Long-Term Treatment With Finasteride Improves ClinicalProgression of Benign Prostatic Hyperplasia in Men With anEnlarged Versus a Smaller Prostate: Data From the MTOPS Trial

Steven A. Kaplan,* Jeannette Y. Lee, Alan G. Meehan†and John W. Kusek for the MTOPS Research Group‡From Weill Cornell Medical College, New York, New York (SAK), University of Arkansas for Medical Sciences, Little Rock,Arkansas (JYL), Merck & Co., Inc., Rahway, New Jersey (AGM), and the National Institute of Diabetes and Digestive andKidney Diseases, Bethesda, Maryland (JWK)

Purpose: This post hoc analysis of the Medical Therapy of Prostatic Symptomstrial examined the effect of finasteride alone compared to placebo on the clinicalprogression of benign prostatic hyperplasia in men with a baseline prostatevolume less than 30 ml, or 30 ml or greater.Materials and Methods: Men were randomized to placebo (737), 4 to 8 mgdoxazosin alone (756), 5 mg finasteride alone (768) or doxazosin plus finasteride(786) (average followup was 4.5 years). Approximately 50% of patients had abaseline prostate volume of 30 ml or greater. The present analysis was based onthe finasteride alone and placebo arms only, and included patients for whombaseline and end of study data were available. We examined the effect of treat-ment on the cumulative percentage of men who did not experience clinicalprogression of benign prostatic hyperplasia by study end.Results: In men with baseline prostate volume 30 ml or greater treatment withfinasteride produced a significant (p �0.001) increase relative to placebo in thecumulative percentage of patients who did not experience clinical progression ofbenign prostatic hyperplasia (finasteride 88.1% vs placebo 77.8%). There was nosignificant (p � 0.441) between-group difference in men with baseline prostatevolume less than 30 ml (91.4% vs 89.1%, respectively).Conclusions: Long-term treatment with finasteride led to a significant beneficialeffect compared to placebo on the clinical progression of benign prostatic hyper-plasia in patients with lower urinary tract symptoms with an enlarged prostate(baseline prostate volume 30 ml or greater). Finasteride had no significant effectcompared to placebo on the clinical progression of benign prostatic hyperplasia inpatients with lower urinary tract symptoms with a smaller prostate (baselineprostate volume less than 30 ml).

Key Words: prostatic hyperplasia, urinary tract, finasteride,

Abbreviations

and Acronyms

AUA-SI � American UrologicalAssociation symptom index

5AR � 5�-reductase

BPH � benign prostatichyperplasia

ITT � intent to treat

LUTS � lower urinary tractsymptoms

MTOPS � Medical Therapy ofProstatic Symptoms

PV � prostate volume

PVR � post-void residual volume

Qmax � maximum urinary flowrate

TRUS � transrectal ultrasound

Submitted for publication June 14, 2010.MTOPS was supported by the following coop-

erative agreements from the National Institute ofDiabetes and Digestive and Kidney Diseases: U01DK49977, U01 DK46416, U01 DK41418, U01 DK46429,U01 DK46431, U01 DK46437, U01 DK46437, U01DK46468, U01 DK46472, U01 DK49880, U01 DK49912, U01 DK49921, U01 DK49951, U01 DK49954,U01 DK49960, U01 DK49961, U01 DK49963, U01DK49964, U01 DK49971, U01 DK49980, as well as bythe National Center on Minority Health and Health

organ size, prostate

THE MTOPS trial, to our knowledge,is the largest and longest placebo con-trolled study to assess the effect ofmedical (drug) therapy on the clinicalprogression of BPH.1,2 In that trialthe risk of clinical progression of BPH

was significantly reduced by finas-

0022-5347/11/1854-1369/0THE JOURNAL OF UROLOGY®

© 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RES

teride (34% relative risk reduction)and doxazosin (39% relative risk re-duction) alone compared to placebo.However, the 2 drugs combined re-sulted in a superior placebo correctedrisk reduction (66% relative risk re-

duction) compared to that for either

Vol. 185, 1369-1373, April 2011Printed in U.S.A.

EARCH, INC. DOI:10.1016/j.juro.2010.11.060

Disparities, National Institutes of Health. Financial sup-port and drug products for MTOPS were also providedby Merck and Pfizer.

