Because of the relatively long latency period of prostate cancer (PCa) and treatment-related morbidity in its management of PCa, the utilization of 5-alpha reductase inhibitors (5ARIs) as a chemo-preventive strategy has been highlighted [1]. This strategy was hypothesized to prevent PCa by decreasing intraprostatic dihydrotestosterone levels. Two large, randomized, placebo-controlled cancer prevention trials were initiated to evaluate the effects of 5ARIs: the Prostate Cancer Prevention Trial (PCPT) for finasteride and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial for dutasteride. Both trials, which were published in the 2000s, demonstrated a similar impact on the risk of PCa development. In the PCPT study, 7 years of finasteride therapy reduced the prevalence of PCa by 24.8% [2]. In the REDUCE trial, dutasteride treatment was associated with a relative risk reduction of 22.8% over 4 years [3], despite the observation of a potentially increased risk of high-grade disease.

Meanwhile, prescriptions of 5ARIs also increased dramatically in Korea, predominantly triggered by the ex-ploding incidence of lower urinary tract symptoms (LUTS), which generally originate from concomitant benign prostate hyperplasia (BPH) along with the extended lifespan. Given the low uptake of prostate-specific antigen (PSA) testing among Korean men (3.1% in 2007 and 7.3% in 2016 among men aged over 40 years [4]) due to the limited social awareness of PCa combined with the lack of a public screening policy [5], the prescription of 5ARIs, for which PSA testing is encouraged to select suitable patients, may promote the identification of PCa by providing repeated opportunities to check men's serum PSA levels. With this background, the purpose of this study was to investigate the influence of 5ARI prescriptions on the detection of PCa utilizing nationwide data during a recent decade.

Although the benefits of PSA-based mass screening policies have remained a matter of debate since 2012 [6-8], serum PSA testing still plays a pivotal role in detecting PCa. Most early-phase PCa cases do not manifest specific symptoms other than ambiguous LUTS, which more frequently originate from concomitant BPH. Indeed, most PCa cases are detected in the non-metastatic stage in Korea [9]. Therefore, the circumstances in which PSA testing is performed provide opportunities to catch PCa in an earlier phase.

Unlike the United States or Europe, which have a long history of clinical applications, ready access to PSA testing, and greater social awareness of PCa, the incidence of PCa in most Asian countries has soared in very recent years. For example, PCa was a relatively less prevalent cancer in Korea until the end of the 20th century. In 2000, PCa became Korean men's 10th most common malignant disease [9]. However, since 2002, when PCa was first reported to be the fifth most common malignant disease among Korean men, its incidence has consistently increased. In 2016, PCa became the fourth most common incident malignancy in men. In the most recent report (2020), it became the third-most common cancer in men and the second-most common among men over 65 years old.

However, this rapidly increasing incidence of PCa was not accompanied by an enhanced public awareness of the disease and its screening strategies. Indeed, in a general survey of 600 members of the Korean population in 2019, only 9.7% of men aged over 40 years were aware of PSA testing, and 83.3% of them had never received PCa screening [5]. Currently, PSA testing is not included in regular check-ups in Korea, which contrasts with the inclusion of tests for other common malignant diseases in men, such as lung, stomach, colon, and liver cancer, which were the first, second, third, and fifth most prevalent malignant diseases among Korean men in 2019 [9]. The nationwide rate of PSA testing during the recent 10-year period (2006-2016), therefore, remained low in Korean men older than 40 years. Although it reached 7.2% in 2016, that figure is still less than a quarter of that reported in the United States [4]. From 2008 to 2016, only around a quarter of men with PCa in Korea underwent repeat PSA testing before a pathologic cancer diagnosis was confirmed [10].

