1370 PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDEdrug alone.1 Finasteride is an inhibitor of type 2, change from baseline to study end in AUA-SI score, Qmax,5AR, which is the predominant 5AR isozyme in the PVR and PV, as well as the cumulative percentage (95% CI) ofprostate that catalyzes the reduction of testosterone to patients who did not have clinical progression of BPH by studythe more potent androgen dihydrotestosterone. Treat- end, were examined in the placebo and ﬁnasteride treatment groups in men with baseline PV less than 30 ml, and comparedment with ﬁnasteride results in a marked decrease in with those with a PV of 30 ml or greater. We also performed aintraprostatic dihydrotestosterone, leading to a reduc- per protocol analysis to assess the consistency of the results oftion in PV, improvement in urinary symptoms and a our ITT analysis for AUA-SI, Qmax, PVR and PV. The perreduction in the risk of serious BPH related outcomes protocol analysis excluded men who had been treated withincluding acute urinary retention and the need for BPH open label medical therapy for BPH or who had undergonerelated surgery.3,4 The beneﬁcial effects of ﬁnasteride are invasive therapy for BPH before the end of study TRUS mea-generally believed to be restricted to men with an en- surement. We used a 1-way ANOVA to compare ﬁnasteridelarged prostate.4 We assessed the long-term effects of with placebo with respect to the change from baseline forﬁnasteride alone compared to placebo on urinary symp- AUA-SI score, Qmax and PV separately for men with baselinetoms and clinical progression of BPH in men enrolled in PV less than 30 ml and those with baseline PV 30 ml or greater.the MTOPS trial subgrouped by baseline PV. We deﬁned For PVR the Wilcoxon rank sum test was used to compare treatment arms with respect to change from baseline. The logmen with a baseline prostate volume of less than 30 ml rank test was used to compare the treatment arms with respectas having a smaller prostate and those with a volume of to time to clinical progression of BPH.30 ml or greater as having an enlarged prostate. RESULTSMATERIALS AND METHODS Baseline and end of study PV measurements were avail-Study Design and Patient Selection able for a total of 1,140 men from the ﬁnasteride andThe design and major outcomes of the MTOPS study have placebo treatment groups (table 1). Baseline PV rangedbeen reported previously.1,2 Men at least 50 years old with from 8.8 to 181.0 ml, with 49% of men having a baselinean AUA-SI score of 8 to 30 and a Qmax of 4 to 15 ml per PV less than 30 ml. Within each PV subgroup (baselinesecond with a voided volume of at least 125 ml wereeligible for the trial. A total of 3,047 men were randomized PV less than 30, or 30 ml or greater) men randomized to1:1:1:1 to placebo, doxazosin (4 to 8 mg), ﬁnasteride (5 mg) placebo or ﬁnasteride were generally similar with respector combination therapy with doxazosin and ﬁnasteride. to baseline demographic and clinical characteristics. MenThe present analysis was based on the ﬁnasteride alone with baseline PV 30 ml or greater were slightly older,and placebo arms only, and included patients for whom and had higher mean PVR and prostate speciﬁc antigenbaseline and end of study data were available. The pri- compared to those with a baseline PV less than 30 ml.mary outcome, overall clinical progression of BPH, wasdeﬁned as the ﬁrst occurrence of an increase from baseline Change in AUA-SI Scoreof at least 4 points in the AUA-SI score (conﬁrmed within In the ITT analysis treatment with ﬁnasteride led to a4 weeks), acute urinary retention, urinary incontinence, signiﬁcant (p 0.045) mean decrease from baseline torenal insufﬁciency or recurrent urinary tract infection. study end in AUA-SI score relative to placebo in menSecondary outcomes included change from baseline to end with baseline PV 30 ml or greater (mean decrease ofof study in AUA-SI score, Qmax and PVR. PV was mea- 5.69 vs 4.65 in the ﬁnasteride and placebo groups,sured by TRUS in all men at baseline and at the end of respectively), whereas there was no signiﬁcant be-year 5 or at the end of study followup, whichever came tween-group difference in the mean change from base-ﬁrst. The average