* Correspondence and requests for reprints:Institute of Bladder and Prostate Health, WeillCornell Medical College, Cornell University, 1300York Ave., F9 West, Box 261, New York, NewYork 10021 (telephone: 212-746-4811; FAX: 212-746-5329; e-mail: kaplans@med.cornell.edu).

† Financial interest and/or other relationshipwith Merck.

‡ A list of the MTOPS study investigators hasbeen provided previously.1

www.jurology.com 1369

PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDE1370

drug alone.1 Finasteride is an inhibitor of type 2,5AR, which is the predominant 5AR isozyme in theprostate that catalyzes the reduction of testosterone tothe more potent androgen dihydrotestosterone. Treat-ment with finasteride results in a marked decrease inintraprostatic dihydrotestosterone, leading to a reduc-tion in PV, improvement in urinary symptoms and areduction in the risk of serious BPH related outcomesincluding acute urinary retention and the need for BPHrelated surgery.3,4 The beneficial effects of finasteride aregenerally believed to be restricted to men with an en-larged prostate.4 We assessed the long-term effects offinasteride alone compared to placebo on urinary symp-toms and clinical progression of BPH in men enrolled inthe MTOPS trial subgrouped by baseline PV. We definedmen with a baseline prostate volume of less than 30 mlas having a smaller prostate and those with a volume of30 ml or greater as having an enlarged prostate.

MATERIALS AND METHODS

Study Design and Patient SelectionThe design and major outcomes of the MTOPS study havebeen reported previously.1,2 Men at least 50 years old withan AUA-SI score of 8 to 30 and a Qmax of 4 to 15 ml persecond with a voided volume of at least 125 ml wereeligible for the trial. A total of 3,047 men were randomized1:1:1:1 to placebo, doxazosin (4 to 8 mg), finasteride (5 mg)or combination therapy with doxazosin and finasteride.The present analysis was based on the finasteride aloneand placebo arms only, and included patients for whombaseline and end of study data were available. The pri-mary outcome, overall clinical progression of BPH, wasdefined as the first occurrence of an increase from baselineof at least 4 points in the AUA-SI score (confirmed within4 weeks), acute urinary retention, urinary incontinence,renal insufficiency or recurrent urinary tract infection.Secondary outcomes included change from baseline to endof study in AUA-SI score, Qmax and PVR. PV was mea-sured by TRUS in all men at baseline and at the end ofyear 5 or at the end of study followup, whichever camefirst. The average duration of followup was 4.5 years.

Statistical AnalysisWe first performed an ITT analysis which included all random-ized men with evaluable PV data. Mean (median for PVR)

Table 1. Baseline and disease characteristics

Baseline PV

Placebo

No. pts 276Mean � SD age 60.3 � 7.1Mean � SD AUA-SI 16.2 � 5.7Mean � SD ml/sec Qmax 10.5 � 2.8Median ml PVR range 38.0 (0–399)Mean � SD ml PV 21.8 � 5.1PV range (ml) 8.8–29.9

Mean � SD ng/ml prostate specific antigen 1.3 � 1.1

change from baseline to study end in AUA-SI score, Qmax,PVR and PV, as well as the cumulative percentage (95% CI) ofpatients who did not have clinical progression of BPH by studyend, were examined in the placebo and finasteride treatmentgroups in men with baseline PV less than 30 ml, and comparedwith those with a PV of 30 ml or greater. We also performed aper protocol analysis to assess the consistency of the results ofour ITT analysis for AUA-SI, Qmax, PVR and PV. The perprotocol analysis excluded men who had been treated withopen label medical therapy for BPH or who had undergoneinvasive therapy for BPH before the end of study TRUS mea-surement. We used a 1-way ANOVA to compare finasteridewith placebo with respect to the change from baseline forAUA-SI score, Qmax and PV separately for men with baselinePV less than 30 ml and those with baseline PV 30 ml or greater.For PVR the Wilcoxon rank sum test was used to comparetreatment arms with respect to change from baseline. The logrank test was used to compare the treatment arms with respectto time to clinical progression of BPH.

