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.

PRIORITY PRESS - 24th Annual Congress of the European Association of Urology

Stockholm, Sweden / March 17-21, 2009

The CombAT study (Combination of Avodart and Tamsulosin) was designed to evaluate the combination of a 5a-reductase inhibitor (5ARI) and an a-blocker in men with moderate-to-severe benign prostatic hyperplasia (BPH) (International Prostate Symptom Score [IPSS]<u>></u>12) at increased risk of disease progression as identified by age <u>></u>50 years, prostate volume <u>></u>30 cc and prostate-specific antigen (PSA) <u>></u>1.5 ng/mL.

Dr. Andrea Tubaro, Department of Urology, La Sapienza University, Rome, Italy, presented results of two-year post-hoc analyses from the four-year CombAT study. He reported that combination therapy with a 5ARI and an a-blocker delivered superior symptom and quality-of-life (QoL) improvement over either of those agents given as monotherapy to men with BPH and mild-to-moderate lower urinary tract symptoms (LUTS). He mentioned that this is important because combination treatment is commonly reserved for men with more severe symptoms, whereas both moderate and severe LUTS are associated with impaired QoL. The two-year primary analysis demonstrates that the 5ARI plus a-blocker combination therapy provides significantly (P<0.001) greater improvement in symptoms and patient-reported QoL compared with dutasteride alone from month 3 and tamsulosin alone from month 9.

Dr. Tubaro stated, “The adjusted mean change from baseline IPSS was a significantly (P<0.05) improved -8.9 points for combination therapy vs. more moderate improvements of -7.6 for the 5ARI and -7.0 for a-blocker monotherapies. The superiority of combination therapy over both monotherapies was independent of baseline IPSS.”

He continued, “Mean improvement from baseline QoL score at month 24 was by -3.0 points with combination therapy vs. -2.7 with 5ARI and -2.4 with a-blocker monotherapies (P<0.001), regardless of baseline values. Thus IPSS and QoL changes with combination therapy corresponded to marked improvement. The proportion of patients with an IPSS <8 at month 24 was significantly higher (P<0.001) with combination therapy (39%) than with 5ARI and a-blocker monotherapy (32% and 29%, respectively).”

The CombAT study has also demonstrated that whereas improvement of IPSS is achieved with combination therapy in both moderate and severe symptom groups, the margins of improvement are actually greater in the more severely symptomatic than in the moderately symptomatic. Additionally, the prior use of an a-blocker had no effect on efficacy of the combination.

Dr. Tubaro concluded that combination therapy delivered superior symptom and QoL improvements compared with either monotherapy, exceeding accepted thresholds for patient-perceived improvements irrespective of baseline symptom severity.

Meaningful Symptom Improvement: Gauging Patient Perception

Dr. Claus Roehrborn, Chair, Department of Urology, University of Texas Southwestern Medical Center, Dallas, noted that symptom improvement magnitude with combination therapy vs. a-blocker monotherapy was similar to that of BPH medical therapies vs. placebo. “But,” he asked, “just how meaningful is that improvement clinically? What does it mean to a patient to be told he can expect a 4- or 5- or 8-point improvement in symptom score? Can he translate that into anything tangible?”

He explained to delegates, “In the CombAT study, we used a new validated 12-question instrument called Patient Perception of Study Medication (PPSM) questionnaire to assess patients’ satisfaction with their treatment. Maximum score was 49 points,” he said. Patients were asked, “Overall, how satisfied are you with the study medication and its effect on your urinary problems?” Those who said they were “very satisfied” had achieved an improvement of -8.7 on their symptom PPMS scale. Those who believed they were “satisfied,” “somewhat satisfied,” “neutral” and “very dissatisfied” scored -6.7, -4.3, -2.5 and -0.4, respectively. “Dissatisfied” and “very dissatisfied” patients had increased symptom scores.

