MTOPS: Doxazosin, Finasteride and Combination Therapy for BPH Progression
MTOPS was a multicenter, double-blind, placebo-controlled randomized trial of doxazosin, finasteride and both drugs together in 3,047 men with lower urinary tract symptoms from BPH, with time to overall clinical progression as the primary endpoint. Over a mean 4.5 years, progression occurred at 4.5 events per 100 person-years with placebo, 2.7 with doxazosin, 2.9 with finasteride and 1.5 with the combination, risk reductions of 39%, 34% and 66%.[1]
- Design and population
- Multicenter, double-blind, placebo-controlled four-arm randomized trial. 3,047 men aged 50 years or older with lower urinary tract symptoms from BPH (AUA symptom score 8 to 30 or 35, maximal flow 4 to 15 mL per second) and no prior BPH treatment.
- Arms
- Placebo versus doxazosin 4 to 8 mg daily versus finasteride 5 mg daily versus doxazosin plus finasteride
- Report and follow-up
- 2003 · Mean 4.5 years in the full-scale study (6.0 years in the 116-man pilot); 75% of men had at least 4 years of data
| Endpoint | Results | Effect | Finding |
|---|---|---|---|
| Overall clinical progression, events per 100 person-years over the study (any of: confirmed AUA symptom score rise of 4 or more points, acute urinary retention, incontinence, renal insufficiency, recurrent UTI or urosepsis) | 4.5 (128 events, n=737) vs 2.7 (85 events, n=756) vs 2.9 (89 events, n=768) vs 1.5 (49 events, n=786) | P <0.001 for combination versus placebo | Met |
| Mean reduction in AUA symptom score at 4 years | 4.9 vs 6.6 vs 5.6 vs 7.4 | P <0.001 for doxazosin and combination, 0.001 for finasteride, each versus placebo over the study | Met |
| Median change in maximal urinary flow rate at 4 years, mL per second | +1.4 (n=519) vs +2.5 (n=567) vs +2.2 (n=551) vs +3.7 (n=574) | P <0.001 for each active group versus placebo over the study | Met |
| Median change in serum PSA at 4 years, percent | +15% (n=618) vs +13% (n=655) vs -50% (n=631) vs -50% (n=673) | — | Descriptive |
| Median change in transrectal ultrasound prostate volume after a mean 4.5 years | Placebo or doxazosin (1,148 men): median increase of 24%. Finasteride or combination in men with large baseline glands (427 men): median decrease of 19%. | — | Descriptive |
Harms: Erectile dysfunction: 3.32 vs 3.56 vs 4.53 vs 5.11; Abnormal ejaculation: 0.83 vs 1.10 vs 1.78 vs 3.05; Decreased libido: 1.40 vs 1.56 vs 2.36 vs 2.51
Design
Men 50 years or older were enrolled at 17 clinical centers from 1993 to 1998: 116 in a pilot phase and 2,931 in the full-scale study. They had an AUA symptom score of 8 to 35 (8 to 30 in the full-scale study, to leave room for a 4-point worsening), a maximal flow of 4 to 15 mL per second and a voided volume of at least 125 mL. Men with prior medical or surgical BPH treatment, a supine blood pressure below 90/70 mm Hg or a PSA above 10 ng/mL were excluded. There was no minimum prostate size: baseline transrectal ultrasound volume averaged 36.3 mL (median 31.0 mL), the mean symptom score was 16.9 and the median PSA was 1.6 ng/mL.[1]
Randomization used the urn method, stratified by center. Merck and Pfizer donated the drugs and placebo tablets made to look and taste like each active drug. Finasteride was 5 mg daily. Doxazosin started at 1 mg and doubled weekly to 8 mg daily; men who could not tolerate 8 mg took 4 mg, and men who tolerated neither counted as having stopped doxazosin. Men who stopped randomized treatment stayed in follow-up.[1]
The primary outcome was the first occurrence of any of the following: a confirmed rise of at least 4 points in the AUA symptom score (repeated within 4 weeks), acute urinary retention, renal insufficiency from BPH (creatinine at least 1.5 mg/dL and at least 50% above baseline), recurrent urinary tract infection (two or more in a year, or urosepsis) or socially or hygienically unacceptable incontinence. Retention with an obvious precipitating cause such as anesthesia counted only after a voiding trial without a catheter failed. A clinical review committee unaware of assignments reviewed events.[1]
