Department of Urology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX

NEW PERSPECTIVES ON BPH 5- -Reductase Inhibitors Prevent the Progression of Benign Prostatic Hyperplasia Claus G. Roehrborn, MD Department of Urology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX Lower urinary tract symptoms (LUTS) associated with clinical benign prostatic hyperplasia (BPH) are a common occurrence in aging men, causing bother and interference with daily activities and affecting disease-specific quality of life. There is increasing evidence to suggest that, in many patients, the signs and symptoms of BPH are progressive. Progression can be measured as continued growth of the prostate gland; worsening of symptoms, bother, or quality of life; deterioration of urinary flow rate; episodes of acute urinary retention (AUR); and need for prostate-related surgery. Furthermore, it has become clear that the risk of disease progression increases with age as well as with increasing prostate volume and serum prostate-specific antigen (PSA) level. The 5- -reductase inhibitor finasteride has been shown not only to improve symptoms, bother, and quality of life but also to prevent progression to AUR and surgery, with a relative risk reduction of over 50%. As the risk for such progression is higher in patients with larger glands or higher serum PSA values at baseline, it is in those patients that finasteride induces an even greater risk reduction, making it a cost-effective treatment choice for patients with LUTS associated with prostatic enlargement. [Rev Urol. 2003;5(suppl 5):S12-S21] 2003 MedReviews, LLC Key words: Lower urinary tract symptoms Benign prostatic hyperplasia Acute urinary retention Disease progression Finasteride Benign prostatic hyperplasia (BPH) and its associated signs, symptoms, and complications represent a considerable health problem to aging men. Although not a life-threatening condition, BPH can adversely affect a patient s quality of life, as evidenced in community- and clinic-based studies. 1 The estimated prevalence of BPH, as shown in community-based studies, is 40% for men in their seventies 2,3 ; histologic evidence of BPH in autopsy studies is found in 60% to 80% of men aged 60 to 69 years. 4 S12 VOL. 5 SUPPL. 5 2003 REVIEWS IN UROLOGY

Prevention of BPH Progression The term BPH is correctly used to describe histopathologic hyperplastic changes in the prostate, but clinicians have commonly used the term to describe a clinical syndrome consisting of 3 components: lower urinary tract symptoms (LUTS), benign prostatic enlargement (BPE), and bladder outlet obstruction (BOO). A fourth term, benign prostatic obstruction (BPO), is used when BOO and BPE occur concurrently. Different combinations of these properties can result in a wide spectrum of clinical manifestations; for example, LUTS can exist in the absence of BPE or BOO. LUTS and BPH predominantly affect patient quality of life by interfering with activities of daily living and social activities. BPH may, however, become a progressive disorder, with progression being defined as a worsening of clinical parameters in the course of the natural history of the disease. These parameters include deterioration of symptoms and disease-specific quality of life, deterioration in urinary flow rate, increase in prostate volume, and outcomes such as acute urinary retention (AUR) and the need for surgery either for AUR or symptoms. The following discussion examines the evidence for progression as measured by these criteria in non- or placebo-treated patients, and examines whether therapy with the 5- reductase inhibitor finasteride can prevent such progression. For such a discussion, it is helpful to first understand the hormonal hypothesis of the pathogenesis of BPH, the crucial role of the 5- -reductase enzyme and its deficiency syndrome, and the early clinical development of the 5- -reductase isoenzyme type 2 inhibitor finasteride. Dihydrotestosterone and BPH The prostate gland is androgendependent, requiring a source of testosterone for its growth, development, differentiation, and function. The development of BPH clearly requires a combination of testicular androgens and aging 5 ; the role of the former is probably more permissive than causative. Evidence for this comes from the fact that men castrated before puberty do not develop BPH, and that genetic diseases inhibiting androgen production or action result in impaired or nonexistent prostate growth. Studies of androgen withdrawal by a variety of medical interventions have clearly shown regression of established BPH. Testosterone, the primary male androgenic steroid hormone, is converted within the prostate to dihydrotestosterone (DHT) in a process facilitated by the enzyme 5- -reductase. DHT, estimated to be up to times more potent than testosterone, preferentially binds to the androgen receptor in target cells. Formation of the androgen receptor