CombaT: (Combination of Avodart and Tamsulosin)

In Review

Roehrborn CG, et al. "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. 51(1):123-131.
PubMed • Full text

Clinical Question

In men with benign prostatic hyperplasia, is treatment with a combination of dutasteride and Tamsulosin more effective than with either drug given as a monotherapy in reducing the time to acute urinary retention or surgical treatment of BPH?

Bottom Line

Combination therapy provides better symptom relief than either medication provided as a monotherapy, at four years

Major Points

Benign Prostatic Hyperplasia (BPH) is common in older men and adversely affects quality of life. First line treatment is by medical management with 5-aplha reductase inhibitors (5-ARIs) and alpha blockers being among the choices available. This study investigates if a combination of these two drug classes (Dutasteride and Tamsulosin) provides better outcomes for patients when compared with either drug given as a monotherapy.

Overall, combination therapy failed to meet the primary endpoint of reducing the time from treatment to Acute Urinary Retention (AUR) or surgical treatment for BPH. Combination therapy was effective in secondary outcomes such as BPH clinical progression, IPSS health status, urinary flow rates and prostate volume reduction.

Of note, the MTOPS study examined a similar combination of therapies for treatment of BPH.

Guidelines

Guidelines for the treatment of Benign Prostatic Hyperplasia, provided by the American Urological Association refer to the following options for treatment of moderate to severe symptoms of BPH:

• Watchful waiting
• Medical Therapies
  • Alpha blockers
  • 5-alpha-reductase inhibitors (5-ARIs)
  • Combination therapy
  • Anticholinergic agents
• Complementary and alternative medicines (CAM) - Not recommended
• Minimally invasive techniques
• Surgical therapies

"Option: The combination of an alpha-blocker and a 5-ARIs (combination therapy) is an appropriate and effective treatment for patients with LUTS associated with demonstrable prostatic enlargement based on volume measurement, PSA level as a proxy for volume, and/or enlargement on DRE.”

Comination therapy, as tested in this trial, is on the conservative end of the treatment options for this condition.

Design

• Multinational, multicentre, randomised, double-blind, parallel group
• N= 4844 randomised
  • Combination: n=1610
  • Dutasteride: n=1623
  • Tamsulosin: n=1611
• Setting: The study is being conducted in Europe, North America, Latin America, and Asia Pacific.
• Enrolment: completed in 2005.
• Mean follow-up: Four years reported in this paper
• Analysis: intention-to-treat
• Primary outcome: time to first event of AUR (acute urinary retention) or BPH related surgery.

Population

Inclusion Criteria

• Males, aged ≥50 years
• Clinical diagnosis of BPH by medical history and physical examination, including a DRE
• IPSS ≥12 points at screening
• PV ≥30 cm3 by TRUS
• Total serum PSA ≥1.5 ng/mL at screening
• Qmax >5 mL/s and ≤15 mL/s and minimum voided volume of ≥125 mL at screening (based on two voids)
• Willing and able to give written informed consent and comply with study procedures
• Fluent and literate in local language with the ability to read, comprehend and record information on the IPSS, BII and PPSM questionnaires.

Exclusion Criteria

• Total serum PSAN10.0 ng/mL at screening
• History or evidence of prostate cancer. Patients with suspicious ultrasound or DRE who have had a negative biopsy within the preceding

6 months and stable PSA are eligible for the study

• Previous prostatic surgery or other invasive procedures to treat BPH
• History of flexible/rigid cystoscopy or other instrumentation of the urethra within 7 days prior to the screening visit
• History of AUR within 3 months prior to screening visit
• Post-void residual volume N250 mL (suprapubic ultrasound) at screening
• Use of any 5ARI, any drugs with antiandrogenic properties or other drugs noted for gynecomastia effects, or could affect PV, within past

6 months of the historical TRUS or screening visit and throughout the study (other than as study medication). Previous use of dutasteride should not be within 12 months of the baseline or historical TRUS. Chronic use of metronidazole is prohibited

• Use of phytotherapy for BPH within 2 weeks of screening visit and/or predicted to need phytotherapy during the study
• Use of any α-adrenoreceptor blockers within 2 weeks of screening visit and/or predicted to need any α blockers other than tamsulosin during the study
• Use of any α-adrenoreceptor agonists or anticholinergics or cholinergics within 48 h prior to all uroflowmetry assessments
• History of postural hypotension, dizziness, vertigo or any other signs and symptoms of orthostasis, which in the opinion of the investigator could be exacerbated by tamsulosin and result in putting the subject at risk of injury