Analysis was by intention to treat with life-table cumulative incidence; invasive BPH therapy and prostate or bladder cancer were censored as competing events. Each active-versus-placebo comparison required P<0.0157, and the sample provided 81% power to detect a 33% reduction in progression. Comparisons between active therapies were not specified by the protocol and used a Bonferroni-adjusted threshold of P<0.0167. Secondary outcomes were the symptom score and maximal flow over time; other outcomes were invasive therapy, PSA and prostate volume.[1]
Results
There were 351 primary events over a mean 4.5 years (6.0 years in the pilot phase): 128 with placebo, 85 with doxazosin, 89 with finasteride and 49 with the combination. Rates were 4.5, 2.7, 2.9 and 1.5 per 100 person-years. Risk reductions versus placebo were 39% with doxazosin (95% CI 20 to 53; P<0.001), 34% with finasteride (14 to 50; P=0.002) and 66% with the combination (54 to 76; P<0.001), each passing the active-versus-placebo threshold. The combination was superior to each single drug (P<0.001 for each); doxazosin and finasteride did not differ significantly. Among the 75% of men with at least 4 years of follow-up, 4-year cumulative incidence was 17% with placebo (95% CI 14 to 20), 10% with doxazosin (8 to 12), 10% with finasteride (8 to 13) and 5% with the combination (4 to 7). The number needed to treat over 4 years to prevent one progression event was 8.4 for the combination, 13.7 for doxazosin and 15.0 for finasteride.[1]
About 78% of events were symptom-score increases of at least 4 points, 12% were acute urinary retention and 9% were incontinence; recurrent urinary infection or urosepsis occurred in five men and no man had renal insufficiency from BPH. Symptom-score rises occurred at 3.6, 1.9, 2.5 and 1.3 per 100 person-years, risk reductions of 45% (doxazosin), 30% (finasteride) and 64% (combination).[1]
Acute urinary retention occurred at 0.6 per 100 person-years with placebo (18 events), 0.2 with finasteride (6 events; risk reduction 68%, P=0.009) and 0.1 with the combination (4 events; risk reduction 81%, P<0.001). Doxazosin (0.4 per 100 person-years; risk reduction 35%, 95% CI −31 to 67) delayed retention but did not significantly lower its cumulative incidence (P=0.23). Invasive BPH therapy was needed by 40 men on placebo (1.3 per 100 person-years) and occurred at 1.3, 0.5 and 0.4 per 100 person-years with doxazosin, finasteride and the combination; risk reductions were 3% (−48 to 37) with doxazosin, 64% (34 to 80) with finasteride and 67% (40 to 82) with the combination. The number needed to treat over 4 years to prevent one man from needing invasive therapy was 25.9 for the combination, 29.0 for finasteride and 60.1 for doxazosin.[1]
The mean 4-year reduction in AUA symptom score was 4.9 with placebo, 6.6 with doxazosin, 5.6 with finasteride and 7.4 with the combination; the combination beat finasteride (P<0.001) and doxazosin (P=0.006), and doxazosin beat finasteride (P=0.001). The median change in maximal flow at year 4 was +1.4 mL per second with placebo, +2.5 with doxazosin, +2.2 with finasteride and +3.7 with the combination, and the combination exceeded each single drug over the study (P<0.001 for each). Median PSA at 4 years rose 15% with placebo and 13% with doxazosin and fell 50% with finasteride and with the combination. Median prostate volume rose 24% in the 1,148 men on placebo or doxazosin and fell 19% in the 427 men on finasteride or the combination who had large baseline glands.[1]
In a preplanned secondary analysis, the 4-year number needed to treat to prevent one progression event was 4.7 with the combination in men with a PSA above 4.0 ng/mL (20% of men) and 4.9 in men with a baseline prostate volume above 40 mL (30% of men); for finasteride it was 7.2 in both subgroups. For invasive therapy, the combination number needed to treat fell to 23.1 and 15.9 in the same subgroups. Baseline PSA and prostate volume predicted progression with placebo and with doxazosin but not with finasteride or the combination.[1]
