A randomized, controlled, repeat-dose study of batefenterol/fluticasone furoate compared with placebo in the treatment of COPD.

BACKGROUND: Batefenterol (BAT) is a bi-functional molecule with both muscarinic antagonist and ß2-adrenoceptor agonist pharmacology. This Phase II, randomized, placebo-controlled, double-blind study evaluated the safety and tolerability of BAT 300 µg with fluticasone furoate (FF) 100 µg administered via the ELLIPTA inhaler (BAT/FF 300/100). METHODS: Subjects with stable chronic obstructive pulmonary disease were randomized 2:1 to receive BAT/FF 300/100 or placebo once daily for 6 weeks. The primary endpoint was change from baseline in 0-4-h weighted mean (WM) heart rate (HR, measured by electrocardiogram [ECG]) on Day 42. Other endpoints included WM and maximum 0-4-h corrected QT interval (ECG on Days 1, 28, and 42), HR measured by Holter monitoring (Day 42), and standard safety assessments. Study protocol was approved by an Investigational Review Board. RESULTS: Sixty-two patients were randomized and received ≥1 dose of study medication (BAT/FF 300/100 n = 42; placebo n = 20). Mean age was 62.5 years (standard deviation [SD] 8.17). Study completion rates were 83% (BAT/FF 300/100) and 100% (placebo). Screening mean (SD) post-bronchodilator percentage-predicted forced expiratory volume in 1 s was 57.57 (11.42) in the BAT/FF 300/100 group and 55.68 (14.03) in the placebo group. BAT/FF 300/100 was non-inferior to placebo for the primary endpoint, treatment difference: - 2.2 beats per minute (bpm), 95% confidence interval [CI]: - 6.2, 1.7). There were no clinically relevant differences between treatment groups in WM or maximum 0-4-h corrected QT interval, or mean HR based on Holter monitoring on Day 42 (BAT/FF 300/100: 76.3 bpm [SD 11.38]; placebo: 84.8 bpm [SD 9.87]). Adverse events (AEs) occurred in 38% (BAT/FF 300/100) and 35% (placebo) of patients. AEs in ≥2 subjects with BAT/FF 300/100 were dysgeusia (10%), diarrhea (7%), nasopharyngitis (7%), and cough (5%). AEs leading to discontinuation occurred in two subjects who received BAT/FF 300/100: post-treatment severe pneumonia (serious AE) and non-serious AEs of moderate vomiting and severe gastroenteritis; both were not considered drug-related. No deaths occurred. CONCLUSIONS: Six weeks of BAT/FF 300/100 treatment was non-inferior to placebo for change from baseline in HR, with no new clinically relevant general or cardiovascular safety signals. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02573870 (submitted October 12, 2015).

Both acute and chronic inflammation are associated with less perineural invasion in men with prostate cancer on repeat biopsy.

OBJECTIVES: To evaluate the association between acute and chronic inflammation with the presence of perineural invasion (PNI) in prostate biopsies positive for prostate cancer (PCa). MATERIAL AND METHODS: We conducted a retrospective analysis of 1 399 prostate biopsies positive for PCa in the Reduction by Dutasteride of PCa Events (REDUCE) study. PCa, acute and chronic prostate inflammation and PNI were assessed by central pathology review. The association between acute and chronic inflammation with PNI was evaluated using chi-squared and Kruskal-Wallis tests, and logistic regression adjusting for clinicopathological and biochemical variables. RESULTS: The presence of PNI was identified in 133 biopsies (9.5%). In all, 267 biopsies (19.1%) had acute inflammation, 1 038 (74.2%) had chronic inflammation, and 255 (18.2%) had both. The presence of both acute and chronic inflammation had a mutual association (P < 0.001). Chronic inflammation was associated with a lower Gleason score (P = 0.009) and lower tumour volume (P < 0.001), while acute inflammation was associated with lower Gleason score (P = 0.04), lower tumour volume (P = 0.004) and higher prostate-specific antigen levels (P = 0.05). In both univariable and multivariable analyses, chronic prostate inflammation was significantly associated with less PNI (univariable odds ratio [OR] 0.54, 95% confidence interval [CI] 0.37-0.79, P = 0.001; multivariable OR 0.65, 95% CI 0.43-0.99, P = 0.045). Acute prostate inflammation was associated with less PNI only in univariable analysis (univariable OR 0.51, 95% CI 0.29-0.89, P = 0.018; multivariable OR 0.63, 95% CI 0.35-1.13, P = 0.12). CONCLUSION: Acute and chronic prostate inflammation were both associated with a lower prevalence of PNI in prostate biopsies positive for PCa. If confirmed, this suggests that inflammation and immunomodulation can serve as areas of potential therapeutic design to mitigate PNI in patients with PCa.

