Is There an Association between 5a Reductase Inhibitors and Metabolic Syndrome? A Narrative Review of the Literature.

Finasteride and dutasteride are 5a Reductase Inhibitors (5a-RIs) and comprise the mainstay of treatment for the management of patients with benign prostatic hyperplasia. 5a-RIs are expressed in a variety of tissues, such as adipose tissues and liver, resulting in a reduction of glucocorticoid levels and affecting androgen regulation and metabolic function. As a result, the administration of these regimens may generate adverse metabolic events, such as liver disease, hyperglycemia, hyperlipidemia, and diabetes mellitus. Although several studies have tried to record these adverse metabolic events both in human subjects and animal models, the exact mechanisms of these actions have not been well described yet in the literature. Further well-designed clinical trials are needed to elucidate the exact role of 5a reductase inhibitors in the progression of the metabolic syndrome. The aim of this study was to systematically review the literature concerning the role of dutasteride or finasteride in the progression of metabolic adverse events and further investigate possible pathophysiologic mechanisms.

Randomized Placebo-Controlled Clinical Trial of Dutasteride for Reducing Heavy Drinking in Men.

BACKGROUND: Prior studies indicate that neuroactive steroids mediate some of alcohol's effects. Dutasteride, widely used to treat benign prostatic hypertrophy, is an inhibitor of 5-alpha reductase enzymes, which play a central role in the production of 5α-reduced neuroactive steroids. The purpose of this study was to test dutasteride's tolerability and efficacy for reducing drinking. METHODS: Men (n = 142) with heavy drinking (>24 drinks per week) and a goal to either stop or reduce drinking to nonhazardous levels were randomized to placebo or 1 mg dutasteride daily for 12 weeks. We hypothesized that dutasteride-treated patients would be more successful in reducing drinking. RESULTS: Generalized linear mixed models that included baseline drinking, treatment, time and their 2-way interaction identified significant interactions of treatment-time, such that dutasteride treatment reduced drinking more than placebo. During the last month of treatment, 25% of dutasteride-treated participants had no hazardous drinking (no heavy drinking days and not more than 14 drinks per week) compared with 6% of placebo-treated participants (P = 0.006; NNT = 6). Sensitivity analysis identified baseline drinking to cope as a factor associated with larger reductions in drinking for dutasteride compared with placebo-treated participants. Dutasteride was well tolerated. Adverse events more common in the dutasteride group were stomach discomfort and reduced libido. CONCLUSION: Dutasteride 1 mg daily was efficacious in reducing the number of heavy drinking days and drinks per week in treatment-seeking men. The benefit of dutasteride compared with placebo was greatest for participants with elevated baseline drinking to cope motives.

The Effect of Tamsulosin, Dutasteride Monotherapy and Tamsulosin-Dutasteride Combination on Prostate Smooth Muscle Contractility in BPH Model Wistar Strain Rattus Novergicus.

Background: Following the c In the management of BPH, Tamsulosin is an example of a-adrenergic receptor blocker drug that is usually used. In addition, dutasteride is also a BPH drug that works as a group of 5 a reductase inhibitor. However, the weakness of long-term administration of a1-adrenergic receptor antagonists can result in upregulation of prostate smooth muscle cell contractility and expression of a-adrenergic mRNA receptors, resulting in hyperactivity and supersensitivity to a-agonists. Objective: Our study aimed to determine the effect of long-term administration of tamsulosin, dutasteride and tamsulosin-dutasteride combination on the contractility of prostate smooth muscle cells in BPH model rats. Methods: This study was designed using an experimental post test only method, control group design. It measured the contractility of prostate smooth muscle cells from samples obtained from the prostatic stroma of experimental animals adult male Rattus norvegicus Wistar strain induced BPH and administered tamsulosin 1 mg/kg/day, dutasteride 0.5 mg/kg/day, and a combination of continuous administration for 1, 6 and 12 consecutive days. Data were analyzed using one way ANOVA if the data distribution was normal or Kruskall Walis if the data distribution was abnormal. Result: The effect of tamsulosin, dutasteride and the combination of tamsulosin with dutasteride on prostate smooth muscle cell contractility in experimental animals Rattus norvegicus Wistar strain showed that tamsulosin administration for six days, twelve days, and the combination of tamsulosin dutasteride for one day got statistically significant different result (p=0.016; p=0.006; p=0.029) compared to the negative control group. In addition, there was a difference between the tamsulosin and dutasteride combination group for 12 days compared to tamsulosin monotherapy for 6 days and 12 days (p=0.160; p=0.010). Conclusion: Continuous administration of monotherapy tamsulosin has an upregulation effect on the sixth to twelfth day. Decreased contractility of prostate smooth muscle cells occurs on the first day but will increase on the sixth to twelfth day. On the other hand, the results of our study also showed that the combination of tamsulosin and dutasteride gave the effect of reducing contractility and was most effective on day 12.

