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Benign Prostatic Hyperplasia: Emerging Findings on Combination Therapeutic Strategies

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

29th Congress of the Société Internationale d’Urologie (SIU)

Paris, France / September 2-6, 2007

According to Dr. Claus Roehrborn, Chair, Department of Urology, University of Texas Southwestern Medical Center, Dallas, the most important finding from the pre-planned two-year interim analysis of the Combination of Avodart and Tamsulosin (CombAT) study is that combination therapy with those agents is significantly superior to either drug alone for improving urinary symptoms of benign prostatic hyperplasia (BPH). He indicated that combination therapy resulted in significantly greater symptom relief than dutasteride monotherapy from month 3, tamsulosin monotherapy from month 9 and significantly greater improvement in peak urinary flow (Qmax) vs. dutasteride and tamsulosin monotherapies from month 6. Moreover, “The benefit was sustained throughout the first two years of treatment.” He added that this trend seemed like it could continue heading into the second half of the four-year trial.

CombAT is an ongoing multicentre, randomized, double-blind, parallel-group trial which enrolled 4844 men aged 50 years or older into three cohorts:1623 to the 5-alpha reductase inhibitor (5ARI) dutasteride 0.5 mg, 1611 to the alpha-blocker tamsulosin 0.4 mg and 1610 to the combination of both given once daily. Dr. Roehrborn reported that to be eligible for enrolment, patients had to have prostate volume >30 cc by transrectal ultrasound (TRUS) and serum prostate-specific antigen (PSA) >1.5 ng/mL but less then 10. Other prerequisites were Qmax between 5 and 15 mL/sec, a minimum voided volume of 125 mL or greater and an International Prostate Symptom Score (IPSS) of at least 12 points.

The primary end point was IPSS change from baseline in all three arms of the study. The IPSS questionnaire assesses lower urinary tract symptoms (LUTS), including incomplete emptying, frequency, hesitancy, urgency, weak stream, intermittency and nocturia.

Results After Two Years

“Men given combination therapy had a significantly greater (P<0.001) symptom benefit on the IPSS than those receiving either dutasteride or tamsulosin alone from the first visit until the two-year time point,” Dr. Roehrborn reported. “The significant symptom relief achieved after three months of combination therapy was not matched in either of those monotherapy arms until month 15 of therapy... The CombAT study is the first to have demonstrated a greater benefit for combination treatment compared to either monotherapy in the first 12 months of treatment” (Figure 1).

He indicated that patients in the alpha-blocker arm achieved a benefit of 4.5 points on the IPSS scale at three months which was maintained throughout the duration until the 24-month interim analysis. The dutasteride-treated men achieved an almost three-point improvement by three months, but then caught up with the tamsulosin group at approximately one year to 15 months and thereafter obtained an even greater symptom benefit that became statistically significant at 21 months. Yet combination-treated patients achieved the greatest benefit, which became apparent at the first assessment, and achieved statistical significance against the 5ARI alone at three months and against the alpha-blocker at nine months.

“With such an improvement in our primary outcome, there is no question that combination therapy among these patients who were at high risk for disease progression with a large prostate and severe LUTS provided the greatest benefit throughout the duration of the trial,” Dr. Roehrborn told delegates. PSA decreased by a median of 56% and 55% in the combination and 5ARI groups, respectively, and increased by 12.5% in the alpha-blocker monotherapy cohort.

Regarding Qmax, Dr. Roehrborn told the audience that tamsulosin achieved an early gain of 1.2 mL/sec in the first six months which dropped off to 1 mL/sec for the remaining 18 months. “Dutasteride excelled above and beyond the tamsulosin group with an improvement starting at 1.2 mL/sec at six months and then rising up to 1.9 mL/sec at 24 months. The combination group benefited most with a 2 mL/sec improvement at six months and reached 2.4 mL/sec at 24 months.” He added, “This is the first study to show a numerical superiority of dutasteride or any 5ARI monotherapy over an alpha-blocker for symptoms and Qmax at 21 months and 12 months, respectively, onward.”

The 5ARI dutasteride works by inhibiting the conversion of testosterone into dihydrotestosterone (DHT). As the only dual-acting agent of its class, it is a competitive and specific inhibitor of both types 1 and 2 isoforms of 5-alpha reductase, and thus capable of significantly suppressing DHT production to 93.7% (Roehrborn et al. Urology 2002;60:434-41). It begins shrinking the prostate and alleviating symptoms in as early as one month of treatment onset.

Figure 1. CombAT: IPSS Score at Two Years in ITT Population


MTOPS and CombAT Analysis

Dr. Jack Barkin, Assistant Professor of Surgery, Division of Urology, University of Toronto, Ontario, highlighted the differences between CombAT and the earlier landmark Medical Therapy of Prostate Symptoms (MTOPS) study, in which combined finasteride/doxazosin was compared to the same drugs given individually. He noted that MTOPS had no prostate volume-based inclusion criteria, and that only a subset of men in the trial were at increased risk of progression by virtue of a prostate volume of 30 cc or greater and/or a PSA >1.5 ng/mL. Moreover, he added, the prostate transition zone was very much smaller, and that no prospective analysis of the potential benefit of combination therapy was conducted.

MTOPS led the way to further studies of combination therapy, employing the type 2-selective 5ARI finasteride. Yet the more recently developed 5ARI dutasteride attains a greater degree and consistency of DHT suppression than finasteride, is 45-fold more effective in inhibiting type 1 5-alpha-reductase and 2.5-fold more effective in inhibiting type 2 (Tian et al. Biochemistry 1995;34:13453-9). In MTOPS, the median decrease in American Urological Association Symptom Index score was greater with doxazosin than finasteride at years 1 and 4. In contrast, mean symptom score reductions in the dutasteride and tamsulosin groups in CombAT were identical at month 15, and were greater in the dutasteride group at month 18 and thereafter. This difference in outcome is likely due in part to the potentially greater overall risk of progression in BPH populations characterized by increased prostate volume and higher PSA levels.

“This post-hoc analysis demonstrated that in men with BPH, the symptom improvement of dutasteride is more durable than that of tamsulosin,” Dr. Barkin indicated.

He noted that a similar proportion of patients in each treatment group reported adverse events in both overall incidence of adverse events and serious adverse events, which were recorded every three months. The safety profile of combination therapy was found to be similar to the monotherapies. However, drug-related events were more common with combination therapy (24%) than with the monotherapies (dutasteride 18%, tamsulosin 16%). The most common adverse events were erectile dysfunction in 7.4%, 6.0% and 3.8%, respectively, followed by retrograde ejaculation in 4.2%, 0.6% and 1.1%, and decreased libido in 1.7%, 1.3% and 0.9%. No statistically significant differences were observed for combination therapy vs. monotherapy with either agent in clinical, laboratory or vital sign thresholds, or digital rectal exam changes.

A small proportion of CombAT patients (58 in total) were diagnosed with prostate cancer during the first two years of the study. Of these, 21 were in the combination group, 11 in the 5ARI group and 26 in the alpha-blocker group.

Summary

Dr. Francesco Montorsi, President, European Society for Sexual Medicine and Professor of Urology, Vita-Salute San Raffaele University, Milan, Italy, declared that it makes good sense to combine agents with dissimilar mechanisms of action, as is commonly done in other fields of medicine, and that such combinations are poised to significantly affect future BPH treatment strategies. He concluded that the various messages from the CombAT study are clear: combination therapy is better than either compound used alone for IPSS symptoms; the study population is at a clinically relevant risk of progression; and combination therapy has a positive impact on peak flow.

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