DHT complex is critical to the subsequent role of androgens in stimulating both normal and hyperplastic growth of the prostate. Although downregulation of androgen receptor levels after puberty has been noted in certain androgendependent tissues, thereby limiting further androgen-dependent growth, downregulation does not appear to occur in the aging prostate or in BPH. Hence, androgen-dependent growth continues even, or especially, in aging men. 6 5- -Reductase Enzyme and Its Deficiency Syndrome Two 5- -reductase enzymes have been identified, each encoded by a separate gene. 7 5- -Reductase type 2 is the major form of the enzyme expressed in prostatic tissues and is also expressed in extraprostatic tissues. It is absent, however, in patients suffering from 5- -reductase deficiency syndrome, as described below. The predominant enzyme in extraprostatic tissues, such as skin and liver, is 5- -reductase type 1, which is expressed and functioning normally in men suffering from clinical 5- reductase deficiency syndrome. Although mrna of 5- -reductase type 1 has been detected in normal 5- -Reductase type 2 enzyme is critical to the normal development of the prostate and hyperplastic growth later in life. prostates as well as in BPH and prostate cancer, there is controversy regarding the presence of this encoded protein in prostate tissues. 5- -Reductase type 2 enzyme is critical to the normal development of the prostate and hyperplastic growth later in life. Its location within the prostate is primarily in the stroma, whereas the binding of DHT to the androgen receptor takes place in the epithelial cell. Persons with 5- -reductase type 2 enzyme deficiency were first observed in the 1960s, when a condition termed pseudovaginal perineoscrotal hypospadias was described. 8,9 These persons are born with a 46XY karyotype, normally differentiated testes, male internal ducts, but ambiguous genitalia. A genetic mutation of the type 2 isoenzyme of 5- -reductase results in defective or deficient enzyme activity. At puberty, the increase in gonadotropins stimulates a significant rise in testosterone level, which allows external genitalia virilization. Although the affected persons are often raised as girls, a gender reassignment takes place after puberty. Adult men with the disorder have normal muscular development and VOL. 5 SUPPL. 5 2003 REVIEWS IN UROLOGY S13

Prevention of BPH Progression continued male sexuality, and other organ systems function normally. However, affected persons do not develop benignly enlarged prostates or prostate cancer; in addition, they do not develop male pattern baldness (alopecia). This experiment of nature" suggests rather strongly that DHT, rather than testosterone, is needed for the development of BPH (as well as prostate cancer). It therefore appeared reasonable to develop a drug that would mimic this genetic defect and inhibit the conversion of testosterone to dihydrotestosterone in exactly the same fashion, presumably bestowing a beneficial effect on the development of or already established BPH. Development of Finasteride Finasteride is a 4-azasteroid compound that prevents the conversion of testosterone to DHT by irreversibly inhibiting the catalytic activity of the 5- reductase type 2 enzyme. It effectively competes with testosterone for the active side of the enzyme without affecting the interaction of testosterone or DHT with the androgen receptor. Selective inhibition of the 5- -reductase type 2 enzyme with finasteride reduces serum DHT levels by approximately 70% and local DHT levels in the prostate, the target organ, by nearly 90%. The failure of finasteride to decrease both serum and prostatic DHT to undetectable or nearly undetectable levels may be explained by the activity of the 5- -reductase type 1 enzyme, which is unaffected by finasteride. Initial Clinical Results One of the earliest clinical trials of finasteride was a dose-finding phase 2 study in which several dosages of up to 80 mg daily were tested 11 ; results led to further studies examining 1-mg and 5-mg daily dosages. The pivotal phase 3 studies were 2 international, multicenter, randomized, controlled trials in which 895 men with BPH received placebo or finasteride, 1 mg or 5 mg, daily for 12 months. 