Understanding Treatment Response in Individual Profiles of Men with Prostatic Enlargement at Risk of Progression.

BACKGROUND: It is unclear how cumulative multivariable effects of clinically relevant covariates impact response to pharmacological treatments for lower urinary tract symptoms (LUTS)/benign prostatic enlargement (BPE). OBJECTIVE: To develop models to predict treatment response in terms of International Prostate Symptom Score (IPSS) and the risk of acute urinary retention (AUR) or BPE-related surgery, based on large data sets and using as predictors baseline characteristics that commonly define the risk of disease progression. DESIGN, SETTING, AND PARTICIPANTS: A total of 9167 patients with LUTS/BPE at risk of progression in three placebo-controlled dutasteride trials and one comparing dutasteride, tamsulosin, and dutasteride + tamsulosin combination therapy (CT) were included in the analysis to predict response to placebo up to 24 mo and active treatment up to 48 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Predictors included age, IPSS, total prostate volume (PV), maximum urinary flow rate (Qmax), prostate-specific antigen, postvoid residual urine (PVR), α-blocker usage within 12 mo, and randomised treatment. A generalised least-squares model was developed for longitudinal IPSS and a Cox proportional-hazards model for time to first AUR/surgery. RESULTS AND LIMITATIONS: The vast majority of patients benefit from dutasteride or CT when compared with tamsulosin alone. The predicted IPSS improvement with dutasteride or CT increased with greater PV and severity of symptoms at baseline. The tamsulosin effect was lower with greater baseline PV and tended to decrease over time. Predicted AUR/surgery risk was greater with tamsulosin versus CT or dutasteride; this risk increased with larger PV, higher PVR, and lower Qmax (all at baseline). An educational interactive web-based tool facilitates visualisation of the results (www.bphtool.com). Limitations include: the placebo and active-treatment predictions are from different studies, the lack of similar studies for external validation, and the focus on a population at risk of progression from the 4-yr CombAT study. CONCLUSIONS: Predictive modelling based on large data sets and visualisation of the risk for individual profiles can improve our understanding of how risk factors for disease progression interact and affect response to different treatments, reinforcing the importance of an individualised approach for LUTS/BPE management. PATIENT SUMMARY: We used data from previous studies to develop statistical models for predicting how men with lower urinary tract symptoms or benign prostate enlargement and at risk of disease complications respond to certain treatments according to their individual characteristics.

The Effect of Long-Term Tamsulosin Monotherapy and Tamsulosin - Dutasteride Combination Therapy on PKC-α Enzyme Expression in Prostate Stromal Tissue.

Background: The α-adrenergic receptor antagonist is the most effective medical therapy to reduce the dynamic component in patients with BPH. However, long-term administration of receptor antagonists can cause upregulation of mRNA receptor expression, resulting in tolerance of drug effectiveness. PKC-α is involved in the process of prostate smooth muscle contraction through activation of the voltage-gated Ca2+ conducted canal, influenced by androgen hormones, especially testosterone, and has an isoform with Twist1, a transcription factor that plays a role in up-regulation of androgen receptors. Objective: The aim of the study was to compare the effect of long-term tamsulosin monotherapy and tamsulosin - dutasteride combination therapy in PKC-α enzyme expression in prostate stromal tissue of Rattus norvegicus rats of Wistar strain. Methods: Out of 80 samples of Rattus norvegicus rats were divided into 8 groups with different interventions: negative control group, positive control group, tamsulosin monotherapy administration for 1 day, 3 day, and 6 day groups, and tamsulosin - dutasteride combination therapy for 1 day, 3 day, and 6 day groups. BPH was induced with 3 mg/kg of testosterone proprionate for 3 weeks, continued with drugs administration according to intervention grouping. Prostate stromal tissue was taken and prepared for PKC-α enzyme measurement with ELISA method. Results: There was a significant difference (p<0.05) in the effect of tamsulosin monotherapy and tamsulosin-dutasteride combination therapy on the PKC-α expression. There was a strong positive relationship between the duration of tamsulosin-dutasteride combination therapy on the PKC-α expression, which means the longer the duration of the combination of tamsulosin-dutasteride combination the higher the PKC-α expression. Conclusion: Administration of long-term tamsulosin - dutasteride combination therapy causes upregulation PKC-α expression more than tamsulosin only.