A later analysis by baseline prostate volume found that below 25 mL the combination was no better than doxazosin alone for progression, invasive therapy, symptom score or maximal flow, while at 25 to under 40 mL and at 40 mL or more it was superior to doxazosin or finasteride alone.[2] A post hoc comparison of the finasteride and placebo arms found that, at a baseline volume of 30 mL or more, 88.1% of finasteride-treated men (n=295) and 77.8% of placebo-treated men (n=288) had no progression by study end (P<0.001); below 30 mL the figures were 91.4% (n=280) and 89.1% (n=276), without a significant difference.[3] In the larger glands prostate volume rose 9.38 mL with placebo and fell 5.79 mL with finasteride.[3] In the quality-of-life analysis of 2,872 men, the BPH Impact Index improved with doxazosin and the combination at year 4, the IPSS quality-of-life score improved in all three drug groups, and SF-36 scores did not differ from placebo.[4]
Surgery and treatment delivery
Of the invasive BPH procedures, 84% were endoscopic (for example transurethral prostatectomy) or open surgery and the remainder were minimally invasive (for example transurethral microwave therapy).[1]
By the end of the study, 27% of men receiving active therapy had stopped doxazosin and 24% had stopped finasteride, and 18% of the combination group had stopped both drugs, most often because of adverse effects. Loss to follow-up ran at 2.5, 2.2, 3.3 and 2.4 per 100 person-years with placebo, doxazosin, finasteride and the combination, below the 5% per year assumed in the sample-size calculation.[1]
Adverse events
Adverse events were reported as rates per 100 person-years as of September 30, 2002 (3,489 person-years with placebo, 3,652 with doxazosin, 3,600 with finasteride and 3,832 with the combination).[1]
| Event | Placebo | Doxazosin | Finasteride | Combination | Above placebo (P<0.05) |
|---|---|---|---|---|---|
| Erectile dysfunction | 3.32 | 3.56 | 4.53 | 5.11 | Finasteride, combination |
| Abnormal ejaculation | 0.83 | 1.10 | 1.78 | 3.05 | Finasteride, combination |
| Decreased libido | 1.40 | 1.56 | 2.36 | 2.51 | Finasteride, combination |
| Dizziness | 2.29 | 4.41 | 2.33 | 5.35 | Doxazosin, combination |
| Postural hypotension | 2.29 | 4.03 | 2.56 | 4.33 | Doxazosin, combination |
| Asthenia | 2.06 | 4.08 | 1.56 | 4.20 | Doxazosin, combination |
| Peripheral edema | 0.66 | 0.88 | 0.72 | 1.25 | Combination |
| Dyspnea | 0.57 | 0.93 | 0.56 | 1.20 | Combination |
Breast cancer was diagnosed in four men who received finasteride alone or with doxazosin, which the authors attributed to chance because two other finasteride trials found no significant excess.[1] In the Brief Male Sexual Function Inventory analysis of 2,783 men, sexual function declined over time in every group; finasteride and the combination produced slight but significant worsening of ejaculatory function versus placebo, the combination also worsened erectile function and sexual problem assessment, and doxazosin alone did not differ from placebo in any domain.[5] First reports of dizziness, orthostatic hypotension, weakness, impotence, decreased libido and abnormal ejaculation were most frequent in year 1 in every group; in the combination group, year-1 rates were 3.4-fold to 10.6-fold higher than later rates.[6]
Limitations
The composite endpoint was dominated by symptom-score increases (78% of events), and the retention and surgery effects rest on small counts: 18 retention events and 40 men with invasive therapy in the placebo group. The protocol did not standardize indications for invasive therapy, which may have varied by site.[1]
The population was men aged 62.6 years on average, 82.3% of them white, with no prior BPH treatment and a PSA of 10 ng/mL or less; median prostate volume was 31.0 mL.[1] The alpha-blocker was doxazosin and the 5-alpha-reductase inhibitor was finasteride. The 4-year cumulative incidences come from the 75% of men with at least 4 years of follow-up.[1] The National Institutes of Health funded the trial with Merck and Pfizer; the paper discloses author equity holdings, consulting fees and honoraria from Merck and Pfizer and grant support from Merck.[1] The volume-stratified finasteride analysis used cutpoints that were not prespecified.[3]
In conversation
- Built on by CombAT (2010). Designed after MTOPS to test dutasteride plus tamsulosin in men with larger prostates and higher PSA, without a placebo arm.