Sleep Problems are Associated with Development and Progression of Lower Urinary Tract Symptoms: Results from REDUCE.

PURPOSE: Although lower urinary tract symptoms and sleep problems often develop together, to our knowledge it is unknown whether sleep disturbances are linked to lower urinary tract symptoms development and progression. As measured by the 6-item MOS-Sleep (Medical Outcomes Study Sleep Scale) survey we examined the relationship between sleep problems, and the development and progression of lower urinary tract symptoms in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study. MATERIALS AND METHODS: REDUCE was a randomized trial testing prostate cancer chemoprevention with dutasteride in men with prostate specific antigen 2.5 to 10 ng/ml and a negative biopsy. At baseline men completed MOS-Sleep and a scaled average was used to calculate the sleep score. Men were followed for 4 years and I-PSS (International Prostate Symptom Score) was completed at baseline and every 6 months. Asymptomatic men had I-PSS less than 8 while symptomatic men had I-PSS 8 or greater. In the placebo arm of 2,588 men not receiving α-blockers or 5α-reductase inhibitors at baseline we tested the association between sleep problems and lower urinary tract symptom development and progression using Cox models. RESULTS: During followup lower urinary tract symptoms developed in 209 of 1,452 asymptomatic men (14%) and 580 of 1,136 (51%) with lower urinary tract symptoms demonstrated progression. On multivariable analysis higher sleep scores were suggestively associated with increased lower urinary tract symptoms in asymptomatic men (quartile 4 vs 1 HR 1.41, 95% CI 0.92-2.17, p = 0.12) and with lower urinary tract symptom progression in symptomatic men (per 10 points of sleep score HR 1.06, 95% CI 1.01-1.12, p = 0.029). CONCLUSIONS: Among men with lower urinary tract symptoms worse sleep scores were associated with the progression of lower urinary tract symptoms and among asymptomatic men worse sleep scores were suggestively associated with the development of lower urinary tract symptoms. If confirmed, these data suggest that sleep problems may precede such symptoms. Whether treating sleep problems would improve lower urinary tract symptoms requires further testing.

Prostate cancer detection using quantitative T2 and T2 -weighted imaging: The effects of 5-alpha-reductase inhibitors in men on active surveillance.

BACKGROUND: T2 -weighted imaging (T2 -WI) information has been used in a qualitative manner in the assessment of prostate cancer. Quantitative derivatives (T2 relaxation time) can be generated from T2 -WI. These outputs may be useful in helping to discriminate clinically significant prostate cancer from background signal. PURPOSE/HYPOTHESIS: To investigate changes in quantitative T2 parameters in lesions and noncancerous tissue of men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo daily for 6 months. STUDY TYPE: Retrospective. POPULATION/SUBJECTS: Forty men randomized to 6 months of daily dutasteride (n = 20) or placebo (n = 20). FIELD STRENGTH/SEQUENCE: Multiparametric 3T MRI at baseline and 6 months. This included a multiecho MR sequence for quantification of the T2 relaxation times, in three regions of interest (index lesion, noncancerous peripheral [PZ] and transitional [TZ] zones). A synthetic signal contrast (T2 Q contrast) between lesion and noncancerous tissue was assessed using quantitative T2 values. Signal contrast was calculated using the T2 -weighted sequence (T2 W contrast). ASSESSMENT: Two radiologists reviewed the scans in consensus according to Prostate Imaging Reporting and Data System (PI-RADS v. 2) guidelines. STATISTICAL TESTS: Wilcoxon and Mann-Whitney U-tests, Spearman's correlation. RESULTS: When compared to noncancerous tissue, shorter T2 values were observed within lesions at baseline (83.5 and 80.5 msec) and 6 months (81.5 and 81.9 msec) in the placebo and dutasteride arm, respectively. No significant differences for T2 W contrast at baseline and after 6 months were observed, both in the placebo (0.40 [0.29-0.49] vs. 0.43 [0.25-0.49]; P = 0.881) and dutasteride arm (0.35 [0.24-0.47] vs. 0.37 [0.22-0.44]; P = 0.668). There was a significant, positive correlation between the T2 Q contrast and the T2 W contrast values (r = 0.786; P < 0.001). DATA CONCLUSION: The exposure to antiandrogen therapy did not significantly influence the T2 contrast or the T2 relaxation values in men on active surveillance for prostate cancer. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1646-1653.

Chronic Prostate Inflammation Predicts Symptom Progression in Patients with Chronic Prostatitis/Chronic Pelvic Pain.