12 The men who received finasteride, 5 mg/d, had a significant decrease in total urinary symptom score, a significant increase in peak urinary flow rate, and a 19% decrease in prostate volume. The men who received finasteride, 1 mg/d, did not have a significant decrease in symptom score, but demonstrated a significant increase in peak urinary flow rate and a nearly identical decrease in prostate volume. The placebo-treated patients had no significant changes in symptom score, flow rate, or prostate volume. As a result of these findings, the 5-mg daily dosage of finasteride was chosen for all future trials. Of note, these pivotal phase 3 trials enrolled patients with moderate to severe symptoms, independent of any other baseline parameters. The only significant inclusion criterion was an enlarged prostate by digital rectal examination in the opinion of the investigator." Although this strategy of enrolling patients with LUTS and clinical BPH without any other specific inclusion criteria was typical at the time when the trials were conducted, later analyses of 2-year and 4-year trials revealed that finasteride exerts its greatest efficacy in patients presenting initially with larger prostate volumes and higher serum PSA levels. In fact, analyses of the placebo groups in these longer-term trials were instrumental in understanding the novel concept of risk assessment and stratification based on clinical parameters. Progression of BPH: Evidence and Risk Assessment The first crucial observation came from a meta-analysis and pooled analysis of 6 randomized clinical trials (North American and international phase 3 finasteride trials; Proscar Safety Plus Efficacy Canadian Two- Year Study [PROSPECT]; Early Intervention trial; Scandinavian Reduction of the Prostate Study The men who received finasteride, 5 mg/d, had a significant decrease in total urinary symptom score, a significant increase in peak urinary flow rate, and a 19% decrease in prostate volume. [SCARP]; and the Veterans Affairs Cooperative Study, which compared terazosin, finasteride, and the combination of these 2 drugs). 13 The investigators compared 1 year of treatment with finasteride, 5 mg, or placebo in men with clinical BPH. The findings for the 2601 men in these trials provided an opportunity to investigate the heterogeneity of the effects seen in the individual studies and to identify pretreatment predictors of outcomes as expressed by symptoms or peak urinary flow rates. Among subjects who received finasteride, symptom severity, as measured by the Quasi-International Prostate Symptom Score (IPSS; range, 0-30), improved by 1.8 points (95% CI, 0.7-2.9) for men with prostate volumes less than 20 ml (n = 72) and by 2.8 points (95% CI, 2.1-3.5) for men with volumes greater than 60 ml (n = 272). Similarly, improvements in peak urinary flow rate ranged from 0.89 ml/s (95% CI, 0.05-1.83) for men with prostate volumes less than 20 ml to 1.84 ml/s (95% CI, 1.37-2.30) for those with volumes greater than 60 ml. The difference in the magnitude of improvement between men who received finasteride and those who received placebo S14 VOL. 5 SUPPL. 5 2003 REVIEWS IN UROLOGY

Prevention of BPH Progression Prostate Volume (ml) 65 60 55 50 45 40 35 30 1 2 3 4 5 6 7 Serum PSA (ng/ml) 75 y 70 y 65 y 60 y 55 y 50 y Figure 1. Prediction of prostate volume by serum prostate-specific antigen (PSA) level in men stratified by age categories. Adapted from Roehrborn CG et al. Urology. 1999; 53:581-589. 14 became significant (ie, no overlap in 95% CI) at baseline prostate volumes greater than 40 ml (assessed by either transrectal ultrasonography or magnetic resonance imaging), which encompasses approximately 50% of the male population. This meta-analysis suggested that finasteride is most effective in men with large prostates, whereas men with small prostates may not be suitable candidates for finasteride therapy for BPH. 13 An even more crucial observation from this meta-analysis was that the placebo-treated patients experienced fewer symptomatic and flow rate improvements with increasing prostate volume. In a meta-analysis of the same controlled trials, a second important observation was made by examining the relationship between serum PSA level and prostate volume at baseline. 14 Serum PSA levels and prostate volumes tended to rise in a log-linear fashion with increasing patient age; because both parameters are related to age, they also proved to be related to each other. As Figure 1 demonstrates, prostate volume is strongly correlated with serum PSA level in men with BPH and no evidence of prostate cancer, and this relationship is dependent on age. Because treatment outcomes were shown in the initial pooled analysis to depend on baseline prostate volume, serum PSA level was thought to estimate the degree of prostate enlargement with sufficient accuracy to be useful for therapeutic decision making. To achieve a specificity of 70% while maintaining a sensitivity of 70%, approximate age-specific criteria for detecting men with prostate glands exceeding 40 ml were PSA levels greater than 1.6 ng/ml, greater than 2.0 ng/ml, and greater than 2.3 ng/ml for men in their fifties, sixties, and seventies, respectively. To detect prostate glands exceeding 30 ml, the corresponding PSA values were greater than 1.4 ng/ml, greater than 1.5 ng/ml, and greater than 1.7 ng/ml, respectively. Based on these 2 crucial observations, it seemed plausible to repeat the meta-analysis of the 1-year controlled trials with serum PSA at baseline as a stratifier and, indeed, the results were similar to those of the prostate volume analysis (Figure 2). 