“This was a regression to the mean,” Dr. Roehrborn noted. “Patients starting at a higher symptom severity level have a longer way to drop. Very satisfied patients who started out with more symptoms require a much greater drop from baseline to be very satisfied. Those who end up very satisfied regardless of baseline scores must be <u><</u>9 at the end of the day. That fits very nicely with our definition of ‘mildly symptomatic’ (<u><</u>7 on the IPSS scale),” he remarked. “If we bring patients to the level of <u><</u>9, they will be very satisfied with their treatment. This is the therapeutic zone that gets patients satisfied.”

Dr. Roehrborn added, “Now, <u><</u>8 points was achieved by 40% in the combination therapy group throughout the two years of the CombAT trial. The subgroup with baseline at 16 to19, the most common symptom range for our patients, achieved 35% to 38%, so the elusive goal cannot be achieved by everybody. But combination therapy nonetheless has a huge margin over both monotherapies in achieving that goal where patients say they are satisfied or very satisfied with the outcome of their treatment. So evidence of the superior effects of combination therapy in the CombAT study was shown within the first year, even when stratified by a variety of baseline criteria.”

The therapeutic zone of “mild,” which Dr. Roehrborn indicated translates for the patient to be very satisfied, was achieved in a higher percentage of patients who underwent combination 5ARI/a-blocker therapy. Symptom improvement exceeded accepted thresholds for patient-perceived moderate or marked improvements regardless of baseline symptom severity. Treatment with combination therapy resulted in a significantly greater proportion of patients achieving mild symptoms at two years. Patient satisfaction data revealed these to be perceptible and meaningful symptom improvements.

CombAT four-year data will provide further insight into long-term clinical outcomes of patients receiving combination therapy and hopefully presented later this year in order to answer additional questions regarding urine retention and surgery.

Risk-stratify LUTS Patients Early

According to Dr. Mark Emberton, Institute of Urology and Nephrology, University College, London, UK, urologists can help men in relieving their symptoms of BPH/LUTS but not as efficacious at keeping them free of symptoms over time.

“The default approach to managing LUTS is based on ‘step-up’ treatment in which additional or alternative medical therapies are considered only if symptoms deteriorate or patients complain, so men are forced to fail before getting the treatment that most suits them,” he explained. “The failure of one treatment strategy acts as a trigger to initiate the next treatment; a wasteful concept.”

Noting that about three-quarters of men with LUTS suffered symptom progression in two recent studies, and that those who progress are known to be two to three times as likely to develop some limitation in an important daily activity, he indicated that it is less known that patients who experience measurable symptomatic progression are far more likely to eventually develop acute urinary retention.

According to Dr. Emberton, present strategy could be improved by risk-stratifying patients early, as is done in other chronic conditions, and allocating appropriate therapy that will result in symptom reduction and maintain the reduction over time. He stated that the ability to identify men at risk exists, and there are available treatments suitable for men at risk of progression.

“When symptoms worsen, it might make sense to allow the individual to present by phone, or contact a nurse to call attention to the situation,” he told delegates. “We might be more active in using IPSS to actually monitor and measure symptoms in a quantitative manner. In a cross-sectional study of 444 men [Naslund et al. Int J Clin Pract 2007;61(9):1437-45], only 33% with an IPSS >7 and enlarged prostate, or PSA <u>></u>1.5, intended to speak with their primary care physician about urinary problems.”

Dr. Emberton concluded that there is a need to proactively encourage patient entry into the care pathway based on the presence of symptoms, rather than wait for men to present when symptoms become bothersome. This would facilitate an alternative approach to the management of BPH in which the patients’ risk of symptom deterioration is assessed at consultation and therapy appropriate to that risk is initiated at the outset.

Summary

As reported here at this year’s EAU congress, two-year results from CombAT confirm the enhanced efficacy of a 5ARI/a-blocker combination when compared to either agent as monotherapy. Experts also highlighted the importance of early treatment initiation by encouraging patients to present to their treating healthcare professional in order to forestall the risk of exacerbating symptoms.