PURPOSE: We examined the 4-year longitudinal association between histological prostate inflammation and chronic prostatitis/chronic pelvic pain syndrome. We also studied the development of new and progressing existing chronic prostatitis/chronic pelvic pain syndrome in men randomized to placebo in the REDUCE (REduction by DUtasteride of prostate Cancer Events) population. MATERIALS AND METHODS: At multiple time points during 4 years univariable and multivariable analyses were performed between acute and chronic inflammation detected on baseline biopsies and the incidence of chronic pelvic pain syndrome-like symptoms, defined as a positive response to CPSI (Chronic Prostatitis Symptom Index) question 1a-perineal pain and/or question 2b-ejaculatory pain and a total pain subscore of at least 4, and progression of chronic prostatitis/chronic pelvic pain syndrome, defined as a 4-point or greater increase from baseline in total CPSI score, in patients with a baseline categorization of chronic prostatitis/chronic pelvic pain syndrome. RESULTS: Of the 4,109 men in the study acute and chronic inflammation was detected in 641 (15.6%) and 3,216 (78.3%), respectively. Chronic prostatitis/chronic pelvic pain syndrome symptom status was available for 2,816 at baseline. Chronic prostatitis/chronic pelvic pain syndrome-like symptoms developed in 317 of 2,150 men without the condition at baseline who had followup data. Acute and chronic inflammation was not associated with the incidence of the symptoms (p >0.1). At a median followup of 12.0 months 109 of 145 men with baseline chronic prostatitis/chronic pelvic pain syndrome and followup data showed symptomatic progression. Chronic but not acute inflammation was significantly associated with shorter time to progression on univariable and multivariable analyses (p = 0.029 and 0.018, respectively). CONCLUSIONS: Inflammation is not associated with an increased risk of chronic prostatitis/chronic pelvic pain syndrome. However, chronic inflammation predicts the risk of symptomatic progression in men in whom chronic prostatitis/chronic pelvic pain syndrome symptoms have been identified.

Does Peak Urine Flow Rate Predict the Development of Incident Lower Urinary Tract Symptoms in Men with Mild to No Current Symptoms? Results from REDUCE.

PURPOSE: We determined whether decreased peak urine flow is associated with future incident lower urinary tract symptoms in men with mild to no lower urinary tract symptoms. MATERIALS AND METHODS: Our population consisted of 3,140 men from the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial with mild to no lower urinary tract symptoms, defined as I-PSS (International Prostate Symptom Score) less than 8. REDUCE was a randomized trial of dutasteride vs placebo for prostate cancer prevention in men with elevated prostate specific antigen and negative biopsy. I-PSS measures were obtained every 6 months throughout the 4-year study. The association between peak urine flow rate and progression to incident lower urinary tract symptoms, defined as the first of medical treatment, surgery or sustained and clinically significant lower urinary tract symptoms, was tested by multivariable Cox models, adjusting for various baseline characteristics and treatment arm. RESULTS: On multivariable analysis as a continuous variable, decreased peak urine flow rate was significantly associated with an increased risk of incident lower urinary tract symptoms (p = 0.002). Results were similar in the dutasteride and placebo arms. On univariable analysis when peak flow was categorized as 15 or greater, 10 to 14.9 and less than 10 ml per second, flow rates of 10 to 14.9 and less than 10 ml per second were associated with a significantly increased risk of incident lower urinary tract symptoms (HR 1.39, p = 0.011 and 1.67, p <0.001, respectively). Results were similar on multivariable analysis, although in the 10 to 14.9 ml per second group findings were no longer statistically significant (HR 1.26, p = 0.071). CONCLUSIONS: In men with mild to no lower urinary tract symptoms a decreased peak urine flow rate is independently associated with incident lower urinary tract symptoms. If confirmed, these men should be followed closer for incident lower urinary tract symptoms.

Dutasteride is associated with reduced risk of transrectal prostate biopsy-associated urinary tract infection and related hospitalizations.

OBJECTIVES: To evaluate whether the use of dutasteride is associated with a lower risk of transrectal prostate biopsy-associated urinary tract infection (TPBA-UTI) among men in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study. METHODS: Retrospective analysis of 6045 men undergoing 2-year repeat prostate biopsy in REDUCE. Participants were randomized to receive dutasteride 0.5 mg or placebo daily. TPBA-UTI was defined as the presence of urinary symptoms and the prescription of antibiotics by the treating physician within 30 days after biopsy. Severe TPBA-UTI was defined as TPBA-UTI requiring hospitalization. Comparison of TPBA-UTI between treatment arms was done using Chi-square test and logistic regression adjusting for participant characteristics. RESULTS: Of the subjects included in the study, 3067 (50.7%) were randomized to the placebo arm and 2978 (49.3%) to the dutasteride arm. A total 51 (0.8%) men had TPBA-UTI, including 38 (1.2%) in the placebo arm and 13 (0.4%) in the dutasteride arm (univariable relative risk [RR] = 0.35, P = 0.001; multivariable odds ratio [OR] = 0.34, P = 0.003). The number needed to treat (NNT) to prevent one TPBA-UTI was 125 subjects. Of these, 14 (28%) had severe TPBA-UTI, including 12 (0.4%) in the placebo arm and only 2 (0.07%) in the dutasteride arm (univariable RR = 0.17, P = 0.021; multivariable OR = 0.17, P = 0.031). The NNT to prevent one severe TPBA-UTI was 309 subjects. CONCLUSION: Among men undergoing a 2-year repeat prostate biopsy, the use of dutasteride for 2 years was associated with a reduced the risk of overall and severe TBPA-UTI. CLINICALTRIALS. GOV IDENTIFIER: NCT00056407.