15 Patients with higher serum PSA levels at baseline had a lesser placebo" response, and the drug-attributable effect, that is, the difference between placebo and finasteride, increased from 0.8 points for PSA levels less than 1.5 ng/ml to 2.9 points for PSA levels of 8 ng/ml to ng/ml. Thus, it was established that finasteride therapy is more appropriate for men with larger prostate glands and higher serum PSA levels, in whom the drug-attributable effect, in terms of symptom score and peak flow rate, is greater. An even more important finding was that, even in 1-year studies, placebo-treated patients had a smaller placebo effect in terms of symptoms and flow rate if they had larger glands and/or higher serum PSA values at baseline. Although the placebo effect is at least in part a unilateral regression to the mean imposed by the inclusion criteria of the trial, 16 it was concluded that non- or placebo-treated patients with large glands and/or higher Prostate volume is strongly correlated with serum PSA level in men with BPH and no evidence of prostate cancer, and this relationship is dependent on age. serum PSA values are at higher risk for deterioration of both symptoms and flow rate. In the interim, 2-year and 4-year placebo-controlled trials were conducted, most notably the Proscar Long Term Efficacy and Safety Study (PLESS), which further evaluated the risk of BPH progression and attempted to stratify risk. PLESS followed a cohort of more than 3000 men with moderate symptoms and enlarged prostate glands who were randomized to treatment with finasteride, 5 mg/d, versus placebo over 4 years. 17 In most control VOL. 5 SUPPL. 5 2003 REVIEWS IN UROLOGY S15

Prevention of BPH Progression continued arms, both placebo and sham, the combined placebo effect interfering with the natural history of the disease is maintained for the entire duration of the study. In this 4-year trial, however, both the mean symptom score and mean maximum flow rate slowly drifted back to baseline after a typical initial placebo response. Therefore, the changes occurring in measurable parameters after the initial placebo effect can be considered to represent the natural history of the Figure 2. Pooled analysis of 1-year studies of finasteride versus placebo demonstrates an increase in the drug-attributable effect on symptoms and a decrease in the placebo response with (A) increasing prostate size and (B) increasing serum prostate-specific antigen (PSA) level. IPSS, International Prostate Symptom Score. Data from Boyle P et al. Urology. 1996;48:398-405 13 ; Boyle P et al. J Urol. 1997;157:134A. 15 A Change in Quasi IPSS B Change in Quasi IPSS 3.0 2.5 2.0 1.5 1.0 0.5 0.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 2.13 <20 2.60 1.5 1.78 1.84 2.07 Finasteride Placebo 20-29 30-39 40-49 50-59 1.95 1.53 1.14 2.33 1.49 Prostate Volume (ml) Finasteride 1.95 0.85 2.24 1.36 Placebo 2.25 0.73 2.37 0.93 1.5-2.5 2.5-4.0 4.0-6.0 6.0-8.0 PSA Level (ng/ml) 2.35 0.89 2.69 60 0.98 3.21 0.32 8.0-.0 disease. The rates of outcomes such as AUR or surgery, as well as change in prostate volume, which are less or not at all susceptible to the placebo effect, are also valid measures of the natural history of the disease. When stratifying the PLESS patient population into tertiles by serum PSA level (0-1.3 ng/ml, 1.4-3.2 ng/ml, and 3.3- ng/ml), 3 distinctly different patterns regarding symptom score and maximum flow rate changes emerge. 18 Although the initial placebo response in the lowest PSA tertile for both symptom and flow rate was maintained over the entire 4 years of follow-up, the middle tertile experienced a slow deterioration of symptoms back to baseline and, in essence, the natural history and progression of disease negated any flow rate gains. In the highest PSA tertile, following an initial 1.5 point decrease during placebo response, symptom score rose steadily over the subsequent years. The score increased by 0.5 points per year, bringing it back to the original baseline level by the end of the study. At 2 years, the initial response in terms of flow rate improvement was completely negated by the progression/natural history of the disease and, at the end of the study, these patients registered a net worsening of the flow rate by a mean of 1.0 ml/s. Similar results regarding changes in symptom score and maximum flow rate over time were obtained when the 150 patients for whom prostate volume measurements were available were divided into tertiles (14-41 ml, 42-57 ml, and 58-150 ml). The PLESS study also periodically assessed bother due to urinary symptoms, disease-specific quality of life, aspects of sexual function, and overall sense of well being. Surprisingly, after an initial placebo response, serum PSA level at baseline also predicted the rate of worsening of bother, quality of life, and certain aspects of sexual function. 19 The most informative populationbased study of the natural history of LUTS and BPH to date is the Olmsted County Study of Urinary Symptoms and Health Status among Men. Results of this study have provided much information about prevalence and severity of urinary symptoms; associated bother, worry and embarrassment, and symptom-related quality of life; and the relationship S16 VOL. 5 SUPPL. 5 2003 REVIEWS IN UROLOGY

