Classic Manuscripts in Urology: Landmark Trials in BPH

Benign prostatic hyperplasia (BPH) is extremely common, affecting up to 25% of men throughout their lifetime.  Over the past 25 years, a number of important clinical trials were completed that define our current medical management of BPH.  These trials should be familiar to all urologists and urology residents; and patients with BPH should know these trials exist and may want to be familiar with their outcomes.

Here we review some of the landmark trials in the medical management of BPH. 

Tamsulosin Investigator Group

Alpha-Blocker Trial
Lepor H.  Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group.  Urology. 1998 Jun;51(6):892-900.

765 men randomized to placebo, 0.4mg or 0.8mg of tamsulosin with the inclusion criteria: age >45, AUA symptom score >13, urinary flow rate (Qmax) 4-15mL/second and post-void residual (PVR) <300cc.  At the study endpoint, improvement in AUA-SS was 5.5, 8.3 and 9.6 points in the placebo, 0.4mg and 0.8mg groups respectively.  This correlated to a 25% AUA-SS improvement in 51%, 70% and 74% of patients.  Urinary flow rates (Qmax) improved by 0.5, 1.75 and 1.78; corresponding to a 30% Qmax improvement in 21%, 31% and 36% of men.

North American Finasteride Trial

5-Alpha Reductase Inhibitor Trial
Gormley GJ, Stoner E, Bruskewitz RC, et al: The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327:1185-1191.

Over a 12 month period, Dr. Gormley and colleagues demonstrated that 5mg of finasteride demonstrated a consistent improvement in symptoms after week 2 through month 12, defining the few week lag period often observed in patients starting finasteride.  In addition, they demonstrated a maximum improvement of 2.7 points on the AUA-SS.  This correlated to an increase in Qmax of 3 mL/sec, a decrease in prostate volume of 19% and the 50% decrease in serum PSA (defining the adjustment in PSA needed for prostate cancer screening).

Proscar Long-term Efficacy and Safety Study (PLESS)

5-Alpha Reductase Inhibitor Trial

McConnell JD, Bruskewitz R, Walsh P, et al: The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557-563.

Dr. McConnell and colleagues evaluated 3,040 men in a multicenter, double-blind, placebo controlled study of finasteride (5mg) over 4 years.  The finasteride group had an average improvement in AUA-SS of 3.3 (compared to 1.8 in the placebo group) that only became evident after 1 year.  Importantly, there was a 57% reduction in acute urinary retention and 55% reduction in surgical intervention at 4 years.

Dutasteride ARIA Studies

5-Alpha Reductase Inhibitor Trial
Roehrborn CG, Boyle P, Nickel JC, et al: Efficacy and safety of a dual inhibitor of 5 alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60:434-441.
Roehrborn CG,Marks LS, Fenter T, et al: Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Urology 2004;63:709-715.

Dr. Roerhborn and colleagues published short- and long-term outcomes of men on the dual-5-ARI inhibitor dutasteride.  Men in this study had moderate-to-severe symptoms based on AUA symptoms score, peak flow <15mL/s and a prostate volume >30cc (average prostate volume 54cc).  AUA symptom scores improved a 6 months and reached a maximum at 24 months compared to placebo.  Similar to the PLESS trial, they found a 25% reduction in prostate volume, 2.2mL/s increase in Qmax, 57% risk reduction of urinary retention and 48% reduction in surgical intervention.

Veterans Affairs Cooperative Study 359

Combination Alpha-Blocker / 5ARI Trial

Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med. 1996;335:533–539.

This was the first trial directly comparing an alpha-blocker and 5ARI, and the first time combination therapy was explored.  1,229 men were randomized to terazosin, finasteride, combination or placebo for 1 year.  This study failed to demonstrate an improvement in finasteride when compared to placebo with respect to symptom scores or urinary flow rates. However, the average prostate size in this study was only 37cc and when subset analyses were performed, it was confirmed that the improvement due to terazosin was independent of prostate volume while finasteride was most effective in larger prostates.