Serum cholesterol and risk of lower urinary tract symptoms progression: Results from the Reduction by Dutasteride of Prostate Cancer Events study.

OBJECTIVE: To determine if cholesterol is a risk factor for the development of lower urinary tract symptoms in asymptomatic men. METHODS: A post-hoc analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study was carried out in 2323 men with baseline International Prostate Symptom Score <8 and not taking benign prostatic hyperplasia or cholesterol medications. Cox proportion models were used to test the association between cholesterol, high-density lipoprotein, low-density lipoprotein and the cholesterol : high-density lipoprotein ratio with incident lower urinary tract symptoms, defined as first report of medical treatment, surgery or two reports of an International Prostate Symptom Score >14. RESULTS: A total of 253 men (10.9%) developed incident lower urinary tract symptoms. On crude analysis, higher high-density lipoprotein was associated with a decreased lower urinary tract symptoms risk (hazard ratio 0.89, P = 0.024), whereas total cholesterol and low-density lipoprotein showed no association. After multivariable adjustment, the association between high-density lipoprotein and incident lower urinary tract symptoms remained significant (hazard ratio 0.89, P = 0.044), whereas no association was observed for low-density lipoprotein (P = 0.611). There was a trend for higher cholesterol to be linked with higher lower urinary tract symptoms risk, though this was not statistically significant (hazard ratio 1.04, P = 0.054). A higher cholesterol : high-density lipoprotein ratio was associated with increased lower urinary tract symptoms risk on crude (hazard ratio 1.11, P = 0.016) and adjusted models (hazard ratio 1.12, P = 0.012). CONCLUSIONS: Among asymptomatic men participating in the REDUCE study, higher cholesterol was associated with increased incident lower urinary tract symptoms risk, though the association was not significant. A higher cholesterol : high-density lipoprotein ratio was associated with increased incident lower urinary tract symptoms, whereas higher high-density lipoprotein was protective. These findings suggest dyslipidemia might play a role in lower urinary tract symptoms progression.

Chronic Prostate Inflammation is Associated with Severity and Progression of Benign Prostatic Hyperplasia, Lower Urinary Tract Symptoms and Risk of Acute Urinary Retention.

PURPOSE: We evaluated associations between histological prostate inflammation, and the development and progression of benign prostatic hyperplasia/lower urinary tract symptoms in men randomized to placebo in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study in a 4-year period. MATERIALS AND METHODS: The association of acute and chronic inflammation detected on baseline biopsies and benign prostatic hyperplasia related parameters, including I-PSS (International Prostate Symptom Score) and prostate volume, at multiple time points during 4 years in men randomized to placebo enrolled in the REDUCE prostate cancer prevention study was analyzed with the Student t-test. The association of inflammation with newly developed benign prostatic hyperplasia/lower urinary tract symptoms and benign prostatic hyperplasia progression in patients with existing benign prostatic hyperplasia/lower urinary tract symptoms was analyzed with univariable and multivariable Cox models. RESULTS: Acute and chronic inflammation was seen in baseline negative biopsies of 641 (15.6%) and 3,216 (78.3%) of the 4,109 men in the study. Chronic but not acute inflammation was associated with slightly higher baseline I-PSS (0.6 difference, p = 0.001) and larger prostate volume (3.2 cc difference, p <0.001), a difference noted throughout the study interval. The presence of acute and chronic inflammation was not associated with the incidence of benign prostatic hyperplasia/lower urinary tract symptoms in men without those conditions at baseline or the progression of symptomatic benign prostatic hyperplasia in men with benign prostatic hyperplasia/lower urinary tract symptoms at baseline. However, an association was observed with more severe inflammation. Chronic inflammation at baseline was associated with an increased risk of acute urinary retention (HR 1.6-1.8, p = 0.001). CONCLUSIONS: Our longitudinal evaluation of REDUCE patients randomized to placebo for 4 years confirmed that chronic inflammation is associated with severity and the progression of benign prostatic hyperplasia and benign prostatic hyperplasia/lower urinary tract symptom outcomes.