Prevention of BPH Progression Incidence Over 4 Years (%) 16 15 14 13 12 11 9 8 7 6 >0.0 >0.5 >1.0 >1.5 >2.0 >2.5 AUR 30 Placebo (n = 1503) 28 Placebo (n = 1503) >3.0 >3.5 >4.0 >4.5 >5.0 >5.5 >6.0 >6.5 >7.0 Baseline PSA Threshold (ng/ml) Incidence Over 4 Years (%) 26 24 22 20 18 16 14 12 >0.0 >0.5>1.0 >1.5 >2.0>2.5 Surgery >3.0 >3.5>4.0 >4.5 >5.0>5.5 Baseline PSA Threshold (ng/ml) >6.0 >6.5>7.0 >7.5 >8.0 Figure 3. Cumulative incidence of acute urinary retention (AUR) and surgery in the placebo-treated patients in the Proscar Long Term Efficacy and Safety Study stratified by serum prostatespecific antigen (PSA) level at baseline. A linear increase in risk is noted with increasing serum PSA value at baseline for both outcomes. between symptoms and other parameters, such as flow rate, prostate volume, and PSA level. 20-22 In the Olmsted County Study, incidence rates of AUR for men with mild symptoms increased from 2.6 cases to 9.3 cases per 00 personyears for men in their forties and men in their seventies, respectively; for those with symptoms worse than mild, incidence rates increased from 3.0 cases to 34.7 cases per 00 person-years, respectively. The relative risk (RR) of AUR was higher for older men, men with moderate to severe symptoms (RR, 3.2), those with flow rates under 12 ml/s (RR, 3.9), and those with prostate volumes greater than 30 ml on transrectal ultrasonography (RR, 3.0), compared with a baseline RR of 1.0 for the corresponding groups. The highest RR by proportional hazard models existed for men aged 60 to 69 years who had symptoms that were worse than mild and a flow rate of less than 12 ml/s (RR,.3), and for men aged 70 to 79 years, unless they had mild symptoms and a flow rate over 12 ml/s. All other stratifications of men older than 70 years had RRs ranging from 12.9 to 14.8 (all compared with men aged 40 to 49 years with mild symptoms and a flow rate over 12 ml/s, for whom the base risk was 1.0). Although age is an important risk factor for AUR for communitydwelling men, other factors can be analyzed for men in trial populations who have already been diagnosed with BPH. In the placebo groups of three 2-year studies 23 and a 4-year study (PLESS), 24-26 prostate volume and serum PSA level were the most important predictors of AUR episodes. Over the 4-year period of PLESS, the incidence of AUR increased from 5.6% to 7.7% in men with serum PSA levels less than 1.4 ng/ml, corresponding to symptoms ranging from mild to severe, and from 7.8% to.2% for those with serum PSA levels of 1.4 ng/ml or higher. In the 2-year studies, the rate of AUR was 8-fold higher in men with serum PSA levels of 1.4 ng/ml or greater (0.4% vs 3.9%) and 3-fold higher in men with prostate volumes of 40 ml or greater (1.6% vs 4.2%). 23 A detailed analysis of data from PLESS showed a near linear increase in risk of AUR with increasing thresholds of serum PSA level, an observation that applies to both spontaneous and precipitated AUR. The risk of both types of AUR increases with rising serum PSA level and prostate volume stratified by tertiles. An analysis of more than 0 possible outcome predictors, alone or in combination, revealed the combination of serum PSA level, urinating more frequently than every 2 hours, symptom problem index, maximum urinary flow rate, and hesitancy as being only slightly superior to PSA level alone in predicting AUR episodes. 26 During PLESS, % (2.5% per year) of the placebo-treated patients underwent surgery for BPH. Although the hazard of undergoing surgery was linear, that is, it remained constant throughout the duration of the study, it differed when patients were stratified into tertiles by either baseline prostate volume or serum PSA level. Similar to the incidence of AUR, the rates of surgery increased from 6.2% to 14.6% for patients in the lowest to the highest PSA tertiles, and from 6.7% to 14.0% for those in the lowest to the highest prostate volume tertiles. Figure 3 shows the risks of surgery and AUR stratified by PSA at baseline, indicating a linear increase in the cumulative incidence of both outcomes with increasing PSA values. These data from population-based VOL. 5 SUPPL. 5 2003 REVIEWS IN UROLOGY S17