RESULTS

Baseline and end of study PV measurements were avail-able for a total of 1,140 men from the finasteride andplacebo treatment groups (table 1). Baseline PV rangedfrom 8.8 to 181.0 ml, with 49% of men having a baselinePV less than 30 ml. Within each PV subgroup (baselinePV less than 30, or 30 ml or greater) men randomized toplacebo or finasteride were generally similar with respectto baseline demographic and clinical characteristics. Menwith baseline PV 30 ml or greater were slightly older,and had higher mean PVR and prostate specific antigencompared to those with a baseline PV less than 30 ml.

Change in AUA-SI Score

In the ITT analysis treatment with finasteride led to asignificant (p � 0.045) mean decrease from baseline tostudy end in AUA-SI score relative to placebo in menwith baseline PV 30 ml or greater (mean decrease of�5.69 vs �4.65 in the finasteride and placebo groups,respectively), whereas there was no significant be-tween-group difference in the mean change from base-line in AUA-SI score in men with baseline PV less than30 ml (mean decrease of �6.01 vs �5.06 in the finas-teride and placebo groups, respectively, table 2, part Aof figure). The AUA-SI score results for the per proto-

han 30 ml Baseline PV 30 ml or Greater

Finasteride Placebo Finasteride

281 288 29560.7 � 7.0 64.1 � 6.9 63.9 � 7.117.2 � 5.8 16.8 � 6.0 17.1 � 5.810.6 � 2.5 10.4 � 2.8 10.5 � 2.736.0 (0–411) 52.0 (0–535) 40.0 (0–552)22.3 � 4.9 47.2 � 17.4 50.4 � 21.1

9.3–29.9 30.0–181.0 30.0–170.3

Less T

1.3 � 1.2 3.1 � 2.3 3.3 � 2.3

PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDE 1371

col analysis were generally consistent with those forthe ITT analysis, with significant between-group dif-ferences achieved for both PV cohorts (part B of fig-ure). The largest improvement with finasteride ob-served in the per protocol analysis occurred at year 2in the baseline PV 30 ml or greater cohort, with amean between-group difference of approximately 2AUA-SI score units. This improvement was generallysustained in years 3 and 4.

Change in Qmax

In the ITT analysis treatment with finasteride led to asignificant (p � 0.002) mean increase from baseline tostudy end in Qmax relative to placebo in men with base-line PV 30 ml or greater (mean increase of 3.31 and 1.78ml per second in the finasteride and placebo groups,respectively), whereas there was no significant between-group difference in the mean change from baseline inQmax in men with baseline PV less than 30 ml (meanincrease of 3.67 and 3.06 ml per second in the finasterideand placebo groups, respectively, table 2). The Qmaxresults for the per protocol analysis were generally con-

Table 2. Effect of finasteride vs placebo on change from baseli

Baseline PV Less Than 30 ml

Placebo Fin

ITTAUA-SI:

No. pts 276 281Mean � SD �5.06 � 5.78 �6.01

p Value 0.054Qmax (ml/sec):

No. pts 273 277Mean � SD 3.06 � 5.96 3.67

p Value 0.268PVR (ml):

No. pts 271 280Median (range) �3.0 (�275, 371) �1.5

p Value 0.992PV (ml):

No. pts 276 281Mean � SD 7.19 � 16.80 0.28

p Value �0.001Per prot

AUA-SI:No. pts 266 276Mean � SD �4.80 � 5.62 �5.99

p Value 0.015Qmax (ml/sec):

No. pts 263 272Mean � SD 2.88 � 5.89 3.75

p Value 0.119PVR (ml):

No. pts 261 275Median (range) �3.0 (�275, 371) 0

p Value 0.888PV (ml):

No. pts 266 276Mean � SD 7.35 � 16.99 0.32

p Value �0.001

sistent with those for the ITT analysis.

Change in PVR

In the ITT analysis treatment with finasteride and pla-cebo led to median reductions from baseline to study endin PVR of �3.0 and �0.5 ml, respectively, in men withbaseline PV 30 ml or greater, and �1.5 vs �3.0 ml,respectively, in men with baseline PV less than 30 ml,although the between-group differences were not statis-tically significant in either of the 2 baseline PV cohorts(table 2). The PVR results for the per protocol analysiswere generally consistent with those for the ITT analysis.