duration of followup was 4.5 years. line in AUA-SI score in men with baseline PV less thanStatistical Analysis 30 ml (mean decrease of 6.01 vs 5.06 in the ﬁnas-We ﬁrst performed an ITT analysis which included all random- teride and placebo groups, respectively, table 2, part Aized men with evaluable PV data. Mean (median for PVR) of ﬁgure). The AUA-SI score results for the per proto-Table 1. Baseline and disease characteristics Baseline PV Less Than 30 ml Baseline PV 30 ml or Greater Placebo Finasteride Placebo FinasterideNo. pts 276 281 288 295Mean SD age 60.3 7.1 60.7 7.0 64.1 6.9 63.9 7.1Mean SD AUA-SI 16.2 5.7 17.2 5.8 16.8 6.0 17.1 5.8Mean SD ml/sec Qmax 10.5 2.8 10.6 2.5 10.4 2.8 10.5 2.7Median ml PVR range 38.0 (0–399) 36.0 (0–411) 52.0 (0–535) 40.0 (0–552)Mean SD ml PV 21.8 5.1 22.3 4.9 47.2 17.4 50.4 21.1PV range (ml) 8.8–29.9 9.3–29.9 30.0–181.0 30.0–170.3Mean SD ng/ml prostate speciﬁc antigen 1.3 1.1 1.3 1.2 3.1 2.3 3.3 2.3
PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDE 1371Table 2. Effect of ﬁnasteride vs placebo on change from baseline in urinary symptoms and prostate volume at study end Baseline PV Less Than 30 ml Baseline PV 30 ml or Greater Placebo Finasteride Placebo Finasteride ITT populationAUA-SI: No. pts 276 281 288 295 Mean SD 5.06 5.78 6.01 5.78 4.65 6.17 5.69 6.40 p Value 0.054 0.045Qmax (ml/sec): No. pts 273 277 282 290 Mean SD 3.06 5.96 3.67 6.97 1.78 5.83 3.31 5.74 p Value 0.268 0.002PVR (ml): No. pts 271 280 282 289 Median (range) 3.0 ( 275, 371) 1.5 ( 221, 262) 0.50 ( 458, 641) 3.0 ( 503, 411) p Value 0.992 0.192PV (ml): No. pts 276 281 288 295 Mean SD 7.19 16.80 0.28 7.98 9.38 17.00 5.79 18.35 p Value 0.001 0.001 Per protocol populationAUA-SI: No. pts 266 276 261 287 Mean SD 4.80 5.62 5.99 5.73 4.16 5.92 5.52 6.13 p Value 0.015 0.008Qmax (ml/sec): No. pts 263 272 257 284 Mean SD 2.88 5.89 3.75 6.92 1.52 5.62 3.19 5.69 p Value 0.119 0.001PVR (ml): No. pts 261 275 256 283 Median (range) 3.0 ( 275, 371) 0 ( 221, 262) 0 ( 421, 641) 3.0 ( 503, 411) p Value 0.888 0.055PV (ml): No. pts 266 276 261 287 Mean SD 7.35 16.99 0.32 8.02 11.38 15.00 5.25 17.63 p Value 0.001 0.001col analysis were generally consistent with those for Change in PVRthe ITT analysis, with signiﬁcant between-group dif- In the ITT analysis treatment with ﬁnasteride and pla-ferences achieved for both PV cohorts (part B of ﬁg- cebo led to median reductions from baseline to study endure). The largest improvement with ﬁnasteride ob- in PVR of 3.0 and 0.5 ml, respectively, in men withserved in the per protocol analysis occurred at year 2 baseline PV 30 ml or greater, and 1.5 vs 3.0 ml,in the baseline PV 30 ml or greater cohort, with a respectively, in men with baseline PV less than 30 ml,mean between-group difference of approximately 2 although the between-group differences were not statis-AUA-SI score units. This improvement was generally tically signiﬁcant in either of the 2 baseline PV cohortssustained in years 3 and 4. (table 2). The PVR results for the per protocol analysisChange in Qmax were generally consistent with those for the ITT analysis.In the ITT analysis treatment with ﬁnasteride led to asigniﬁcant (p 0.002) mean increase from baseline to Change in PVstudy end in Qmax relative to placebo in men with base- In the ITT analysis treatment with ﬁnasteride led toline PV 30 ml or greater (mean increase of 3.31 and 1.78 a signiﬁcantly (p 0.001) greater improvement fromml per second in the ﬁnasteride and placebo groups, baseline to study end in PV in men with baseline PVrespectively), whereas there was no signiﬁcant between- 30 ml or greater (mean decrease in PV of 5.79 mlgroup difference in the mean change from baseline in with ﬁnasteride compared to a mean increase of 9.38Qmax in men with baseline PV less than 30 ml (mean ml with placebo) and in men with baseline PV lessincrease of 3.67 and 3.06 ml per second in the ﬁnasteride than 30 ml (mean increase in PV of 0.28 ml withand placebo groups, respectively, table 2). The Qmax ﬁnasteride vs a mean increase of 7.19 ml with placebo,results for the per protocol analysis were generally con- table 2). The results from the per protocol analysissistent with those for the ITT analysis. were consistent with those from the ITT analysis.