Prevention of BPH Progression continued A Incidence of AUR (%) 12 8 6 4 2 0 11.6% 16 Placebo (n = 1503) Finasteride (n = 1513) Placebo (n = 1503) Finasteride (n = 1513) 14 Incidence of Surgery (%) B 12 9.9% 5.8% 8 6.2% 3.8% 6 5.2% 5.4% 2.9% 1.9% 2.6% 4 2 3.0% 35% 54% 66% 0 51% 48% 0.0-1.3 1.4-3.2 3.3-12.0 0.0-1.3 1.4-3.2 3.3-12.0 Baseline PSA Tertile (ng/ml) Baseline PSA Tertile (ng/ml) 14.6% 74% Figure 4. Incidence rates of (A) spontaneous or precipitated AUR and (B) surgery in placebo- and finasteride-treated patients in the Proscar Long Term Efficacy and Safety Study stratified by prostate-specific antigen (PSA) tertiles. As the risks of AUR and surgery increase with increasing serum PSA level, the relative risk reduction with finasteride becomes greater. Data from Roehrborn CG et al. Urology. 1999;53:473-480. 29 studies and the placebo groups of large randomized trials clearly support the notion that BPH can be a progressive condition and that certain baseline parameters, such as age, prostate volume, and serum PSA level, allow risk stratification. This information can be used to examine the ability of finasteride to prevent such disease progression. Finasteride Prevents the Progression of BPH The first evidence that finasteride may prevent outcomes such as AUR or surgery came from a meta-analysis of the three 2-year controlled trials of finasteride versus placebo. A total of 81 occurrences of AUR were reported: 24 (1.1%) of 2113 subjects in the finasteride group and 57 (2.7%) of 29 subjects in the placebo group. 27 The hazard ratio was consistent in all 3 studies; in the pooled data set, there was a 57% decrease in the hazard rate for occurrence of AUR with finasteride treatment compared with placebo over the 2-year study period (P <.001). In addition, over the 2-year study period, 227 surgical interventions were recorded: 89 (4.2%) of 2113 subjects in the finasteride group and 138 (6.5%) of 29 in the placebo group. The hazard ratio was again consistent across the 3 studies, with a 34% reduction in the hazard rate for occurrence of surgery with finasteride therapy compared with placebo (P <.002). Following these data, results of the 4-year PLESS study finally and convincingly demonstrated the ability of finasteride to reduce the risk of BPH progression as measured by any of Figure 5. Cumulative incidence of spontaneous or precipitated acute urinary retention (AUR), surgery, or either event for the (A) placebo-treated patients and (B) finasteride-treated patients in the Proscar Long Term Efficacy and Safety Study. For those who received placebo, these risks increased with increasing serum PSA level, whereas they remained relatively flat for the finasteride-treated patients. A 30 25 Either Surgery AUR Either Surgery AUR 25 B 30 Cumulative Incidence (%) 20 15 5 Cumulative Incidence (%) 20 15 5 0 >0.0 >0.5 >1.0 >1.5 >2.0 >2.5 >3.0 >3.5 >4.0 >4.5 >5.0 >5.5 >6.0 >6.5 >7.0 >7.5 >8.0 0 >0.0 >0.5 >1.0 >1.5 >2.0 >2.5 >3.0 >3.5 >4.0 >4.5 >5.0 >5.5 >6.0 >6.5 >7.0 >7.5 >8.0 PSA Level (ng/ml) PSA Level (ng/ml) S18 VOL. 5 SUPPL. 5 2003 REVIEWS IN UROLOGY

Prevention of BPH Progression Probability of AUR or BPH-Related Surgery (%) 20 15 5 Double-Blind 0 0 1 2 3 4 5 6 the previously mentioned characteristics deterioration of symptoms and disease-specific quality of life, deterioration in urinary flow rate, increase in prostate volume, and outcomes such as AUR and the need for surgery for either AUR or symptoms. Data from long-term open-label extension studies have demonstrated that the improvements in LUTS and peak urinary flow rate are maintained for up to 8 years of follow-up, Placebo Study Year Fin 5 mg Open Finasteride Extension Placebo Fin Fin Fin Figure 6. Cumulative probability for acute urinary retention (AUR) or surgery related to benign prostatic hyperplasia (BPH) in the Proscar Long Term Efficacy and Safety Study and during 2 years of open-label extension, during which all patients received finasteride (Fin). The risk for the subjects who had previously received placebo flattened and was similar to that of the finasteride-treated patients during years 5 and 6. with no attenuation of efficacy 28 and no indication of the changes normally seen during the natural history of the disease, as reported in the Olmsted County Study. 20,22 The long-term, open-label extension studies also have shown a durable reduction in prostate volume by 20% or greater up to 8 years and longer, 28 with no suggestion of any volume increases as was reported in the Olmsted County Study, 21 indicating that the risk of future prostate growth is completely eliminated with finasteride therapy. The risk of AUR and/or surgery was shown to increase with increasing serum PSA level (prostate volume) in placebo-treated patients, whereas it remained flat in patients who received finasteride, resulting in an improved relative risk reduction for patients with higher serum PSA values at baseline (Figures 4 and 5). 29 Two points are noteworthy: First, the risk is linear, that is, for each unit increase in PSA level, there is an increase in the risk of AUR and/or surgery. Second, although not shown, the same observations hold true for baseline prostate volume as a risk stratifier. 