Change in PV

In the ITT analysis treatment with finasteride led toa significantly (p �0.001) greater improvement frombaseline to study end in PV in men with baseline PV30 ml or greater (mean decrease in PV of �5.79 mlwith finasteride compared to a mean increase of 9.38ml with placebo) and in men with baseline PV lessthan 30 ml (mean increase in PV of 0.28 ml withfinasteride vs a mean increase of 7.19 ml with placebo,table 2). The results from the per protocol analysis

rinary symptoms and prostate volume at study end

Baseline PV 30 ml or Greater

Placebo Finasteride

ion

288 295�4.65 � 6.17 �5.69 � 6.40

0.045

282 2901.78 � 5.83 3.31 � 5.74

0.002

282 289262) �0.50 (�458, 641) �3.0 (�503, 411)

0.192

288 2959.38 � 17.00 �5.79 � 18.35

�0.001ulation

261 287�4.16 � 5.92 �5.52 � 6.13

0.008

257 2841.52 � 5.62 3.19 � 5.69

�0.001

256 283262) 0 (�421, 641) �3.0 (�503, 411)

0.055

261 28711.38 � 15.00 �5.25 � 17.63

�0.001

ne in u

asteride

populat

� 5.78

� 6.97

(�221,

� 7.98

ocol pop

� 5.73

� 6.92

(�221,

� 8.02

were consistent with those from the ITT analysis.

PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDE1372

Clinical Progression of BPH

Treatment with finasteride led to a significant(p �0.001) increase relative to placebo in the cumu-lative percentage of men who did not meet the cri-teria for the clinical progression of BPH in men withbaseline PV 30 ml or greater (finasteride 88.1%, vsplacebo 77.8%), whereas no significant between-group difference was observed in men with baselinePV less than 30 ml (91.4% vs 89.1%, table 3).

Mean (SE) change from baseline in AUA-SI over time for ITT pohad been crossed over to open label medical therapy or who hadtrial. Pbo, placebo. Fin, finasteride.

Table 3. Effect of finasteride vs placebo on cumulative percent

Baseline PV Less Than 30

Placebo

No. pts 276 2Cumulative % (95% CI) 89.1 (84.8, 92.3)

p Value 0.367

DISCUSSION

5AR inhibitors are generally recommended for usein patients with symptomatic BPH with an enlargedprostate.4 The wide distribution of baseline PV (8.8to 181.0 ml) for men enrolled in the MTOPS studyprovided the opportunity to examine the long-term (4or more years) effects of the 5AR inhibitor finasteridealone compared to placebo on urinary symptoms and

on (A) and per protocol population (B) (excluding patients whoive therapy before end of study TRUS measurement) in MTOPS

study end of men without clinical progression of BPH

Baseline PV 30 ml or Greater

eride Placebo Finasteride

288 295.5, 94.2) 77.8 (72.5, 82.1) 88.1 (83.9, 91.3)

pulatiinvas

age at

ml

Finast

8091.4 (87

�0.001

PROSTATE SIZE AND SYMPTOM IMPROVEMENT WITH FINASTERIDE 1373

the clinical progression of BPH in patients withsmaller and larger prostates. Although we did notdefine the volume criterion for an enlarged prostate apriori, our categorization of PV 30 ml or greater asenlarged is consistent with currently accepted cutpoints.

We observed in an ITT analysis that treatmentwith finasteride led to a statistically significant re-duction compared to placebo in the clinical progres-sion of BPH in patients with LUTS with an enlargedprostate (baseline PV 30 ml or greater), whereastreatment with finasteride did not demonstrate asignificant effect relative to placebo on the clinicalprogression of BPH in patients with a smaller pros-tate (baseline PV less than 30 ml). Additionally, theITT analysis showed that finasteride producedsignificant improvement compared to placebo inAUA-SI score and Qmax in men with an enlargedprostate but not in those with a smaller prostate. Inthose men who had not been treated with open labelmedical therapy for BPH or those who had under-gone invasive therapy for BPH before the end ofstudy TRUS measurement, finasteride led to an im-provement in AUA-SI relative to placebo by year 2 inthe baseline PV 30 ml or greater cohort of approxi-mately 2 units, with this improvement being generallysustained 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 orgreater (5.79 ml decrease) than in those with a base-line PV less than 30 ml (0.28 ml increase) may haveresulted in relieving symptomatic prostatic obstruc-tion, which may have contributed to the added benefitsof finasteride on urinary symptoms and the clinicalprogression of BPH in these patients.

