Combination treatment with tamsulosin and dutasteride was superior to monotherapy with either compound in reducing benign prostatic hyperplasia (BPH) symptoms as well as the risk for disease progression. The combination is also most beneficial for patients with larger prostates, a review published in the journal Therapeutic Advances in Urology reported.
The study, by Konstantinos Dimitropoulos and Stavros Gravas from the University of Thessaly, Greece, offered an overview of evidence from various clinical trials on the benefits of combination therapy. The article, “Fixed-dose combination therapy with dutasteride and tamsulosin in the management of benign prostatic hyperplasia,“ clearly shows that combination treatment is the more effective approach than treatment with tamsulosin or dutasteride separately.
These drugs exert their actions through different mechanisms — tamsulosin is a blocker of the adrenergic α1 receptor, and dutasteride is a 5α reductase inhibitor (5αRI). Drugs using different approaches to reach the same goal are often ideal for combination treatment, achieving synergistic effects while holding adverse effects to a low rate.
Early clinical trials investigating the combination of these drug classes, compared to respective monotherapies, showed them superior to 5αRI treatment but not to therapy with an α-blocker. But these trials were criticized for being too short, and longer trials were soon initiated. The MTOPS trial explored combination treatment with doxazosin and finasteride — an α-blocker and 5αRI, respectively — over four years. The trial found the combination superior to either monotherapy in reducing both symptoms and the risk of symptom deterioration. Also, the trial showed that the risk of acute urinary retention and need for surgery was reduced by both the combined treatment and by finasteride, but not by doxazosin.
The CombAT trial was the first to explore the efficacy of a tamsulosin and dutasteride combination versus monotherapy with either drug. Considering that the onset of treatment effect is slow for dutasteride, the trial had a four-year follow-up period, and included patients with moderate to severe lower urinary tract symptoms (LUTS) associated with BPH and at risk for disease progression.
This combination therapy was found superior to either as monotherapy in improving symptoms and quality of life. Likewise, the combination reduced the risk of acute urinary retention and BPH-related surgery compared to monotreatment. This study also provided evidence that a tamsulosin and dutasteride combination is superior in slowing disease progression. Importantly, the efficacy of treatment was most beneficial in men with larger prostates and higher PSA levels at treatment start.
More in-depth analyses revealed that urinary storage and voiding symptoms were reduced to a greater extent with combination treatment compared to both monotherapies. Ethnical differences in 5-αR activity, prostate volume, LUTS severity, and the levels of prostate specific antigen have been seen in several studies. CombAT, however, did not find any differences in treatment efficacy due to ethnic background.
CombAT trial results are supported by other data. A separate retrospective analysis of two nationally representative databases showed that every month of delay adding a 5α-RI to an α-blocker increased the probability of symptom progression at the end of one year. In patients where combination treatment is indicated, this meant that immediately starting with the combination or quickly adding a 5α-RI to an α-blocker is more beneficial than continuing with monotherapy.
A tamsulosin and dutasteride combination in the CombAT trial, however, was associated with a somewhat higher rate of side effects compared to either as monotherapy: 28 percent compared to 21 (tamsulosin) and 19 (dutasteride) percent, respectively. The rate of treatment discontinuation due to adverse events was nevertheless the same in all three trial groups. The most common combination side effects were erectile and ejaculatory dysfunction, and the frequency seemed to drop with duration of treatment — 12 percent during the study’s first year compared to 2 percent during year four.
A fixed capsule dose preparation of 0.5 mg dutasteride and 0.4 mg tamsulosin was approved by the U.S. Food and Drug Administration in 2010 for BPH patients with an enlarged prostate. The approval was followed by the CONDUCT trial, investigating if immediate treatment with the combination drug was better compared to watchful waiting — monitoring of symptom deterioration — or the initiation of tamsulosin. Considering that patients in this study could be randomized to watchful waiting, only patients with moderate BPH were included. In the watchful waiting group, 61 percent started tamsulosin treatment, indicating a high rate of deterioration. Results again clearly supported the combination treatment for reducing symptoms. Disease progression rate was reduced by 43 percent on the combination treatment versus watchful waiting and tamsulosin treatment alone.
While higher quality of life scores were reported by the combination group, there was no difference in treatment satisfaction among groups. As in the CombAT trial, erectile dysfunction and retrograde ejaculation were the most common side effects. This trial also found that side effects were more common on combination treatment but declined over time.
Cost-effectiveness analyses also showed fixed dose combination tablets were superior to simultaneous administration of dutasteride and tamsulosin. One analysis concluded that four years of combination therapy using the fixed dose preparation would lead to 1,758 fewer surgical procedures, and 972 fewer episodes of acute urinary retention.
The authors also noted that the fixed dose combination would likely improve adherence to treatment.
Based on the results from these trials, major societies, such as the European Association of Urology and American Urological Association, recommend tamsulosin and dutasteride combination treatment for men with moderate to severe BPH-related LUTS who are those at risk of disease progression.