29 Open-label extension of the PLESS study indicates that the risk of AUR (or surgery) in the subjects who received placebo for 4 years adjusted to the risk observed in the finasteride-treated patients after these patients switched to open-label finasteride in years 5 and 6 (Figure 6). Conclusions In some patients, LUTS and BPH can be a progressive disorder. To practice cost-effective medicine, it is paramount to identify patients at base- Figure 7. (A) Progression of benign prostatic hyperplasia (BPH). (B) Prevention/reversal of progression of BPH with finasteride. PSA, prostate-specific antigen. A Glandular Epithelium B Finasteride Glandular Epithelium Prostate Volume Need for Surgery Prostate Volume Need for Surgery Symptoms PSA Risk of Retention Symptoms PSA Risk of Retention Bother Flow Rate Prostate Growth Bother Flow Rate Prostate Growth VOL. 5 SUPPL. 5 2003 REVIEWS IN UROLOGY S19

Prevention of BPH Progression continued line or at first presentation who are at risk for progression and, thus, in need of effective therapy to prevent progression and alter the natural history of the disease (disease modification). A significant database of clinical findings has been amassed demonstrating that such baseline parameters exist. In a patient population of men with LUTS and BPH, for which age is of less relevance, prostate volume and serum PSA level are equally valuable tools to predict the risk of progression for an individual patient. Clearly, prostate volume values will not be available for all patients; because measurement of prostate volume is invasive, physicians may prefer to use serum PSA level as a predictor. Higher serum PSA levels indicate a higher proportion of glandular epithelium and, in general, a larger prostate volume (Figure 7A). As prostate volume increases, there is a greater tendency for symptom progression, increase in bother, worsening of peak urinary flow rate and other urodynamic parameters, increased prostate growth and, with that, a heightened risk of AUR and the subsequent need for surgery. Finasteride acts at the site of the risk factor the glandular epithelium. By inducing atrophy through apoptosis in the glandular epithelial component of the prostate, finasteride causes serum PSA levels to drop 50% (Figure 7B) and prostate volume to decrease 20% to 25%, and this prostate shrinkage is maintained for at least 8 years. In parallel, symptom and bother scores decrease and peak urinary flow rate increases, effects that are also maintained over prolonged observation periods in openlabel extension trials. Not only is prostate growth halted, but the reduction in prostate size is also maintained, apparently as long as the patient takes the medication. With these effects in place, the risk of AUR and the need for subsequent BPH-related surgery is significantly reduced, as shown in the PLESS study as well as the open-label extension of the PLESS study. Finasteride has been shown to be effective in reducing the risk of BPH progression and/or in preventing progression altogether, as measured by all parameters considered significant indicators of BPH being a progressive disease. The effect of finasteride is more pronounced in patients at higher risk for progression, that is, those with larger prostate volumes and higher serum PSA values at baseline. In this population of men, treatment with finasteride is a costeffective therapeutic strategy. References 1. Girman CJ, Jacobsen SJ, Tsukamoto T, et al. Health-related quality of life associated with lower urinary tract symptoms in four countries. Urology. 1998;51:428-436. 2. Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet. 1991;338:469-471. 3. Jacobsen SJ, Girman CJ, Guess HA, et al. New diagnostic and treatment guidelines for benign prostatic hyperplasia: potential impact in the United States. Arch Intern Med. 1995; 155:477-481. 4. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol. 1984;132:474-479. 5. McConnell JD. Benign prostatic hyperplasia: hormonal treatment. Urol Clin North Am. 1995;22:387-400. 6. Barrack ER, Bujnovszky P, Walsh PC. Subcellular distribution of androgen receptors in human normal, benign hyperplastic, and malignant prostatic tissues: characterization of nuclear salt-resistant receptors. Cancer Res. 1983;43:17-1116. 7. Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem. 1994;63:25-61. 