The Association between Phosphodiesterase Type 5 Inhibitors and Prostate Cancer: Results from the REDUCE Study.

PURPOSE: Despite routine use of phosphodiesterase type 5 inhibitor to treat erectile dysfunction the role in prostate cancer chemoprevention remains unclear. Only a few studies have explored the link between phosphodiesterase type 5 inhibitor use and prostate cancer. We tested the association between phosphodiesterase type 5 inhibitor and prostate cancer risk in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial. MATERIALS AND METHODS: REDUCE was a 4-year multicenter study testing the effect of daily dutasteride on prostate cancer risk in men with prostate specific antigen 2.5 to 10.0 ng/ml and negative biopsy who underwent study mandated biopsies at 2 and 4 years. The association of phosphodiesterase type 5 inhibitor with overall prostate cancer risk and disease grade (Gleason 2-6 and 7-10) was examined using adjusted logistic and multinomial regression analysis. Secondary analysis was performed to explore the association between phosphodiesterase type 5 inhibitor and prostate cancer risk in North American men, given the significantly higher use of phosphodiesterase type 5 inhibitor in these subjects. RESULTS: Phosphodiesterase type 5 inhibitor was not associated with prostate cancer diagnosis (OR 0.90, 95% CI 0.68-1.20, p = 0.476), low grade disease (OR 0.93, 95% CI 0.67-1.27, p = 0.632) or high grade disease (OR 0.85, 95% CI 0.51-1.39, p = 0.508). An inverse trend was seen between phosphodiesterase type 5 inhibitor and prostate cancer diagnosis in North American men but this was not statistically significant (OR 0.67, 95% CI 0.42-1.07, p = 0.091). CONCLUSIONS: Phosphodiesterase type 5 inhibitor use was not associated with decreased prostate cancer diagnoses on post-hoc analysis of REDUCE. In North American men, who had much higher baseline use of phosphodiesterase type 5 inhibitor, this treatment was associated with an inverse trend of prostate cancer diagnosis that approached but did not reach statistical significance.

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.

Does Obesity Modify the Ability of Prebiopsy Prostate Specific Antigen to Detect Prostate Cancer on Repeat Biopsy? Results from the REDUCE Study.

PURPOSE: Higher body mass index is linked to lower prostate specific antigen. This has given rise to concerns that prostate specific antigen may be less reliable for predicting prostate cancer among obese men. We tested the accuracy of prebiopsy prostate specific antigen for predicting prostate cancer across body mass index categories. MATERIALS AND METHODS: We used the REDUCE study, which tested dutasteride for prostate cancer risk reduction in men with a prostate specific antigen of 2.5 to 10.0 ng/ml and a negative pre-study biopsy. All men were required to have a biopsy at 2 and 4 years independent of prostate specific antigen. We assessed the performance of prebiopsy prostate specific antigen to predict overall and high grade prostate cancer (Gleason sum 7 or greater) in each body mass index group using AUC. RESULTS: Of 6,103 men who had a 2-year biopsy 1,646 (27%) were normal weight, 3,209 (53%) were overweight and 1,248 (20%) were obese. Mean adjusted prostate specific antigen for normal weight, overweight and obese subjects on placebo was 7.73, 7.17 and 6.79 ng/ml (p-trend=0.192), and on dutasteride 3.16, 2.93 and 2.62 ng/ml (p=0.008). AUC analysis using raw prostate specific antigen data for predicting prostate cancer ranged from 0.60 to 0.64 in the placebo arm and 0.58 to 0.66 in the dutasteride arm with no difference across body mass index categories (p-interactions ≥0.212). Similar results were found for high grade prostate cancer with AUC ranging from 0.69 to 0.70 in the placebo arm and 0.65 to 0.75 in the dutasteride arm but no differences across body mass index categories (p-interactions ≥0.157). CONCLUSIONS: Among men with a previous negative biopsy the accuracy of prebiopsy prostate specific antigen to predict overall and high grade prostate cancer was independent of body mass index.

Baseline Prostate Atrophy is Associated with Reduced Risk of Prostate Cancer in Men Undergoing Repeat Prostate Biopsy.

