br ARIs in the prevention of prostate cancer Prostate

5ARIs in the prevention of prostate cancer Prostate cancer continues to be a leading cause of male deaths worldwide. In 2009, it was estimated there would be 192,280 new cases of prostate cancer with a predicted 27,360 deaths [25]. Because androgens, and specifically DHT, play a large role in both normal and cancerous prostate growth, inhibition of the androgenic pathway has been explored as an option in prostate cancer prevention. Further enabling this type of approach was the development of 5ARIs, with their much lower risk of the adverse side effects previously associated with androgen-deprivation therapy. In the landmark Prostate Cancer Prevention Trial (PCPT) [26], the Chaetocin australia was tested that the 5AR-2 inhibitor finasteride could reduce the risk of prostate cancer. The PCPT was a double-blind, randomized, placebo-controlled Phase III study involving 18,882 men with a low risk of developing prostate cancer based on a PSA level of ≤3.0ng/ml and a normal digital rectal exam (DRE). Men received placebo or 5mg finasteride daily for a period of seven years. PSA levels were measured and DREs were performed annually. To address concerns about potential study bias toward the finasteride or placebo group during the course of the study, an end-of-study biopsy was performed on all participants. The primary endpoint of the PCPT was the development of prostate cancer, either during the study or at the seven-year endpoint biopsy. In the PCPT it was found that 18.4% of men in the finasteride group developed prostate cancer as opposed to 24.4% in the placebo group [27]; this was statistically significant (P<0.001). Medical events and side effects were more common in the finasteride group, while LUTS, such as urinary retention, frequency, and urinary tract infection, were more common in the placebo group. Of concern, more high-grade tumors (Gleason score 7–10) were found in the finasteride group as compared to the placebo group (6.4% and 5.1%, respectively P=0.005). Much debate has resulted with regards to interpretation of these data and whether finasteride treatment results in a higher incidence of high-grade prostate cancer [28]. Since the completion of the study, numerous groups have extensively examined the data and have identified potential for biases that could account for this apparent increase in high-grade tumors [29], [30], [31], [32]. Some of these are: increased sensitivity of PSA and DREs in diagnosing cancer in the finasteride group, smaller prostate volume in the finasteride group resulting in an increased chance of detection of high-grade cancers, and the possibility that finasteride inhibits growth of low-grade cancers better than high-grade, leading to an increase in the latter. Both 5AR-1 and 5AR-2 are expressed at higher levels in localized high-grade cancers [33], which might help to explain the inability of finasteride to inhibit growth of these cancers. Additionally, there is some evidence that men with low testosterone levels, as could be achieved with 5AR inhibition, develop higher grade tumors [34]. Taken together, it has been proposed that these factors combine to level the differences between the placebo and finasteride group with respect to development of high-grade prostate tumors [35], [36] and there is no associated risk of developing high-grade cancer with finasteride therapy. Since 5AR-1 expression is increased in prostate cancer, dutasteride, which inhibits 5AR-1 in addition to 5AR-2, might be expected to deliver a better outcome than that with finasteride. To examine this, another large Phase III trial, the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial [37], [38], tested the dual 5ARI dutasteride in much the same way that finasteride was used in the PCPT, but with some notable differences in study design [38]. The REDUCE trial was an international, multi-center, double-blind, randomized, placebo-controlled study designed to study the ability of dutasteride to prevent prostate cancer development in men with a high risk of prostate cancer. To be enrolled in the study, men needed to be between 50 and 75 years old, have a serum PSA of 2.5–10ng/ml and needed to have a negative 6–12 core biopsy within six months of enrollment. Whereas the PCPT assumed absence of prostate cancer in participants based on clinical data such as PSA, the REDUCE trial required a negative biopsy at enrollment to exclude any men already having prostate cancer. Over 8000 subjects were randomized to receive placebo or 0.5mg dutasteride daily and were evaluated every six months for IPSS and PSA (free and total). TPV was measured by ultrasound at baseline and 2 and 4 years, with 10 core biopsies also performed at the 2 and 4-year periods. The primary endpoint of this study, as with the PCPT, was biopsy detectable prostate cancer at 2 and 4 years after treatment. To gain further insights, several secondary endpoints were also examined including Gleason score of cancer at diagnosis, HGPIN at biopsy, tumor volume, percent of cores with cancer at diagnosis, the number of cancer positive cores, the treatment alteration score, the incidence of intervention for cancer, and overall survival. Based on knowledge gained from the PCPT, tumor aggressiveness was determined not only by Gleason score, but by additional biomarkers for apoptosis, proliferation and tumor differentiation.