Characteristics of prostate biopsy in patients under the dutasteride treatment.

We performed a retrospective study to clarify the characteristics of prostate biopsies in patients treated with dutasteride, a benign prostate hyperplasia treatment drug that inhibits 5α-reductase. We studied the digital clinical data of 677 patients, including 96 cases treated with dutasteride, with suspected localized prostate cancer. All patients underwent transrectal ultrasonography-guided prostate biopsy between 2014 and 2017 in our department. A propensity score matching analysis was performed based on prostate-specific antigen (PSA) (calculated as double the PSA value for the dutasteride group) and age. Ninety-six patients in each of the dutasteride and control groups were assessed and their characteristics were compared. The characteristics of the patients in the dutasteride and control groups were well balanced by matching. There were fewer prostate cancer-positive patients in the dutasteride group. When comparing only the prostate cancer-positive patients in each group, there were significantly more cases of high-grade cancers and abnormal magnetic resonance imaging (MRI) findings in the dutasteride group. In the dutasteride group, abnormal MRI findings and advanced age were significant predictors of high grade cancer. This study shows the characteristics of prostate biopsies in patients treated with dutasteride and indicates that patients on dutasteride with advanced age and abnormal MRI findings should undergo prostate biopsy.

Prostate-specific antigen density during dutasteride treatment for 1 year predicts the presence of prostate cancer in benign prostatic hyperplasia after the first negative biopsy (PREDICT study).

OBJECTIVES: To prospectively evaluate the detection rate of prostate cancer, and to identify the risk factors of prostate cancer detection after a 1-year administration of dutasteride and first negative prostate biopsy. METHODS: Patients with benign prostatic hyperplasia who presented high prostate-specific antigen levels after the first negative prostate biopsy were administered 0.5 mg dutasteride daily for 1 year. They underwent a repeat prostate biopsy after 1 year. The primary end-point was the detection rate of prostate cancer. The secondary end-point was the ability of prostate-specific antigen kinetics to predict prostate cancer detection. Prostate-specific antigen was measured before the initial prostate biopsy and at 6, 9 and 12 months after starting dutasteride. Patients were classified into a prostate cancer and a non-prostate cancer group. RESULTS: Prostate cancer was detected in 15 of 149 participants (10.1%). The total prostate-specific antigen change between the prostate cancer and non-prostate cancer group at 1 year was significantly different (P = 0.002). Although prostate-specific antigen levels at baseline did not significantly differ between study groups (P = 0.102), prostate-specific antigen levels at 6, 9 and 12 months were significantly different (P = 0.002, P = 0.001 and P < 0.001, respectively). The mean reduction rate of prostate-specific antigen density between the prostate cancer and non-prostate cancer group at 1 year was significantly different (-4.25 ± 76.5% vs -38.0 ± 28.7%, P = 0.001). Using a multivariate analysis, a >10% increase of prostate-specific antigen density at 1 year post-dutasteride treatment was the only predictive risk factor for prostate cancer after the first negative prostate biopsy (odds ratio 11.238, 95% confidence interval 3.112-40.577, P < 0.001). CONCLUSION: In the present study cohort, >10% increase in prostate-specific antigen density represented the only significant predictive risk factor for prostate cancer diagnosis in patients with elevated prostate-specific antigen after the first negative prostate biopsy.

Model-based meta-analysis of the time to first acute urinary retention or benign prostatic hyperplasia-related surgery in patients with moderate or severe symptoms.

AIMS: Combination therapy of 5α-reductase inhibitor and α-blocker is a guideline-endorsed therapeutic approach for patients with moderate-to-severe lower urinary tract symptoms or benign prostatic hyperplasia (LUTS/BPH) who are at risk of disease progression. We aimed to disentangle the contribution of clinical and demographic baseline characteristics affecting the risk of acute urinary retention or BPH-related surgery (AUR/S) from the effect of treatment with drugs showing symptomatic and disease-modifying properties. METHODS: A time-to-event model was developed using pooled data from patients (n = 10 238) enrolled into six clinical studies receiving placebo, tamsulosin, dutasteride or tamsulosin-dutasteride combination therapy. A parametric hazard function was used to describe the time to first AUR/S. Covariate model building included the assessment of relevant clinical and demographic factors on baseline hazard. Predictive performance was evaluated by graphical and statistical methods. RESULTS: An exponential hazard model best described the time to first AUR/S in this group of patients. Baseline International Prostate Symptom Score, prostate-specific antigen, prostate volume and maximum urine flow were identified as covariates with hazard ratio estimates of 1.04, 1.08, 1.01 and 0.91, respectively. Dutasteride monotherapy and tamsulosin-dutasteride combination therapy resulted in a significant reduction in the baseline hazard (56.8% and 66.4%, respectively). By contrast, the effect of tamsulosin did not differ from placebo. CONCLUSIONS: Our analysis showed the implications of disease-modifying properties of dutasteride and tamsulosin-dutasteride combination therapy for the risk of AUR/S. It also elucidated the contribution of different baseline characteristics to the risk of these events. The use of tamsulosin monotherapy (symptomatic treatment) has no impact on individual long-term risk.

