Monotherapy
Finasteride is the most extensively studied 5ARI. Boyle et al. performed a meta-analysis of six randomized, placebo-controlled clinical trials [
12]. The most significant finding was a positive correlation between mean baseline prostate volume and mean change in symptom score or
Q
max. Symptoms decreased by 1.8 points on the Quasi-International Prostate Symptom Score (IPSS) Scale and
Q
max increased by 0.9 ml/s in men with prostate volumes < 20 ml compared with 2.8 points and 1.8 ml/s for men with prostate volumes > 60 ml [
12]. The difference between finasteride and placebo becomes significant for men, with a baseline prostate volume of > 40 ml. Following this meta-analysis, the outcomes of the 4-year Proscar Long-term Efficacy and Safety Study (PLESS) were released [
13]. Finasteride reduced prostate volume by 18% compared with an increase of 14% with placebo, improved symptom scores (3.3 points vs. 1.3 for placebo) and increased
Q
max (1.9 vs. 0.2 ml/s for placebo) [
13].
The combined analysis of the AUA-BPH Guidelines Panel found that finasteride leads to an IPSS improvement of 3.4 points at 12 months in both randomized placebo-controlled and open-label extension studies [
14]. Symptom improvement is durable for up to 6 years in patients who maintained treatment. In addition, finasteride achieves a sustained
Q
max improvement of approximately 2 ml/s. In most trials, 5ARIs are slightly less effective than α-blockers.
More recently, data from the monotherapy arm of the Medical Therapy of Prostatic Symptoms (MTOPS) study showed that prostate volume decreased by a median of 19% in patients receiving finasteride when compared with 24% increase in those receiving placebo [
15]. Significant improvements over time in the IPSS and
Q
max occurred in all monotherapy groups compared with the placebo group.
The clinical efficacy of dutasteride was evaluated in the three pivotal, 2-year, randomized, double-blind, placebo-controlled phase III trials [
16]. Pooled analysis of these studies included 4,325 men and showed that dutasteride achieved a 4.5-point IPSS reduction resulting in a net difference of 2.2 points compared with placebo.
Q
max improved significantly in the dutasteride group from 1 month, with an increase of 2.2 ml/s reported at 24 months (compared with 0.6 in the placebo group). A 26% reduction in prostate volume relative to placebo was found, with significant reductions from 1 month after treatment initiation and continuation until study end-point at 2 years. Following the completion of the blinded phase, 2,340 men entered the open-label, 24-months extension trial [
17]. Dutasteride further reduced IPSS significantly; at the end of the 48-month trial, IPSS was reduced by 6.5 points in men who received dutasteride during the entire study period and by 5.6 points in men who were initially treated with placebo and later with dutasteride. In contrast to previous findings with finasteride, there was no difference in the efficacy between prostate volumes 30–39 and ≥ 40 ml.
In a 12-month, randomized, comparative study, the Enlarged Prostate International Comparator Study (EPICS), 1,630 patients older than 50 years were randomized to dutasteride (
n = 813) or finasteride (
n = 817) [
18]. After 1 year of treatment, prostate volume reduction from baseline was similar in both groups at 27.4%. Improvements in IPSS (6.2 vs. 5.8) and
Q
max (2.1 vs. 1.8 ml/s) were greater for dutasteride than finasteride, but not statistically significant.
Combination therapy
It is reasonable to assume that the combination of a 5ARI and α-blocker, which have different and complementary modes of action, would potentially maximize treatment response. However, the first randomized, placebo-controlled trials with a follow-up ≤ 12 months did not report superiority of combination treatment. Both the PRospective European DoxazosIn and Combination Therapy (PREDICT) trial (using doxazosin and/or finasteride) and the Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study (using terazosin and/or finasteride) showed that combination therapy was superior to 5ARI monotherapy, but failed to demonstrate a significant benefit over α-blocker monotherapy [
19,
20]. The MTOPS Study with a follow-up of > 4 years was conducted to address the question of long-term benefit [
15]. Although it was designed as a progression trial, MTOPS demonstrated that long-term combination therapy is superior to either α-blocker or 5ARI monotherapy in improving LUTS and
Q
max. The 4-year mean reduction in IPSS was 4.9, 6.6, 5.6, and 7.4 in the placebo, doxazosin, finasteride, and combination therapy groups, respectively. Similarly, the mean improvement in
Q
max was 2.8, 4.0, 3.2, and 5.1 ml/s, respectively. IPSS decrease and
Q
max increase in either active treatment was significantly better than placebo, doxazosin was significantly better than finasteride, and combination treatment was significantly better than either monotherapy.
