Reports

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.

103rd Annual Meeting of the American Urological Association

Orlando, Florida / May 17-22, 2008

CombAT Findings

Two-year results from the ongoing Combination of Avodart and Tamsulosin (CombAT) study were presented here by separate investigators. It was designed to compare the relative effects of the combination of the 5a-reductase inhibitor (5ARI) dutasteride and the a-blocker tamsulosin in men with clinically diagnosed benign prostatic hyperplasia (BPH) vs. either agent alone. A total of 4844 men with an entry prostate volume of at least 30 cc were randomized to either dutasteride 0.5 mg/day or tamsulosin 0.4 mg/day, or the combination, for four years.

At baseline, mean prostate volumes were approximately 55 cc in all three arms, while mean International Prostate Symptom Scores (IPSS) were 16.6 in the combination arm and 16.4 in the two monotherapy arms. Baseline mean IPSS question 8 scores were identical at 3.6 in all three arms, as was the mean BPH Impact Index (BII) at 5.3. Baseline Qmax was >5 mL/s but <u><</u>15 mL/s, while the minimum voided volume was <u>></u>125 mL.

Storage and Voiding

Dr. Edgardo Becher, University of Buenos Aires, Argentina, reminded delegates that dutasteride and tamsulosin could be expected to have different effects on storage and voiding symptoms because they have different modes of action. Noting that voiding symptoms included incomplete emptying, intermittency, reduced flow and straining, Dr. Becher and colleagues observed significantly greater reductions in total IPSS score at 24 months for the combination at 6.2 points vs. 4.9 points for the dutasteride monotherapy arm and 4.3 for the tamsulosin arm (P<0.0001 vs. both dutasteride and tamsulosin). On the IPSS storage subscale, the combination produced a significantly greater reduction than either monotherapy arm at 2.2 points vs. 1.7 points for dutasteride and 1.6 points for tamsulosin (P<0.001 vs. both single-agent arms). Similarly significant reductions in voiding scores were also observed in the combination arm at 4 points vs. 3.2 for the dutasteride arm and 2.7 for the tamsulosin cohort (P<0.001 compared to both monotherapy arms).

Prostate Size and Disease Progression

Regarding change from baseline in the IPSS storage scores across prostate volume tertiles, investigators found consistently greater reductions in storage scores for the combination strategy across all prostate volume tertiles (30 to <42 cc, 42 to <58 cc and <u>></u>58 cc). The same pattern was also seen across all three tertiles of prostate volumes in voiding symptoms, where there was a 3.9-point reduction in the smallest and the medium-sized prostates in the combination arm and a 4.2-point reduction in those with the largest prostates. Comparable reductions with dutasteride were between 2.9 and 3.6 points from the smallest to the largest prostates, and between 3.2 and 2.3 points with tamsulosin. “Dutasteride also significantly reduced voiding scores compared with tamsulosin and matched tamsulosin on storage scores,” Dr. Becher added. He noted that from the 15th month onward, the difference between storage scores for tamsulosin and dutasteride was small but remained constant.

Improvement in Quality of Life

The dual 5ARI did provide greater relief in terms of voiding symptoms than tamsulosin, while for storage symptoms—including frequency, urgency and nocturia—dutasteride provided comparable relief compared with tamsulosin. Only 5% or fewer of the men in each treatment group, including the combination group, withdrew from the study because of adverse events.

In a separate presentation, Dr. Jack Barkin, Director, The Male Health Centre, Toronto, and Adjunct Clinical Professor of Surgery, University of Toronto, Ontario, reported on changes in the BII from baseline out to 24 months across the three treatment groups. The BII measures physical discomfort, worry about BPH symptoms, how much trouble it is causing, and its impact on quality of life and day-to-day activities.

Investigators also evaluated question 8 of the IPSS questionnaire—“what I call motivation,” remarked Dr. Barkin. “In other words, if you had to stay this way for the rest of your life, how would you feel about it? This tells me whether or not the patient wants me to intervene.” Noting that a 0.5 change in the BII is considered a slight improvement, a 1.1 change a moderate improvement and a 2.2 change a marked improvement, only the combination approached what would be considered a marked improvement at 24 months with a change of 2.1 points.

Figure 1. Change from Baseline IPSS Storage and Voiding Scores at Month 24

The 5ARI alone was associated with a 1.7 BII change and tamsulosin a 1.5 BII change (P<u><</u>0.002 for the combination vs. dutasteride and P<u><</u>0.008 for the combination vs. tamsulosin). Again dividing the cohort into tertiles of prostate volume, investigators found a very consistent and significantly greater reduction in BII scores with the combination across all three tertiles: a 2.1-point change in the smallest prostates, a 2-point change in medium-sized prostates and a 2.2-point change in the largest prostates. Comparable reductions in BII for dutasteride across the three tertiles of prostate volumes were 1.6, 1.8 and 1.8 for small, medium and large prostates, and 1.8, 1.4 and 1.2 for tamsulosin.

Regarding changes in question 8 on the IPSS—namely, patient perception or satisfaction with their symptoms—“again, the combination far outstripped the response from baseline with respect to either monotherapy arm and the monotherapy arms were virtually identical at two years,” reported Dr. Barkin. Differences in IPSS question 8 between the three treatment arms were also maintained in all prostate volume tertiles.

CombAT Implications

In a discussion of the findings, Dr. Barkin concurred that it is generally perceived that the 5ARIs are more effective in larger prostates. However, as he pointed out, a sizable proportion of the CombAT cohort were Asian and when investigators looked at the Asian population (approximately 350 men), their prostate volumes were smaller at the outset, the average being about 38 cc. Nevertheless, the numbers in terms of response to the three treatment strategies “were virtually identical, so it appears that even in the smaller prostates, we are seeing a comparable and reproducible response to treatment,” he noted.

Dr. Barkin stated, “The key results from CombAT are that combination therapy for the BPH patient is the way to go, specifically, early on and in the high-volume prostate; there is no question that the 5ARI plus the a-blocker gets you immediate symptom response and prevents the need for surgery and the risk of going into urinary retention over the long term. So when it comes to quality-of-life considerations from a patient standpoint—and this is true for the majority of patients presenting with BPH—we can expect a considerable response and improvement with this approach.”

Dr. Barkin conceded that the length of treatment patients need to be kept on combination therapy has not yet been determined. Yet he did note that suggestions from several other trials in which a 5ARI was used in combination with an a-blocker, one for six months and the second for nine months, indicated that between 77% and 82% of patients maintained symptom control and quality of life after the a-blocker was discontinued and they remained on the 5ARI alone.

Dr. Barkin concluded, “This information gives us some comfort and indication as to how to use these drugs, because if you can remove one of the drugs, you may reduce the side- effect profile and maintain quality of life at the same time.”