1372 PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDEMean (SE) change from baseline in AUA-SI over time for ITT population (A) and per protocol population (B) (excluding patients whohad been crossed over to open label medical therapy or who had invasive therapy before end of study TRUS measurement) in MTOPStrial. Pbo, placebo. Fin, ﬁnasteride.Clinical Progression of BPH DISCUSSIONTreatment with ﬁnasteride led to a signiﬁcant(p 0.001) increase relative to placebo in the cumu- 5AR inhibitors are generally recommended for uselative percentage of men who did not meet the cri- in patients with symptomatic BPH with an enlargedteria for the clinical progression of BPH in men with prostate.4 The wide distribution of baseline PV (8.8baseline PV 30 ml or greater (ﬁnasteride 88.1%, vs to 181.0 ml) for men enrolled in the MTOPS studyplacebo 77.8%), whereas no signiﬁcant between- provided the opportunity to examine the long-term (4group difference was observed in men with baseline or more years) effects of the 5AR inhibitor ﬁnasteridePV less than 30 ml (91.4% vs 89.1%, table 3). alone compared to placebo on urinary symptoms andTable 3. Effect of ﬁnasteride vs placebo on cumulative percentage at study end of men without clinical progression of BPH Baseline PV Less Than 30 ml Baseline PV 30 ml or Greater Placebo Finasteride Placebo FinasterideNo. pts 276 280 288 295Cumulative % (95% CI) 89.1 (84.8, 92.3) 91.4 (87.5, 94.2) 77.8 (72.5, 82.1) 88.1 (83.9, 91.3) p Value 0.367 0.001
PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDE 1373the clinical progression of BPH in patients with commonly observed in the clinical setting (less than 25smaller and larger prostates. Although we did not to 40 ml or greater).1,3–7 About half of the men enrolleddeﬁne the volume criterion for an enlarged prostate a in the MTOPS study had an enlarged prostate at base-priori, our categorization of PV 30 ml or greater as line as deﬁned by PV 30 ml or greater. Whether aenlarged is consistent with currently accepted cut similar proportion of men with an enlarged prostate aspoints. seen in the MTOPS study present to physicians with We observed in an ITT analysis that treatment bothersome symptoms of LUTS associated with BPHwith ﬁnasteride led to a statistically signiﬁcant re- is uncertain. Given the signiﬁcantly lower rate of clin-duction compared to placebo in the clinical progres- ical progression of BPH observed in men with PV 30sion of BPH in patients with LUTS with an enlarged ml or greater who were treated with ﬁnasteride com-prostate (baseline PV 30 ml or greater), whereas pared to placebo, patients with symptomatic BPH withtreatment with ﬁnasteride did not demonstrate a an enlarged prostate and their treating physicianssigniﬁcant effect relative to placebo on the clinical should consider the beneﬁts observed in this studyprogression of BPH in patients with a smaller pros- from treatment with ﬁnasteride when determiningtate (baseline PV less than 30 ml). Additionally, the treatment choice.ITT analysis showed that ﬁnasteride produced There were a number of limitations of our analy-signiﬁcant improvement compared to placebo in sis. While the data analysis plan for the MTOPSAUA-SI score and Qmax in men with an enlarged study prespeciﬁed examination of the effect of PV onprostate but not in those with a smaller prostate. In outcomes, the cut points for these subgroups werethose men who had not been treated with open label not prespeciﬁed. However, the use of 30 ml ormedical