8. Walsh PC, Madden, JD, Harrod MJ. Familial incomplete male pseudohermaphroditism, type 2: decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med. 1974;291:944-949. Main Points Benign prostatic hyperplasia (BPH) and its associated signs, symptoms, and complications represent a considerable health problem to aging men. Testosterone is converted within the prostate to dihydrotestosterone (DHT) in a process facilitated by the enzyme 5- -reductase. DHT, estimated to be up to times more potent than testosterone, preferentially binds to the androgen receptor in target cells. Men with 5- -reductase deficiency syndrome do not develop BPH or prostate cancer, which strongly suggests that DHT, rather than testosterone, is needed for the development of these conditions. Selective inhibition of the 5- -reductase type 2 enzyme with finasteride reduces serum DHT levels by approximately 70% and local DHT levels in the prostate, the target organ, by nearly 90%. PLESS convincingly demonstrated the ability of finasteride to reduce the risk of BPH progression as measured by the following clinical parameters: deterioration of symptoms and disease-specific quality of life, deterioration in urinary flow rate, increase in prostate volume, and outcomes such as acute urinary retention (AUR) and the need for surgery for either AUR or associated symptoms. Finasteride therapy is more appropriate for men with larger prostate glands and higher serum prostate-specific antigen levels, in whom the drug-attributable effect, in terms of symptom score and peak flow rate, is greater. S20 VOL. 5 SUPPL. 5 2003 REVIEWS IN UROLOGY

Prevention of BPH Progression 9. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE. Steroid 5 alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science. 1974;186:121-123.. McConnell JD, Wilson JD, George FW, et al. Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab. 1992;74:505-508. 11. Stoner E for the Finasteride Study Group. The clinical effects of a 5 alpha-reductase inhibitor, finasteride, on benign prostatic hyperplasia. J Urol. 1992;147:1298 1302. 12. Gormley GJ, Stoner E, Bruskewitz RC, et al, for the Finasteride Study Group. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med. 1992;327:1185-1191. 13. Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: metaanalysis of randomized clinical trials. Urology. 1996;48:398-405. 14. Roehrborn CG, Boyle P, Gould AL, Waldstreicher J. Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology. 1999;53:581-589. 15. Boyle P, Roehrborn C, Gould L. Baseline serum PSA levels predict degree of symptom improvement following therapy of BPH with finasteride [abstract]. J Urol. 1997;157:134A. 16. Sech SM, Montoya JD, Bernier PA, et al. The so-called placebo effect" in benign prostatic hyperplasia treatment trials represents partially a conditional regression to the mean induced by censoring. Urology. 1998;51:242-250. 17. McConnell JD, Bruskewitz R, Walsh P, et al, for the Finasteride Long-Term Efficacy and Safety Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med. 1998; 338:557-563. 18. Roehrborn CG, Boyle P, Bergner D, et al, for the PLESS Study Group. Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo. Urology. 1999;54:662-669. 19. Bruskewitz R, Girman CJ, Fowler J, et al, for the PLESS Study Group. Effect of finasteride on bother and other health-related quality of life aspects associated with benign prostatic hyperplasia: Proscar Long-term Efficacy and Safety Study. Urology. 1999;54:670-678. 20. Jacobsen SJ, Girman CJ, Guess HA, et al. Natural history of prostatism: longitudinal changes in voiding symptoms in community dwelling men. J Urol. 1996;155:595-600. 21. Rhodes T, Girman C, Jacobson D, et al. Longitudinal prostate volume in a communitybased sample: 7 year followup in the Olmsted County Study of Urinary Symptoms and Health Status among Men. J Urol. 2000;163(4 suppl):249. Abstract 15. 22. Roberts RO, Jacobsen SJ, Jacobson DJ, et al. Longitudinal changes in peak urinary flow rates in a community based cohort. J Urol. 2000;163:7-113. 23. Marberger MJ, Andersen JT, Nickel JC, et al. Prostate volume and serum prostate-specific antigen as predictors of acute urinary retention: combined experience from three large multinational placebo-controlled trials. Eur Urol. 2000;38:563-568. 24. Kaplan S, Garvin D, Gilhooly P, et al, for the PLESS Study Group. Impact of baseline symptom severity on future risk of benign prostatic hyperplasia-related outcomes and long-term response to finasteride. Urology. 2000;56:6-616. 25. Roehrborn CG, Bruskewitz R, Nickel GC, et al, for the PLESS Study Group. Urinary retention in patients with BPH treated with finasteride or placebo over 4 years. Characterization of patients and ultimate outcomes. Eur Urol. 2000;37:528-536. 26. Roehrborn CG, Malice M, Cook TJ, Girman CJ. Clinical predictors of spontaneous acute urinary retention in men with LUTS and clinical BPH: a comprehensive analysis of the pooled placebo groups of several large clinical trials. Urology. 2001;58:2-216. 27. Andersen JT, Nickel JC, Marshall VR, et al. Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia. Urology. 1997;49:839-845. 28. Vaughan D, Imperato-McGinley J, McConnell J, et al. Long-term (7 to 8-year) experience with finasteride in men with benign prostatic hyperplasia. Urology. 2002;60:40-44. 29. Roehrborn CG, McConnell JD, Lieber M, et al, for the PLESS Study Group. Serum prostatespecific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology. 1999;53:473-480. VOL. 5 SUPPL. 5 2003 REVIEWS IN UROLOGY S21