The outcomes of this observational study also show how the limited social perception of PSA testing negatively affects PCa detection. In contrast to the well-known randomized controlled trials (RCTs) that were published approximately 2 decades ago, which consistently reported that 5ARIs reduced the development of PCa by 23%-25% [2,3], the detection of PCa among individuals who were prescribed 5ARIs was instead significantly higher, by about 15%, in this study. Considering the limited opportunities for PSA testing among Korean men during the study period in the absence of a social screening policy and a low social perception of PCa, the prescription of 5ARIs may provide additional opportunities for exposure to PSA testing. In 2007, 73% of nationwide PSA testing was associated with receiving 5ARIs according to this study. In the same year, only 3.12% of men aged 40 received PSA testing [4]. During the study decade, the subjects with 5ARIs had almost twice as high an average number of repeated PSA tests than their non-5ARI counterparts (3.98 vs. 2.18, p<0.001).

Another interesting aspect of this study was that the non-5ARI group had almost twice the overall mortality of the 5ARI group (HR, 1.96; p<0.001), even after adjusting for age. Because the current Korean NHISS does not provide detailed oncologic data, including tumor stage and grade, a direct comparison of tumor aggressiveness between groups was not possible. However, inferences can be made from the data for radiation therapy, which tends to be selected and carried out for patients with advanced stages of disease. Specifically, the fact that PCa patients without previous 5ARI administration had a significantly higher likelihood of radiation therapy implies the more aggressive nature of PCa detected in the non-5ARI group, suggesting possible benefits from earlier cancer detection through more frequent PSA testing. This finding is also inconsistent with those of previous RCTs on 5ARIs, which reported the development of high-grade cancer in patients who received longer-term administration of 5ARIs [11,12].

If the administration of 5ARIs provokes the biological tumorigenesis of PCa, then a higher incidence of PCa would be observed in subjects with a longer duration of 5ARI administration. With data covering a decade, we could trace the impact of PCa detection among the patients who were prescribed 5ARIs. As shown in Fig. 1, the development of PCa was significantly prevented by the prolonged administration of 5ARIs, especially 3 years after the initial induction and beyond. This observation matches the protective effects of 5ARIs reported in the long-term outcomes of the PCPT and REDUCE trials. At the 16-year follow-up point, Unger et al. [13] reported that men treated with finasteride had a 21.1% lower risk of PCa compared with placebo. Using a registry in Sweden, Wallerstedt et al. [14] evaluated 23,442 men exposed to finasteride or dutasteride for any length of time during an 8-year study period. Treatment with 5ARls reduced the overall risk of developing PCa, and the effect was more prominent with more prolonged drug exposure (HR, 0.81 for 0.1-2 years vs. HR, 0.31 for 6-8 years).

The authors are well aware of the limitations of this study. First, we could not differentiate significant disease from indolent PCa based on the limited structure of the NHISS. Most RCTs on the efficacy of PSA testing have consistently focused on detecting significant cancer because of the need to consider concerns regarding the overdiagnosis and overtreatment of insignificant PCa. Furthermore, the current version of the NHISS does not contain information on cancer-specific survival, including PCa. Thus, this study could not assess the cost-effectiveness aspect of repeated PSA testing, which was enhanced by the administration of 5ARIs. Second, because the NHISS data did not contain PSA information from private, non-insurance-covered health check-ups, some of those included in the analysis as nonscreened may have been adequately tested. However, given the current reported average retirement age of 51.2 years, according to the most recent employment data among Korean men in 2021 [15], the omission of private PSA testing data likely had a limited impact on the outcomes of this study, since about 90% of the registered PCa cases in Korea are in people older than 60. Furthermore, the reported disparities in PSA testing among Korean men with different socioeconomic statuses should be considered [16]. Third, this observational study design could not identify causal relationships. The advanced age in the 5ARI group may have resulted in the higher detection of PCa than in their non-5ARI-taking counterparts. Nonetheless, the outcomes from this study, showing that the prescription of 5ARI paradoxically increased the detection of PCa, support the need for expanding a PSA testing-based screening strategy against PCa, balancing the enhanced detection of PCa with cost-effectiveness in prolonging the expected lifespan, given an asymptomatic nature of PCa until its progression into metastatic disease.

According to this observational study in a country with limited uptake of PSA testing, the prescription of 5ARIs, which encourages repeated PSA testing to select suitable patients, enhanced the detection of PCa more than in their non-5ARI-taking counterparts. With prolonged 5ARI administration, the incidence of PCa increased for 3 years, followed by a continuous decrease thereafter.