The Combination of Avodart and Tamsulosin (CombAT) trial compared the efficacy of dutasteride and tamsulosin alone with the efficacy of combination therapy in men with larger prostates (> 30 ml) and higher serum PSA concentrations (1.5–10 μg/l) [
21]. However, the trial did not have a placebo arm. In the pre-planned 2-year analysis, the combination treatment provided a significantly greater improvement in symptoms than either monotherapy alone [
21]. At 2 years, the mean decrease from baseline IPSS was 6.2 with combination therapy, 4.9 with dutasteride, and 4.3 with tamsulosin. A statistically significant difference was achieved for combination therapy over dutasteride alone from month 3 and over tamsulosin alone from month 9. A combination therapy was also significantly more effective than either monotherapy in improving
Q
max at month 6 throughout month 24. The adjusted mean
Q
max increase in the combination group was 2.4 ml/s and significantly greater than for dutasteride and tamsulosin (1.9 and 0.9 ml/s, respectively). The adjusted mean decrease from baseline prostate volume was 26.9% in the combination therapy group and 28.0% in the dutasteride group but unchanged for tamsulosin-treated patients.
Post hoc analyses of 2-year data from the CombAT study provided useful insights into the impact of several baseline parameters on changes of IPSS and
Q
max [
22]. It was found that combination therapy was more effective than tamsulosin or dutasteride monotherapy alone in improving IPSS and
Q
max after 2 years regardless of baseline parameters [
22]. When compared with tamsulosin, dutasteride showed greater IPSS improvement in certain subgroups, most notably in those men with values higher than the median: IPSS > 16, prostate volume > 49 ml, PSA > 3.5 μg/l, and IPSS-QoL score ≥ 4. In addition, dutasteride alone or in combination was associated with significantly greater improvements in
Q
max compared with tamsulosin.
The 4-year data of the CombAT study has been published recently [
23]. For patients who completed the study period, mean change in IPSS from baseline to year 4 was significantly higher for the combination therapy compared with tamsulosin or dutasteride alone (−7.3, −4.9, −6.4, respectively). Decrease in IPSS-QoL score was significantly greater for the combination treatment (−1.5) compared with tamsulosin (−1.1) or dutasteride (−1.3).
Q
max improvement was significantly higher for combination treatment (2.4 ml/s) compared with tamsulosin (0.7 ml/s) or dutasteride (2 ml/s). There was a tendency towards a continuous decrease in IPSS and continuous increase in
Q
max for dutasteride monotherapy and combination treatment over time, whereas both parameters worsened again during tamsulosin treatment after 15–18 months. Interestingly, postvoid residual urine significantly decreased in the treatment arms containing dutasteride, but not with tamsulosin alone. Table
2 displays the key RCTs with 5ARIs.
Table 2
Key randomized trials with 5α-reductase inhibitors in men with benign prostatic enlargement and LUTS
| 24 | Placebo | 2,109 | | | | | | 1b |
Finasteride | 2,113 | NA | NA | NA | −34c
| −57c
|
| 48 | Placebo | 1,503 | −1.3 | +0.2 | +14.0 | | | 1b |
Finasteride | 1,513 | −3.3c
| +1.9c
| −18.0c
| −55c
| −57c
|
| 54 | Placebo | 737 | −4.0 | 1.4 | +24.0 | | | 1b |
Doxazosin | 756 | −6.0c
| 2.5c
| +24.0 | −3 | −35 |
Finasteride | 768 | −5.0c
| 2.2c
| −19.0c,d
| −64c,d
| −68c,d
|
Combination | 786 | −7.0c,d,e
| 3.7c,d,e
| −19.0c,d
| −67c,d
| −81c,d
|
| 24 | Placebo | 2,158 | −2.3 | 0.6 | +1.5 | | | 1b |
Dutasteride | 2,167 | −4.5c
| 2.2c
| −25.7c
| −48c
| −57c
|
| 24 | Tamsulosin | 1,611 | −4.3 | 0.9 | 0.0 | | | 1b |
Dutasteride | 1,623 | −4.9 | 1.9 | −28.0 | NA | NA |
Combination | 1,610 | −6.2d,e
| 2.4d,e
| −26.9d
| NA | NA |
| 48 | Tamsulosin | 1,611 | −3.8 | 0.7 | +4.6 | | | 1b |
Dutasteride | 1,623 | −5.3 | 2.0 | −28.0d
| −31.1d
| −18.3d
|
Combination | 1,610 | −6.3d,e
| 2.4d,e
| −27.3d
| −70.6d
| −67.6d
|