therapy for BPH or those who had under- greater to deﬁne an enlarged prostate is consistentgone invasive therapy for BPH before the end of with current practice.8 In addition, we performed astudy TRUS measurement, ﬁnasteride led to an im- subgroup analysis which may be subject to bias.9provement in AUA-SI relative to placebo by year 2 in There were several strengths to our study includingthe baseline PV 30 ml or greater cohort of approxi- the large sample size, the wide distribution of base-mately 2 units, with this improvement being generally line PV and long-term followup.sustained through year 4 of the study (part B of ﬁg-ure). The larger improvement in PV seen in patientstreated with ﬁnasteride with a baseline PV of 30 ml or CONCLUSIONSgreater (5.79 ml decrease) than in those with a base- In this post hoc analysis of MTOPS trial data, long-line PV less than 30 ml (0.28 ml increase) may have term (4 or more years) treatment with ﬁnasterideresulted in relieving symptomatic prostatic obstruc- led to a signiﬁcant beneﬁcial effect compared to pla-tion, which may have contributed to the added beneﬁts cebo on the clinical progression of BPH in patientsof ﬁnasteride on urinary symptoms and the clinical with LUTS with an enlarged prostate (baseline PVprogression of BPH in these patients. 30 ml or greater). Finasteride had no signiﬁcant Finasteride is approved for the treatment of BPH effect compared to placebo on the clinical progres-symptoms in men with an enlarged prostate based on sion of BPH in patients with LUTS with a smallerlarge long-term studies of men with a wide range of PV prostate (baseline PV less than 30 ml).REFERENCES1. McConnell JD, Roehrborn CG, Bautista OM et al: The sia (2003). Chapter 1: Diagnosis and treatment 7. McConnell JD, Bruskewitz R, Walsh P et al: The long-term effect of doxazosin, ﬁnasteride, and com- recommendations. J Urol 2003; 170: 530. effect of ﬁnasteride on the risk of acute urinary bination therapy on the clinical progression of benign retention and the need for surgical treatment 5. Kaplan SA, McConnell JD, Roehrborn CG et al: prostatic hyperplasia. New Engl J Med 2003; 349: among men with benign prostatic hyperplasia. Fi- Combination therapy with doxazosin and ﬁnas- 2387. nasteride Long-Term Efﬁcacy and Safety Study teride for benign prostatic hyperplasia in patients Group. N Engl J Med 1998; 338: 557.2. Bautista OM, Kusek JW, Nyberg LM et al: Study with lower urinary tract symptoms and a baseline design of the Medical Therapy of Prostatic Symptoms total prostate volume of 25 ml or greater. J Urol 8. Jacobsen SJ, Jacobson DJ, Girman CJ et al: Treat- (MTOPS) trial. Control Clin Trials 2003; 24: 224. 2006; 175: 217. ment for benign prostatic hyperplasia among com- munity dwelling men: the Olmsted County study of3. Proscar® product label. Available at http://www. 6. Kaplan SA, Roehrborn CG, McConnell JD et al: urinary symptoms and health status. J Urol 1999; accessdata.fda.gov/drugsatfda_docs/label/2010/ Long-term treatment with ﬁnasteride results in a 162: 1301. 020180s033lbl.pdf. Accessed March 2010. clinically signiﬁcant reduction in total prostate vol- ume compared to placebo over the full range of 9. Wang R, Lagakos SW, Ware JH et al: Statistics in4. AUA Practice Guidelines Committee: AUA guide- baseline prostate sizes in men enrolled in the medicine–reporting of subgroup analyses in clini- line on management of benign prostatic hyperpla- MTOPS trial. J Urol 2008; 180: 1030. cal trials. N Engl J Med 2007; 357: 2189.