Finasteride is approved for the treatment of BPHsymptoms in men with an enlarged prostate based on

large long-term studies of men with a wide range of PV

REFERENCES

line on management of benign prostatic hyperpla- MTOPS trial. J Urol 2008; 1

commonly observed in the clinical setting (less than 25to 40 ml or greater).1,3–7 About half of the men enrolledin the MTOPS study had an enlarged prostate at base-line as defined by PV 30 ml or greater. Whether asimilar proportion of men with an enlarged prostate asseen in the MTOPS study present to physicians withbothersome symptoms of LUTS associated with BPHis uncertain. Given the significantly lower rate of clin-ical progression of BPH observed in men with PV 30ml or greater who were treated with finasteride com-pared to placebo, patients with symptomatic BPH withan enlarged prostate and their treating physiciansshould consider the benefits observed in this studyfrom treatment with finasteride when determiningtreatment choice.

There were a number of limitations of our analy-sis. While the data analysis plan for the MTOPSstudy prespecified examination of the effect of PV onoutcomes, the cut points for these subgroups werenot prespecified. However, the use of 30 ml orgreater to define an enlarged prostate is consistentwith current practice.8 In addition, we performed asubgroup analysis which may be subject to bias.9

There were several strengths to our study includingthe large sample size, the wide distribution of base-line PV and long-term followup.

CONCLUSIONS

In this post hoc analysis of MTOPS trial data, long-term (4 or more years) treatment with finasterideled to a significant beneficial effect compared to pla-cebo on the clinical progression of BPH in patientswith LUTS with an enlarged prostate (baseline PV30 ml or greater). Finasteride had no significanteffect compared to placebo on the clinical progres-sion of BPH in patients with LUTS with a smaller

prostate (baseline PV less than 30 ml).

1. McConnell JD, Roehrborn CG, Bautista OM et al: Thelong-term effect of doxazosin, finasteride, and com-bination therapy on the clinical progression of benignprostatic hyperplasia. New Engl J Med 2003; 349:2387.

2. Bautista OM, Kusek JW, Nyberg LM et al: Studydesign of the Medical Therapy of Prostatic Symptoms(MTOPS) trial. Control Clin Trials 2003; 24: 224.

3. Proscar® product label. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020180s033lbl.pdf. Accessed March 2010.

4. AUA Practice Guidelines Committee: AUA guide-

sia (2003). Chapter 1: Diagnosis and treatmentrecommendations. J Urol 2003; 170: 530.

5. Kaplan SA, McConnell JD, Roehrborn CG et al:Combination therapy with doxazosin and finas-teride for benign prostatic hyperplasia in patientswith lower urinary tract symptoms and a baselinetotal prostate volume of 25 ml or greater. J Urol2006; 175: 217.

6. Kaplan SA, Roehrborn CG, McConnell JD et al:Long-term treatment with finasteride results in aclinically significant reduction in total prostate vol-ume compared to placebo over the full range ofbaseline prostate sizes in men enrolled in the

80: 1030.

7. McConnell JD, Bruskewitz R, Walsh P et al: Theeffect of finasteride on the risk of acute urinaryretention and the need for surgical treatmentamong men with benign prostatic hyperplasia. Fi-nasteride Long-Term Efficacy and Safety StudyGroup. N Engl J Med 1998; 338: 557.

8. Jacobsen SJ, Jacobson DJ, Girman CJ et al: Treat-ment for benign prostatic hyperplasia among com-munity dwelling men: the Olmsted County study ofurinary symptoms and health status. J Urol 1999;162: 1301.

9. Wang R, Lagakos SW, Ware JH et al: Statistics inmedicine–reporting of subgroup analyses in clini-

cal trials. N Engl J Med 2007; 357: 2189.