employed to reduce the risk of the most common cancer in men. It remains in use for treatment of LUTS but with the lingering concern that it may increase the risk of high-grade disease. Additionally, as the original study only included men with PSA levels of 3.0 ng/mL or less, the effect of the drug vis-à-vis prostate cancer prevention in men with LUTS, who often have higher PSA levels, has not been studied.

Against this backdrop, the study of Wallerstedt et al., published in this issue of the Journal, addresses the impact of 5-ARI in a large Swedish cohort with reasonably long follow-up (10). Study strengths include a baseline PSA, duration of 5-ARI use, and grade-specific PCA diagnoses in a stable population setting. Like the PCPT, the study found that 5-ARI use reduced the risk of prostate cancer, primarily affecting lower-grade cancer detection, and had no impact on risk of higher-grade disease. From a study design standpoint, men were included one year after their first PSA test. While this was included to remove prevalent cases, it eliminated the most evident cancers as the cohort began their follow-up. Interestingly, among the men with the shortest 5-ARI exposure, there was a 56% increase in the risk of high-grade disease, a similar observation as in PCPT. This observation is consistent with a detection bias as it was not seen in men with longer exposure.

The study by Wallerstadt et al. (10) has limitations as it wasn’t a randomized trial. Data identified men who were prescribed the medication but not those who took the medication. Outcomes for men who had already begun a 5-ARI are unknown. As prostate size is directly related to PSA levels and thus to risk of LUTS, baseline PSA levels were higher in men receiving a 5-ARI. Similarly, as PSA levels are directly related to the likelihood of a prostate biopsy, prior prostate biopsies were more common in men receiving a 5-ARI. Finally, as age is related to risk of LUTS, men on 5-ARIs were older. (Of interest, risk of PCA and risk of high-grade PCA are both directly related to age [11].) We have previously demonstrated that many of these factors (eg, age) are related to the likelihood that a biopsy is performed (12). As the 5-ARI group was older and with the fall in PSA with treatment, there may have been fewer biopsies among this group of subjects. While some of these factors may bias the study against finasteride, others have the opposite effect. In a cohort design, it is impossible to correct for these biases, and the results should be interpreted with caution.

The unique contribution of the study from Wallerstadt et al. that cannot be addressed by prior randomized studies of 5-ARIs is the study population, including men with PSA levels greater than 3.0 ng/mL. The lack of an increase in diagnosis of high-grade PCA should provide reassurance to patients/physicians who are receiving/prescribing 5-ARIs for management of LUTS. Ultimately, however, it will require long-term follow-up of phase III clinical trials of these agents to confirm the true impact of these agents on risk of PCA morbidity/mortality.

Notes

Affiliations of authors: Medical Center, CHRISTUS Santa Rosa Hospital, San Antonio, TX (ITJr); Fred Hutchinson Cancer Research Center, Seattle, WA (PG, CT).

The authors have no conflicts of interest to disclose.

References