Model-based meta-analysis of individual International Prostate Symptom Score trajectories in patients with benign prostatic hyperplasia with moderate or severe symptoms.

AIMS: International Prostate Symptom Score (IPSS) is a marker of lower urinary tract symptoms (LUTS) deterioration or improvement in benign prostate hyperplasia (BPH). Whereas changes in IPSS relative to baseline have been used as endpoints in clinical trials, little attention has been given to the time course of symptoms. The current investigation aimed to develop a drug-disease model to describe individual IPSS trajectories in moderate and severe BPH patients. METHODS: A model-based meta-analytical approach was used including data from 10 238 patients enrolled into Phase III and IV studies receiving placebo, tamsulosin, dutasteride or combination therapy over a period of up to 4 years. Model predictive performance was assessed using statistical and graphical criteria. Subsequently, simulations were performed to illustrate the implications of treatment with drugs showing symptomatic and disease-modifying properties in patients with varying disease progression rates. RESULTS: Improvement and worsening of IPSS could be characterized by a model including a sigmoid function which disentangles drug effects from placebo and varying disease progression rates on IPSS. Mean estimate (95% confidence intervals) for the disease progression rate was 0.319 (0.271-0.411) month-1 . Treatment effect on IPSS (DELTA) was found to be 0.0605, 0.0139 and 0.0310 month-1 for placebo, tamsulosin and combination therapy, respectively. In addition, it appears that individual trajectories can be clustered together into different phenotypes describing the underlying disease progression rate (i.e. slow, moderate and fast progressors). CONCLUSIONS: The availability of a drug-disease model enables the evaluation of interindividual differences in disease progression rate, deterioration of symptoms and treatment effects on LUTS/BPH.

Impact of disease progression on individual IPSS trajectories and consequences of immediate versus delayed start of treatment in patients with moderate or severe LUTS associated with BPH.

PURPOSE: Despite superiority of tamsulosin-dutasteride combination therapy versus monotherapy for lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH), patients at risk of disease progression are often initiated on α-blockers. This study evaluated the impact of initiating tamsulosin monotherapy prior to switching to tamsulosin-dutasteride combination therapy versus immediate combination therapy using a longitudinal model describing International Prostate Symptom Score (IPSS) trajectories in moderate/severe LUTS/BPH patients at risk of disease progression. METHODS: Clinical trial simulations (CTS) were performed using data from 10,238 patients from Phase III/IV dutasteride trials. The effect of varying disease progression rates was explored by comparing profiles on- and off-treatment. CTS scenarios were investigated, including a reference (immediate combination therapy) and six alternative virtual treatment arms (delayed combination therapy of 1-24 months). Clinical response (≥ 25% IPSS reduction relative to baseline) was analysed using log-rank test. Differences in IPSS relative to baseline at various on-treatment time points were assessed by t tests. RESULTS: Delayed combination therapy initiation led to significant (p < 0.01) decreases in clinical response. At month 48, clinical response rate was 79.7% versus 74.1%, 70.3% and 71.0% and IPSS was 6.3 versus 7.6, 8.1 and 8.0 (switchers from tamsulosin monotherapy after 6, 12 and 24 months, respectively) with immediate combination therapy. More patients transitioned from severe/moderate to mild severity scores by month 48. CONCLUSIONS: CTS allows systematic evaluation of immediate versus delayed combination therapy. Immediate response to α-blockers is not predictive of long-term symptom improvement. Observed IPSS differences between immediate and delayed combination therapy (6-24 months) are statistically significant.

Chronic baseline prostate inflammation is associated with lower tumor volume in men with prostate cancer on repeat biopsy: Results from the REDUCE study.