Baseline Characteristics

Baseline characteristics did not differ substantially between the three treatment groups. Details for the combination group are listed below:

• Mean age: 66
• White ethnicity: 88%
• Mean IPSS score: 16.6
• Mean prostate volume: 54.7
• Mean PSA: 4
• Mean QMax: 10.9
• Mean post void residual volume: 68.2
• Sexually active: 73%
• Previous alpha-blocker use: 50%
• Previous 5-ARI use: 11%

Interventions

• Randomized to one of:
  • Combination - 0.5 mg dutasteride once daily + 0.4 mg tamsulosin once daily
  • Dutasteride - 0.5 mg dutasteride once daily + placebo tamsulosin
  • Tamsulosin - 0.4 mg tamsulosin once daily + placebo dutasteride

Outcomes

Primary Outcomes

Undergoing BPH-related surgery at 4 years

The time to first AUR or BPH-related surgery was significantly lower with combination therapy versus tamsulosin (p <0.001); there was no significant difference between combination therapy and dutasteride (p = 0.18).

Secondary Outcomes

Benign prostatic hyperplasia clinical progression

Time to first BPH clinical progression was significantly different in favour of combination therapy versus tamsulosin and dutasteride ( p < 0.001 for both comparisons). Combination therapy reduced the relative risk of BPH clinical progression by 44.1% compared with tamsulosin and 31.2% compared with dutasteride.

Change in International Prostate Symptom Score and benign prostatic hyperplasia-related health status (question 8)

Combination therapy provided a greater change in IPSS scores at four years (-6.3) than either tamsulosin (-3.8, p<0.001) or dutasteride (-5.3, p<0.001).

International Prostate Symptom Score responders (≥25% and ≥3-point improvement)

The proportions of men with an IPSS response ≥25% at month 48 were 67%, 52%, and 61% in the combination, tamsulosin, and dutasteride groups, respectively ( p < 0.01 for combination versus each monotherapy).

At month 48, the proportions of men with a ≥3-point IPSS improvement were 71%, 59% and 66% in the combination, tamsulosin, and dutasteride groups, respectively ( p < 0.01 for combination versus each monotherapy).

Maximum urinary flow rate

At month 48, the adjusted mean increase in Qmax from baseline was 2.4 ml/s for combination therapy versus 0.7 ml/s ( p < 0.001) for tamsulosin and 2.0 ml/s ( p = 0.05) for dutasteride (Fig. 5). These changes in Qmax resulted in mean values at month 48 of 13.3, 11.5, and 12.8 ml/s in the combination, tamsulosin, and dutasteride groups, respectively.

Total and transition zone prostate volume

At month 48, the adjusted mean percentage change from baseline in total prostate volume was 27.3% for combination therapy, +4.6% ( p < 0.001) for tamsulosin, and 28.0% ( p = 0.42) for dutasteride. At month 48, the adjusted mean percentage change from baseline in transition zone volume in a subset of 656 menwas 17.9% for combination therapy, +18.2% ( p < 0.001) for tamsulosin, and 26.5% ( p = 0.053) for dutasteride.

Adverse Events

• There was no statistically significant difference in the incidence of "Any adverse event" reported across the three treatment groups.
• Adverse events considered to be drug related occurred more frequently in the combination treatment group (p<0.001).
• The incidence of the composite term cardiac failure was higher in the combination (14 of 1610; 0.9%) and tamsulosin monotherapy (10 of 1611; 0.6%) groups than in the dutasteride group (4 of 1623; 0.2%).
• Prostate cancer was reported as an adverse event in 142 men: 37 (2.3%) in the combination group, 42 (2.6%) in the dutasteride group, and 63 (3.9%) in the tamsulosin group.
• Serum PSA decreased from baseline by a median of 57.1% and 56.0% in the combination and dutasteride groups, respectively, and increased by 18.4% in the tamsulosin group.

Criticisms

• The trial lacked a placebo control group
• The study recruited men with a higher prostate volume than is typically seen.
• Possibly could account for competing risks in the analysis, given the long follow up and the age of men recruited.

Funding

• GlaxoSmithKline, who own and market Dutasteride and combination therapies. Funding extended to consultancies of listed authors, together with speaking appointments and employment. Funding included a contractor to draft and edit the manuscript. This may account for the use of trade names in describing the drug treatments in some places within the manuscript.