It has been shown that PSA performance in detecting PCa can be improved by the use of a new biomarker PCA3. Firstly described by Bussemakers et al. [22] PCA3 is a prostate-specific non-coding RNA which is highly over-expressed in more than 95 % of primary prostate tumours, with a median 66-fold up-regulation compared with adjacent non-cancer prostate tissue [22, 23]. The specificity of this marker for PCa has been confirmed by its lack of expression in other types of human tumours [23]. PCA3 has been demonstrated that might be helpful in different setting of patients: first diagnosis, prior negative biopsy, characterization of tumour, selection of patients for active surveillance and to calculate the risk of PCa (Table 5.2). Data from recent studies showed that PCA3 sensitivity ranges from 47 % to 69 %, specificity ranges from 66 % to 83 %, PPV ranges from 59 % to 97.4 %, NPV ranges from 87.7% to 98 % and AUC ranges from 0.65 to 0.74 [24]. European and American repeat biopsy studies have provided evidence that PCA3 values can add specificity to a diagnostic algorithm for PCa in men with previous negative biopsy. Haese et al. [25] showed that the PCA3 score had a greater diagnostic accuracy with a cut-off of 35 than %fPSA with a cut-off of 25 % and the diagnostic accuracy of the PCA3 assay is independent of the number of previous negative biopsies and of serum total PSA level. Emerging data are now available on the relationship between PCA3 and PCa features. In the study of Auprich et al. [26], PCA3 score was correlated with five distinct pathologic end points: low volume disease (<0.5 ml), insignificant PCa, extracapsular invasion (ECE), seminal vesicle invasion (SVI) and aggressive disease defined as Gleason sum >7. PCA3 scores were significantly lower in low-volume disease and insignificant PCa (p ≤ 0.001) but not significantly elevated in pathologically confirmed ECE (p = 0.4) or SVI (p = 0.5). Higher PCA3 scores were associated with aggressive disease (p < 0.001). PCA3 score may be useful also to improve the selection of patients for active surveillance (AS) in addition to the current criteria. Ploussard et al. [27] revealed that PCA3 is independently associated with small volume disease (<0.5 ml) (p < 0.001) and pathologically confirmed insignificant PCa. The risk of having cancer ≥0.5 ml and a significant PCa was increased threefold in men with a PCA3 score ≥25 compared with men with a PCA3 score <25. In a multivariate analysis, taking into account other AS criteria (biopsy criteria, PSA density and Magnetic Resonance Imaging findings), a high PCA3 score (≥25) was an important predictive factor for tumour volume >0.5 (OR: 5.4, p = 0.010) and a significant PCa (OR: 12.7, p = 0.003). Recent data [28] suggest that the new biomarker PCA3 can be successfully incorporated into clinical tools for risk assessment, like Prostate Cancer Prevention Trial risk calculator (PCPT). Since its publication in 2006, the PCPT calculator combined six risk factors (PSA, DRE, age, race, history of biopsy and prostate biopsy) for PCa. Ankerst et al. [28] demonstrated that when PCA3 is incorporated into the PCPT risk calculator, the diagnostic accuracy significantly improved. On the basis of these summarized results, European guidelines recommend to use the PCA3 score together with PSA and other clinical risk factors in a nomogram or other risk stratification tools to make a decision with regard to first or repeat biopsy.

At this point of the discussion, readers should clearly understand how much it is important for a marker to be chosen by the urologist to discriminate the indolent from the aggressive PCa in order to choose which to treat and avoid overdiagnosis and overtreatment. The major helping came from the use of 5α reductase inhibitors (5ARI) in patients at risk of PCa. The 5ARI, widely utilized for the treatment of BPH, block the conversion of testosterone to dihydrotestosterone inhibiting the enzyme 5α reductase. Finasteride inhibits selectively the type 2 isoform of 5α reductase; dutasteride is a dual inhibitor of the type 1 and 2 isoforms of the enzyme. The rationale for the use of 5ARI in the detection of PCa is based on the fact that they suppress PSA production related to benign prostatic hyperplasia (BPH) progression, so, consequently, they significantly impact the validity of PSA as a marker for PCa. Two recent and large clinical trials demonstrated that the use of 5α reductase inhibitors can prevent PCa: The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) [29] and the Prostate Cancer Prevention Trial (PCPT) [30]. The REDUCE study [29] compared dutasteride, at dose of 0.5 mg daily, with placebo in men with PSA level of 2.5 to 10 ng/ml and a prior negative prostate biopsy. The end points were PCa detection on biopsy after 2 and 4 years of treatment and Gleason score at biopsy, the presence of pre-neoplastic lesions and other end points related to BPH. Andriole et al. concluded that dutasteride reduced the risk of incident PCa detected on biopsy: 659/3,305 (19.9 %) in the treated group and 858/3,424 (25 %) in the placebo group had PCa. Dutasteride was associated with a relative risk reduction of 22.8 % (95 % CI, 15.2–29.8, p < 0.001). They observed a significant difference between the two groups according to Gleason score at biopsy: 437 tumours in the treated group and 617 in control group were Gleason score of 5 to 6. Other results were: a reduction of the number of cases of pre-neoplastic lesions in the dutasteride group and an improvement of many outcomes related to BPH. The PCPT [30] was designed to reduce the prevalence of PCa after 7 years of treatment. They concluded that the prevalence of PCa was reduced by 24.8 % in the finasteride group compared with the placebo group and that the absolute numbers of high-grade tumours (GS ≥ 7) were higher in the treated group (280/757, 37 %) than in placebo group (237/1,068, 22.2 %). Later, they also examined the impact of finasteride on the sensitivity and AUC of PSA for detecting PCa, in particular high-grade PCa (GS ≥ 7). The sensitivities of PSA were uniformly greater in the finasteride group than in the placebo group: 37.8 % (95 % CI = 34.2–41.4), 53.0 % (95 % CI = 47.0–59.0) and 64.2 % (95 % CI = 53.8–74.6) for PCa, Gleason grade 7 or higher and Gleason grade 8 or higher disease, respectively in the finasteride arm compared with 24.0 % (95 % CI = 21.5–26.5), 39.2 % (95 % CI = 33.0–45.4) and 49.1 % (95 % CI =35.9–62.3), respectively, in the placebo arm. Compared data of these two trials are summarized in Table 5.3.