Barry MJ1, Williford WO, Chang Y, Machi M, Jones KM, Walker-Corkery E, Lepor H.  Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients?  J Urol. 1995 Nov;154(5):1770-4.

In this analysis of the VA359 study, Dr. Barry and colleagues defined slight, moderate and marked improvement in AUA-SS as 3, 5 and 8 points respectively.

Medical Therapy of Prostate Symptoms (MTOPS)

Combination Alpha-Blocker / 5ARI Trial
McConnell JD1, Roehrborn CG, Bautista OM, Andriole GL Jr, Dixon CM, Kusek JW, Lepor H, McVary KT, Nyberg LM Jr, Clarke HS, Crawford ED, Diokno A, Foley JP, Foster HE, Jacobs SC, Kaplan SA, Kreder KJ, Lieber MM, Lucia MS, Miller GJ, Menon M, Milam DF, Ramsdell JW, Schenkman NS, Slawin KM, Smith JA; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group.The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia.N Engl J Med. 2003 Dec 18;349(25):2387-98.


The MTOPS Trial was a prospective, multi-center, randomized, double-blind trial where 3047 patients randomized to doxazosin, finasteride or both versus placebo.  Mean prostate volume was 36cc, mean IPSS 16.7 and Qmax ranged from 4-15mL/s.  Over an average follow-up of 4.5 years, the risk reduction for progression (increase in IPSS of 4, acute urinary retention or surgery) was 39% for doxazosin, 34% for finasteride, and 67% for combination therapy compared with placebo.  The risk of acute urinary retention did not change for patients on doxazosin (although time to AUR was longer), but was reduced 68% for men on finasteride and 81% for patients on combination-therapy.  Similarly, there was no difference in surgical rates for patients on doxazosin, but a 64% and 67% reduction for men on finasteride or combination therapy respectively.  Importantly, the MTOPS trial also demonstrated a dramatic reduction in hematuria for patients on finasteride (63% hematuria recurrence on placebo, 14% recurrence in finasteride).

Combination of Avodart and Tamsulosin Trial (CombAT)

Combination Alpha-Blocker / 5ARI Trial

Roehrborn CG, Siami P, Barkin J, Damião R, Becher E, Miñana B, Mirone V, Castro R, Wilson T, Montorsi F; CombAT Study Group.  The influence of baseline parameters on changes in international prostate symptom score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the CombAT study.  Eur Urol. 2009 Feb;55(2):461-71. doi: 10.1016/j.eururo.2008.10.037. Epub 2008 Nov 6.

Roehrborn CG, Siami P, Barkin J, Damião R, Major-Walker K, Nandy I, Morrill BB, Gagnier RP, Montorsi F; CombAT Study Group. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study.  Eur Urol. 2010 Jan;57(1):123-31. doi: 10.1016/j.eururo.2009.09.035. Epub 2009 Sep 19. Erratum in: Eur Urol. 2010 Nov;58(5):801.

In the multicenter, randomised, double-blind, parallel-group CombAT Trial, 4,844 men with age >50, IPSS>12, and prostate volume >30cc were randomized to tamsulosin, dutasteride or combination.  These researchers found improvements in acute urinary retention and surgical interventions in men who were taking dutasteride or combination therapy compared to those on tamsulosin alone.  These improvements were most evident in men with a prostate volume >42cc.  

In summary, we can draw the following conclusions from these studies:

• Significant improvements in AUA-SS are considered greater than 3 points.
• Alpha blockers can begin working as quickly as 8 hours.
• The effects of 5ARI may not be felt for 2 weeks to 2 months, and may take 6-12 months to reach their maximum benefit. 
• 5ARIs reduces the risk of acute urinary retention and surgical treatment associated with BPH.
• 5ARIs are effective only on men with larger prostates (>40g).

This blog was written by Mark W. Ball, MD, urology resident at the Brady Urological Institute at Johns Hopkins.