BACKGROUND: To evaluate whether baseline acute and chronic prostate inflammation among men with initial negative biopsy for prostate cancer (PC) is associated with PC volume at the 2-year repeat prostate biopsy in a clinical trial with systematic biopsies. METHODS: Retrospective analysis of 886 men with negative baseline prostate biopsy and positive 2-year repeat biopsy in the Reduction by Dutasteride of PC Events (REDUCE) study. Acute and chronic inflammation and tumor volume were determined by central pathology. The association of baseline inflammation with 2-year repeat biopsy cancer volume was evaluated with linear and Poisson regressions controlling for demographics and laboratory variables. RESULTS: Chronic, acute inflammation, and both were detected in 531 (60%), 12 (1%), and 84 (9%) baseline biopsies, respectively. Acute and chronic inflammation were significantly associated with each other (P < 0.001). Chronic inflammation was associated with larger prostate (P < 0.001) and lower pre-repeat biopsy PSA (P = 0.01). At 2-year biopsy, baseline chronic inflammation was associated with lower mean tumor volume (2.07 µl vs. 3.15 µl; P = 0.001), number of biopsy cores involved (1.78 vs. 2.19; P < 0.001), percent of cores involved (17.8% vs. 22.8%; P < 0.001), core involvement (0.21 µl vs. 0.31 µl; P < 0.001), and overall percent tumor involvement (1.40% vs. 2.01%; P < 0.001). Results were unchanged in multivariable analysis. Baseline acute inflammation was not associated with any tumor volume measurement. CONCLUSION: In a cohort of men with 2-year repeat prostate biopsy positive for PC after a negative baseline biopsy, baseline chronic inflammation was associated with lower PC volume.

A randomised, double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate-resistant prostate cancer.

BACKGROUND: Bicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration-resistant prostate cancer (CRPC). By reducing intracellular dihydrotestosterone, dutasteride (dual 5-alpha reductase inhibitor) could increase the effectiveness of bicalutamide in this setting. The objective of the study is therefore to prospectively evaluate dutasteride plus bicalutamide in men with asymptomatic, non-metastatic CRPC with rising prostate-specific antigen (PSA). METHODS: Prostate cancer patients with rising PSA whilst on first-line androgen deprivation therapy (ADT) were randomised (1:1) in a double-blind trial to receive bicalutamide 50mg plus placebo or bicalutamide 50mg plus dutasteride 3.5mg once daily for 18 months. Randomisation was stratified by centre; treatment assignments were generated using GlaxoSmithKline's RandAll System. Subjects who completed 18 months could participate in the 2-year extension. Central laboratory and study sites/monitors remained treatment-blinded. Primary end-point was time to disease progression (TDP) up to 42 months (defined as PSA progression from baseline or nadir, radiographic disease progression, death from prostate cancer or receipt of rescue medication). FINDINGS: There was no statistically significant difference in TDP in 127 men treated with bicalutamide/dutasteride (n=62) compared with bicalutamide/placebo (n=65) (hazard ratio (HR)=0.94 [95% confidence interval (CI) 0.61, 1.46]; p=0.79). The estimated median TDP was 425 days (95% CI 302, 858) in the bicalutamide/placebo group and 623 days (95% CI 369, 730) in the bicalutamide/dutasteride group. There was no statistically significant difference between the treatment groups for any secondary efficacy end-points, including time to treatment failure or PSA response. In the multivariate analysis, age, non-White race, higher baseline testosterone and lower baseline PSA were associated with longer TDP. Adverse events were comparable between treatment groups. INTERPRETATION: In men with non-metastatic CRPC, adding dutasteride to bicalutamide did not significantly prolong TDP. Prospective data are provided concerning the common practice of using bicalutamide in this setting.

Solifenacin or mirabegron could improve persistent overactive bladder symptoms after dutasteride treatment in patients with benign prostatic hyperplasia.