PURPOSE: We evaluated whether the presence and severity of baseline prostate atrophy in men with initial biopsy negative for prostate cancer was associated the risk of subsequent prostate cancer detection in a clinical trial with scheduled study mandated biopsies. MATERIALS AND METHODS: We retrospectively analyzed the records of 3,084 men 50 to 75 years old with prostate specific antigen between 2.5 and 10 ng/ml, and a prior negative biopsy in the placebo arm of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study who completed at least 1 per-protocol biopsy. Prostate cancer (defined as present or absent) and prostate atrophy (graded as absent, mild or moderate/marked) was assessed by central pathology review. The association of baseline atrophy with positive 2 and 4-year repeat biopsies was evaluated with logistic regression, controlling for baseline covariates. RESULTS: Baseline prostate atrophy was detected in 2,143 men (70%) and graded as mild and moderate/marked in 1,843 (60%) and 300 (10%) baseline biopsies, respectively. Patients with atrophy were older and had a larger prostate, and more acute and chronic prostate inflammation. At 2-year biopsy the prostate cancer incidence was 17% (508 cases). Baseline atrophy was significantly associated with lower prostate cancer risk (univariable and multivariable OR 0.60, 95% CI 0.50-0.74 and OR 0.67, 95% CI 0.54-0.83, p <0.001, respectively) at the 2-year biopsy. These results were similar at the 4-year biopsy (univariable and multivariable OR 0.70, 95% CI 0.53-0.93 and OR 0.72, 95% CI 0.53-0.97, p = 0.03, respectively). Relative to no atrophy the prostate cancer risk at the 2-year repeat biopsy was lower for mild atrophy (OR 0.69, 95% CI 0.55-0.86) and moderate/marked atrophy (OR 0.51, 95% CI 0.34-0.76, each p <0.001). CONCLUSIONS: Baseline prostate atrophy in men with a prostate biopsy negative for prostate cancer was independently associated with subsequent lower prostate cancer detection.

Metabolic syndrome-like components and prostate cancer risk: results from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study.

OBJECTIVE: To evaluate the relationship between number of metabolic syndrome (MetS)-like components and prostate cancer diagnosis in a group of men where nearly all biopsies were taken independent of prostate-specific antigen (PSA) level, thus minimising any confounding from how the various MetS-like components may influence PSA levels. SUBJECTS/PATIENTS AND METHODS: We analysed data from 6426 men in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study with at least one on-study biopsy. REDUCE compared dutasteride vs placebo on prostate cancer risk among men with an elevated PSA level and negative pre-study biopsy and included two on-study biopsies regardless of PSA level at 2 and 4 years. Available data for MetS-like components included data on diabetes, hypertension, hypercholesterolaemia, and body mass index. The association between number of these MetS-like components and prostate cancer risk and low-grade (Gleason sum <7) or high-grade (Gleason sum >7) vs no prostate cancer was evaluated using logistic regression. RESULTS: In all, 2171 men (34%) had one MetS-like component, 724 (11%) had two, and 163 (3%) had three or four. Men with more MetS-like components had lower PSA levels (P = 0.029). One vs no MetS-like components was protective for overall prostate cancer (P = 0.041) and low-grade prostate cancer (P = 0.010). Two (P = 0.69) or three to four (P = 0.15) MetS-like components were not significantly related to prostate cancer. While one MetS-like component was unrelated to high-grade prostate cancer (P = 0.97), two (P = 0.059) or three to four MetS-like components (P = 0.02) were associated with increased high-grade prostate cancer risk, although only the latter was significant. CONCLUSION: When biopsies are largely PSA level independent, men with an initial elevated PSA level and a previous negative biopsy, and multiple MetS-like components were at an increased risk of high-grade prostate cancer, suggesting the link between MetS-like components and high-grade prostate cancer is unrelated to a lowered PSA level.

Baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: results from the REDUCE study.

BACKGROUND: The current study was performed to evaluate whether baseline acute and chronic prostate inflammation among men with an initial negative biopsy for prostate cancer (PCa) increased the risk of subsequent PCa detection in a clinical trial with systematic biopsies. METHODS: A retrospective analysis was performed of 6238 men aged 50 years to 75 years with prostate-specific antigen levels between 2.5 ng/mL and 10 ng/mL and a prior negative biopsy in the REduction by DUtasteride of PCa Events study who completed a 2-year biopsy. PCa, acute prostate inflammation, and chronic prostate inflammation were assessed by central review. The association between inflammation in baseline prostate biopsies and positive 2-year and 4-year repeat biopsies was evaluated with the chi-square test and logistic regression analysis adjusting for baseline covariates. RESULTS: Acute and chronic inflammation and both were detected in 46 baseline biopsies (1%), 3931 baseline biopsies (63%), and 892 baseline biopsies (14%), respectively. Acute and chronic inflammation were found to be significantly associated with each other (P<.001). Acute inflammation at baseline biopsy was associated with younger age, lower prostate-specific antigen levels, and a smaller prostate (all P<.01), whereas chronic inflammation was associated with older age and larger prostate glands (all P<0.01). At the 2-year biopsy, the prevalence of PCa was 14% (N=900 patients). On univariable and multivariable analysis, both acute and chronic inflammation were found to be significantly associated with a lower PCa risk (acute univariable: odds ratio [OR], 0.65 [P<.001] and multivariable: OR, 0.75 [P=.012] and chronic univariable: OR, 0.61 [P<.001] and multivariable: OR, 0.65 [P<.001]). At the time of 4-year biopsy, only acute inflammation was found to be associated with a lower PCa risk. CONCLUSIONS: Baseline acute and chronic inflammation were both found to be independently associated with a lower PCa risk. From a clinical standpoint, inflammation in negative biopsies for PCa may lower the risk of subsequent PCa detection.