CombAT tested dutasteride with tamsulosin, whereas MTOPS used doxazosin with finasteride in men with no minimum prostate size.[1] EAU 2026 states that the 1-year MTOPS results, like earlier 6-to-12-month trials, showed no advantage of combination over the alpha-blocker alone, and that this may reflect different inclusion and exclusion criteria and baseline characteristics than CombAT, in which combination was superior from month 9.[7]
Guidelines and approvals
- AUA (2026). For men with LUTS/BPH and an estimated prostate volume above 30 cc and/or PSA above 1.5 ng/mL, clinicians should offer a 5-alpha-reductase inhibitor in combination with an alpha-blocker as a treatment option . The rationale cites MTOPS for lower rates of urinary retention and progression to surgery.[8]
- EAU (March 2026). Offer combination treatment with an alpha-1 blocker and a 5-alpha-reductase inhibitor to men with moderate-to-severe LUTS and an increased risk of disease progression (for example prostate volume above 40 mL) . The guideline rates the MTOPS findings level of evidence 1b and advises combination only when treatment longer than 12 months is intended.[7]
Report history
| Published | Report | Cutoff | Headline results | Citation |
|---|---|---|---|---|
| 2003-12-18 | Primary report (mean 4.5 years) · primary | — | Overall clinical progression, events per 100 person-years over the study (any of: confirmed AUA symptom score rise of 4 or more points, acute urinary retention, incontinence, renal insufficiency, recurrent UTI or urosepsis): 4.5 (128 events, n=737) vs 2.7 (85 events, n=756) vs 2.9 (89 events, n=768) vs 1.5 (49 events, n=786); P <0.001 for combination versus placebo Met Combination therapy versus each single drug, overall clinical progression over the study: Doxazosin and finasteride did not differ significantly from each other. The protocol did not specify active-versus-active comparisons; they used a Bonferroni-adjusted threshold of P<0.0167. Number needed to treat to prevent one progression event over 4 years: 8.4 for combination, 13.7 for doxazosin, 15.0 for finasteride.; P <0.001 for combination versus doxazosin and for combination versus finasteride Cumulative incidence of overall clinical progression at 4 years, among the 75% of men with at least 4 years of follow-up: 17% (95% CI 14 to 20; 122 events) vs 10% (8 to 12; 73 events) vs 10% (8 to 13; 78 events) vs 5% (4 to 7; 42 events); P <0.001 for combination versus placebo Confirmed AUA symptom score increase of 4 or more points, events per 100 person-years: 3.6 vs 1.9 vs 2.5 vs 1.3; — Acute urinary retention, events per 100 person-years over the study: 0.6 (18 events) vs 0.4 (9 events by year 4) vs 0.2 (6 events) vs 0.1 (4 events); P 0.009 finasteride and <0.001 combination, each versus placebo Invasive therapy for BPH, events per 100 person-years over the study: 1.3 (40 men) vs 1.3 vs 0.5 vs 0.4; P <0.001 for finasteride and for combination, each versus placebo Mean reduction in AUA symptom score at 4 years: 4.9 vs 6.6 vs 5.6 vs 7.4; P <0.001 for doxazosin and combination, 0.001 for finasteride, each versus placebo over the study Met Median change in maximal urinary flow rate at 4 years, mL per second: +1.4 (n=519) vs +2.5 (n=567) vs +2.2 (n=551) vs +3.7 (n=574); P <0.001 for each active group versus placebo over the study Met Median change in serum PSA at 4 years, percent: +15% (n=618) vs +13% (n=655) vs -50% (n=631) vs -50% (n=673); — Descriptive Median change in transrectal ultrasound prostate volume after a mean 4.5 years: Placebo or doxazosin (1,148 men): median increase of 24%. Finasteride or combination in men with large baseline glands (427 men): median decrease of 19%.; — Descriptive Number needed to treat over 4 years for overall clinical progression in men with PSA above 4.0 ng/mL (20% of men) or baseline prostate volume above 40 mL (30% of men): Preplanned secondary analysis. For progression: 4.7 (PSA above 4.0) and 4.9 (volume above 40 mL) with combination, 7.2 in both subgroups with finasteride. For invasive therapy with combination: 23.1 and 15.9. Baseline PSA and prostate volume predicted progression in the placebo and doxazosin groups but not in the finasteride or combination groups.; — | McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. *N Engl J Med.* 2003;349(25):2387-2398. doi:10.1056/NEJMoa030656 DOI |
| 2006 | Baseline prostate volume of 25 mL or more · secondary | — | Clinical progression, need for invasive therapy, symptom score and maximal flow by baseline total prostate volume (under 25 mL, 25 to under 40 mL, 40 mL or more): Under 25 mL, combination was no better than doxazosin alone on any of these outcomes. At 25 to under 40 mL and at 40 mL or more, combination was superior to doxazosin or finasteride alone. The abstract gives no event counts.; — | Kaplan SA, McConnell JD, Roehrborn CG, et al. Combination therapy with doxazosin and finasteride for benign prostatic hyperplasia in patients with lower urinary tract symptoms and a baseline total prostate volume of 25 ml or greater. *J Urol.* 2006;175(1):217-220. doi:10.1016/S0022-5347(05)00041-8 DOI |
| 2011-02-22 | Finasteride versus placebo by prostate volume · post-hoc | — | Cumulative percentage without clinical progression at study end, baseline prostate volume 30 mL or more (finasteride versus placebo): 77.8% (95% CI 72.5 to 82.1; n=288) vs 88.1% (83.9 to 91.3; n=295); P <0.001 Cumulative percentage without clinical progression at study end, baseline prostate volume under 30 mL (finasteride versus placebo): 89.1% (95% CI 84.8 to 92.3; n=276) vs 91.4% (87.5 to 94.2; n=280); P 0.367 Mean change in AUA symptom score from baseline to study end, baseline volume 30 mL or more (intention to treat): -4.65 (n=288) vs -5.69 (n=295); P 0.045 Mean change in maximal urinary flow rate from baseline to study end, mL per second, baseline volume 30 mL or more (intention to treat): +1.78 (n=282) vs +3.31 (n=290); P 0.002 Mean change in prostate volume from baseline to study end, mL, baseline volume 30 mL or more (intention to treat): +9.38 (n=288) vs -5.79 (n=295); P <0.001 | Kaplan SA, Lee JY, Meehan AG, et al. Long-term treatment with finasteride improves clinical progression of benign prostatic hyperplasia in men with an enlarged versus a smaller prostate: data from the MTOPS trial. *J Urol.* 2011;185(4):1369-1373. doi:10.1016/j.juro.2010.11.060 DOI |
| 2013-01-25 | Quality of life through 4 years · pro | — | Quality-of-life instruments over 4 years versus placebo: Doxazosin and combination improved the BPH Impact Index at year 4; each drug group improved the IPSS quality-of-life score. Longitudinal BPH Impact Index and IPSS quality-of-life scores improved in all drug groups. No group differed from placebo on the SF-36 subscales or summary scores. The abstract gives no scores.; — | Fwu CW, Eggers PW, Kaplan SA, et al. Long-term effects of doxazosin, finasteride and combination therapy on quality of life in men with benign prostatic hyperplasia. *J Urol.* 2013;190(1):187-193. doi:10.1016/j.juro.2013.01.061 DOI |