OBJECTIVE: To evaluate the clinical response and adverse events (AEs) of solifenacin (SOL) or mirabegron (MIR) in benign prostatic hyperplasia patients with persistent overactive bladder (OAB) symptoms after dutasteride (DUT) treatment. METHODS: Fifty cases with residual OAB symptom score (OABSS) ≥ 5 and OABSS Q3 ≥ 2 after at least 6 months treatment of DUT were included in this study. Patients were administered 5 mg/d of SOL (N = 25) or 50 mg/d of MIR (N = 25), and International Prostate Symptom Score (IPSS) and OABSS were prospectively collected at 4 and 12 weeks. The safety was evaluated by changes in postvoided residual urine volume and the incidence of AEs. RESULTS: After DUT administration, the mean prostate volume, IPSS, and OABSS were 39.0 mL, 17.6, and 8.1, respectively. SOL 5 mg significantly reduced the IPSS, OABSS, and OABSS Q3 at 4 and at 12 weeks (-3.1, -2.7, -1.3; P <.05); however, 4 patients could not continue the SOL treatment owing to AEs. All patients could continue the 12 weeks of MIR treatment, and MIR 50 mg reduced IPSS and OABSS at 4 weeks and reduced IPSS, OABSS, and the OABSS Q3 (-3.0, -2.5, -0.9; P <.05) at 12 weeks. Postvoided residual urine volume increased by ≥ 100 mL after treatment in 2 cases in the SOL group but not in any patient in the MIR group. CONCLUSION: Additional SOL or MIR might result in amelioration of the persistent OAB symptom after DUT treatment in patients with an enlarged prostate.

Efficacy and safety of a fixed-dose combination of dutasteride and tamsulosin treatment (Duodart(®) ) compared with watchful waiting with initiation of tamsulosin therapy if symptoms do not improve, both provided with lifestyle advice, in the management of treatment-naïve men with moderately symptomatic benign prostatic hyperplasia: 2-year CONDUCT study results.

OBJECTIVE: To investigate whether a fixed-dose combination (FDC) of 0.5 mg dutasteride and 0.4 mg tamsulosin is more effective than watchful waiting with protocol-defined initiation of tamsulosin therapy if symptoms did not improve (WW-All) in treatment-naïve men with moderately symptomatic benign prostatic hyperplasia (BPH) at risk of progression. PATIENTS AND METHODS: This was a multicentre, randomised, open-label, parallel-group study (NCT01294592) in 742 men with an International Prostate Symptom Score (IPSS) of 8-19, prostate volume ≥30 mL and total serum PSA level of ≥1.5 ng/mL. Patients were randomised to FDC (369 patients) or WW-All (373) and followed for 24 months. All patients were given lifestyle advice. The primary endpoint was symptomatic improvement from baseline to 24 months, measured by the IPSS. Secondary outcomes included BPH clinical progression, impact on quality of life (QoL), and safety. RESULTS: The change in IPSS at 24 months was significantly greater for FDC than WW-All (-5.4 vs -3.6 points, P < 0.001). With FDC, the risk of BPH progression was reduced by 43.1% (P < 0.001); 29% and 18% of men in the WW-All and FDC groups had clinical progression, respectively, comprising symptomatic progression in most patients. Improvements in QoL (BPH Impact Index and question 8 of the IPSS) were seen in both groups but were significantly greater with FDC (P < 0.001). The safety profile of FDC was consistent with established profiles of dutasteride and tamsulosin. CONCLUSION: FDC therapy with dutasteride and tamsulosin, plus lifestyle advice, resulted in rapid and sustained improvements in men with moderate BPH symptoms at risk of progression with significantly greater symptom and QoL improvements and a significantly reduced risk of BPH progression compared with WW plus initiation of tamsulosin as per protocol.

Decision analysis of dutasteride use for patients with negative prostate biopsy.

OBJECTIVE: To determine whether the additional benefits of improved prostate cancer detection associated with 5α-reductase inhibitors are sufficient to warrant chemoprevention in the case where the degree of prostate cancer risk reduction is deemed inadequate. METHODS: We reanalyzed data from REDUCE, a randomized trial of dutasteride for prostate cancer chemoprevention in men with prior negative biopsy. We evaluated whether statistical models using prostate-specific antigen (PSA) and PSA velocity could help predict the result of repeat prostate biopsy separately for dutasteride and placebo groups. Area under the curve was evaluated by 10-fold cross-validation. RESULTS: PSA velocity improved discrimination at 4 years in the dutasteride group but not at 2 years nor in the placebo group. At 2 years, dutasteride improved discrimination of PSA slightly (0.616 vs. 0.603 for any grade cancer; 0.681 vs. 0.676 for high-grade disease). Between-group differences in cancer rates at 4 years were small. CONCLUSION: Clinicians who are willing to treat at least 23 patients with dutasteride for 2 years to avoid 1 prostate cancer diagnosis should offer dutasteride after initial negative biopsy. Clinicians not willing to do so might consider dutasteride for its additional benefit of reducing unnecessary biopsy, although this benefit is apparent only under very restrictive conditions. It is difficult to justify extending treatment with dutasteride for >2 years.