Asian Race and Risk of Prostate Cancer: Results from the REDUCE Study.

BACKGROUND: Global prostate cancer incidence rates are lower in Asian men than Caucasian men. Whether this is the result of less screening in Asian men remains to be determined. We examined whether Asian race was associated with prostate cancer diagnosis in the Reduction by Dutasteride of Cancer Events (REDUCE) study. METHODS: REDUCE was a 4-year, multicenter, randomized trial of dutasteride versus placebo for prostate cancer prevention among men who underwent prostate-specific antigen (PSA)-independent biopsies at 2 and 4 years. Eligible men were ages 50 to 75 years, had PSA between 2.5 and 10 ng/mL, and a negative prestudy prostate biopsy. We tested the association between Asian and Caucasian race and prostate cancer diagnosis using logistic regression. RESULTS: Of 8,122 men in REDUCE, 5,755 (71%) were Caucasian and 105 (1.8%) were Asian. Asians had lower body mass index (24.8 vs. 26.9 kg/m2, P < 0.001), had smaller prostate volume (35.0 vs. 43.5 cc, P < 0.001), and were less likely to have abnormal digital rectal exams (P = 0.048), but were similar in baseline age, PSA, family history of prostate cancer, and smoking status compared with Caucasian men (all P ≥ 0.164). Asian men were equally likely to receive any on-study biopsy compared with Caucasian men (P = 0.634). After adjusting for potential confounders, Asian men were less likely to be diagnosed with prostate cancer during the 4-year study (OR = 0.49; 95% confidence interval, 0.28-0.88; P = 0.016), compared with Caucasian men. CONCLUSIONS: In REDUCE, where all men underwent biopsies largely independent of PSA, Asian race was associated with lower prostate cancer diagnosis. IMPACT: These findings suggest that lower prostate cancer risk in Asian men may be due to biological, genetic, and/or lifestyle factors.

Randomized dose-finding study of batefenterol via dry powder inhaler in patients with COPD.

BACKGROUND: Batefenterol is a novel bifunctional muscarinic antagonist ß2-agonist in development for COPD. The primary objective of this randomized, double-blind, placebo-controlled, active comparator, Phase IIb study was to model the dose-response of batefenterol and select a dose for Phase III development. PATIENTS AND METHODS: Patients aged ≥40 years with COPD and FEV1 ≥30% and ≤70% predicted normal were randomized equally to batefenterol 37.5, 75, 150, 300, or 600 µg, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg once daily. The primary and secondary endpoints were weighted-mean FEV1 over 0-6 hours post-dose and trough FEV1, analyzed by Bayesian and maximum likelihood estimation Emax of dose-response modeling, respectively, on day 42. RESULTS: In the intent-to-treat population (N=323), all batefenterol doses demonstrated statistically and clinically significant improvements from baseline vs placebo in the primary and secondary endpoints (191.1-292.8 and 182.2-244.8 mL, respectively), with a relatively flat dose-response. In the subgroup reversible to salbutamol, there were greater differences between batefenterol doses. Lung function improvements with batefenterol ≥150 µg were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed. CONCLUSION: Batefenterol 300 µg may represent the optimal dose for Phase III studies.

Baseline prostate atrophy is associated with lower tumor volume in men with prostate cancer on repeat biopsy.

BACKGROUND: Prostate atrophy (PA) is commonly identified in prostate biopsies. Previous studies suggest PA may be associated with lower PCa risk. However, it remains unclear whether PA is associated with smaller, less aggressive, and less advanced tumors. Thus, we sought to determine whether the presence and severity of baseline PA in men with initial biopsy negative for prostate cancer (PCa) is associated with PCa volume at 2- and 4-year repeat biopsy. METHODS: We performed a retrospective analysis of 927 men 50-75-years-old with negative baseline biopsy and positive 2- or 4-year repeat biopsy for PCa in the Reduction by Dutasteride of PCa Events study. PA (present or absent), PA severity (mild or moderate/marked), and tumor volume were determined by central pathology. The association of baseline PA with repeat biopsy PCa volume was evaluated with linear and Poisson regressions in uni- and multivariable analyses. RESULTS: PA was identified in 559 (60%) baseline biopsies and was mild in 491 (88%) and moderate/marked in 68 (12%). PA was associated with larger prostate volumes (P < 0.001). At 2-year biopsy, PA was associated with lower overall mean total tumor volume (2.21 vs. 2.94 µL; P = 0.016), mean number of biopsy cores involved (1.85 vs. 2.08; P = 0.016), mean percent of cores involved (18.4% vs. 20.7%; P = 0.008), average core involvement (0.23 vs. 0.29 µL; P = 0.019) and overall mean percent tumor involvement (1.82% vs. 2.33%; P = 0.018). Similar results were found in multivariable analysis and analysis of 4-year repeat biopsies. Compared to mild PA, moderate/marked PA was associated with greater reduction in tumor volume. CONCLUSION: Amongst subjects with repeat prostate biopsy positive for PCa after negative baseline biopsy, the presence and severity of baseline PA were associated with lower PCa volume. This suggests PA may be associated with less aggressive PCa.