| 2013-12-14 | Sexual function through 4 years · pro | — | Change in sexual function over 4 years versus placebo: Sexual function declined over time in all groups. Finasteride and combination had slight but significant worsening of ejaculatory function versus placebo; combination also had significant worsening of erectile function and sexual problem assessment. Doxazosin alone did not differ from placebo in any domain. The abstract gives no scores.; — | Fwu CW, Eggers PW, Kirkali Z, et al. Change in sexual function in men with lower urinary tract symptoms/benign prostatic hyperplasia associated with long-term treatment with doxazosin, finasteride and combined therapy. *J Urol.* 2014;191(6):1828-1834. doi:10.1016/j.juro.2013.12.014 DOI |
| 2015-12-08 | Time course of adverse experiences · secondary | — | Incidence of first reports of dizziness, orthostatic hypotension, weakness, impotence, decreased libido and abnormal ejaculation at year 1 versus later years: In every treatment group, incidence was significantly higher at year 1 than afterward. In the combination group, year-1 rates were 3.4-fold to 10.6-fold higher than later rates. At year 1, orthostatic hypotension and dizziness were higher with doxazosin and combination than placebo, and the three sexual adverse experiences were higher with finasteride and combination than placebo. The abstract gives no rates.; — | Kaplan SA, Lee JY, Meehan AG, et al. Time course of incident adverse experiences associated with doxazosin, finasteride and combination therapy in men with benign prostatic hyperplasia: the MTOPS trial. *J Urol.* 2016;195(6):1825-1829. doi:10.1016/j.juro.2015.11.065 DOI |
References
1. McConnell JD, Roehrborn CG, Bautista OM, et al. "The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia." N Engl J Med. 2003;349(25):2387-2398. doi:10.1056/NEJMoa030656
2. Kaplan SA, McConnell JD, Roehrborn CG, et al. "Combination therapy with doxazosin and finasteride for benign prostatic hyperplasia in patients with lower urinary tract symptoms and a baseline total prostate volume of 25 ml or greater." J Urol. 2006;175(1):217-220. doi:10.1016/S0022-5347(05)00041-8
3. Kaplan SA, Lee JY, Meehan AG, Kusek JW. "Long-term treatment with finasteride improves clinical progression of benign prostatic hyperplasia in men with an enlarged versus a smaller prostate: data from the MTOPS trial." J Urol. 2011;185(4):1369-1373. doi:10.1016/j.juro.2010.11.060
4. Fwu CW, Eggers PW, Kaplan SA, et al. "Long-term effects of doxazosin, finasteride and combination therapy on quality of life in men with benign prostatic hyperplasia." J Urol. 2013;190(1):187-193. doi:10.1016/j.juro.2013.01.061
5. Fwu CW, Eggers PW, Kirkali Z, et al. "Change in sexual function in men with lower urinary tract symptoms/benign prostatic hyperplasia associated with long-term treatment with doxazosin, finasteride and combined therapy." J Urol. 2014;191(6):1828-1834. doi:10.1016/j.juro.2013.12.014
6. Kaplan SA, Lee JY, Meehan AG, Kusek JW. "Time course of incident adverse experiences associated with doxazosin, finasteride and combination therapy in men with benign prostatic hyperplasia: the MTOPS trial." J Urol. 2016;195(6):1825-1829. doi:10.1016/j.juro.2015.11.065
7. Cornu JN, Elterman D, Hashim H, et al. EAU Guidelines on Non-Neurogenic Male Lower Urinary Tract Symptoms (LUTS). Arnhem: EAU Guidelines Office; March 2026. Section 5.2.7.a.
8. Goueli R, Badlani GH, Welliver C, et al. "Management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: AUA guideline (2026) Part II: medical management." J Urol. 2026;216(2):152-160. doi:10.1097/JU.0000000000005098