Serum cholesterol and risk of high-grade prostate cancer: results from the REDUCE study.

BACKGROUND: Epidemiologic evidence for a serum cholesterol-prostate cancer link is mixed. Prostate-specific antigen (PSA) is positively correlated with cholesterol, potentially increasing PSA-driven biopsy recommendations in men with high cholesterol, though biopsy compliance may be lower in men with comorbid conditions. These potential biases may affect PSA-driven biopsy rates and subsequent prostate cancer detection in men with high serum cholesterol. Our objective was to test the association between serum cholesterol and prostate cancer risk in men receiving PSA independent, study-mandated prostate biopsies. METHODS: We conducted a post hoc analysis of data from 4974 non-statin users in REDUCE, a randomized trial in men with elevated PSA and a negative baseline biopsy. Men underwent 2- and 4-year trial-mandated prostate biopsies. Associations between baseline serum levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and prostate cancer risk, overall and by Gleason grade (<7 vs. ≥7), were examined using multivariable logistic regression. RESULTS: High total serum cholesterol was associated with an increased risk of high-grade prostate cancer diagnosis (OR per 10 mg/dL 1.05; 95% CI 1.00-1.09; p = 0.048), but cholesterol was unrelated to either overall or low-grade prostate cancer risk (p-values >0.185). There was no association between serum LDL and overall, low- or high-grade prostate cancer risk (p-values >0.137). In contrast, elevated serum HDL was associated with increased risk of both overall (OR per 10 mg/dL 1.08; 95% CI 1.01-1.16; p = 0.033) and high-grade prostate cancer (OR per 10 mg/dL 1.14; 95% CI 1.01-1.28; p = 0.034). CONCLUSIONS: In REDUCE, where all men received PSA independent, trial-mandated biopsies thus ensuring complete prostate cancer ascertainment, high total serum cholesterol and high HDL were associated with increased risk of high-grade prostate cancer, supporting a cholesterol-prostate cancer link.

PSA predicts development of incident lower urinary tract symptoms: results from the REDUCE study.

BACKGROUND: The relationship between baseline prostate-specific antigen (PSA) and development of lower urinary tract symptoms (LUTS) in asymptomatic and mildly symptomatic men is unclear. We sought to determine if PSA predicts incident LUTS in these men. METHODS: A post-hoc analysis of the 4-year REDUCE study was performed to assess for incident LUTS in 1534 men with mild to no LUTS at baseline. The primary aim was to determine whether PSA independently predicted incident LUTS after adjusting for the key clinical variables of age, prostate size, and baseline International prostate symptom score (IPSS). Incident LUTS was defined as the first report of medical treatment, surgery, or sustained clinically significant symptoms (two IPSS >14). Cox proportional hazards, cumulative incidence curves, and the log-rank test were used to test our hypothesis. RESULTS: A total of 1534 men with baseline IPSS <8 were included in the study cohort. At baseline, there were 335 men with PSA 2.5-4 ng/mL, 589 with PSA 4.1-6 ng/mL, and 610 with PSA 6-10 ng/mL. During the 4-year study, 196 men progressed to incident LUTS (50.5% medical treatment, 9% surgery, and 40.5% new symptoms). As a continuous variable, higher PSA was associated with increased incident LUTS on univariable (HR 1.09, p = 0.019) and multivariable (HR 1.08, p = 0.040) analysis. Likewise, baseline PSA 6-10 ng/mL was associated with increased incident LUTS vs. PSA 2.5-4 ng/mL in adjusted models (HR 1.68, p = 0.016). This association was also observed in men with PSA 4.1-6 ng/mL vs. PSA 2.5-4 ng/mL (HR 1.60, p = 0.032). CONCLUSIONS: Men with mild to no LUTS but increased baseline PSA are at increased risk of developing incident LUTS presumed due to benign prostatic hyperplasia.