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.

102nd Annual Meeting of the American Urological Association

Anaheim, California / May 19-24, 2007

According to Dr. Claus Roehrborn, Chair, Department of Urology, University of Texas, Southwestern Medical Center, Dallas, as the North American population of older men increases, prostate disease has emerged as a major health issue. The U.S. Census Bureau estimates individuals aged 65 years and older will increase from 171 million in 2000 to 327 million by 2050 in developed countries and from 249 million to almost 2 billion in developing nations. More than 80% of men between the ages of 70 and 80 years have evidence of benign prostatic hyperplasia (BPH), and the prevalence of prostate cancer in that age group exceeds 40%.

Pathophysiology and Symptoms of Benign Prostatic Hyperplasia

A contemporary view of BPH encompasses multiple clinical, anatomic and pathophysiologic changes, Dr. Roehrborn told attendees. Histologic stromoglandular hyperplasia remains a central feature in many cases. However, improved understanding of the underlying processes has led to the recognition that bothersome lower urinary tract symptoms (LUTS) is a common clinical aspect, and pathophysiologic compression of the urethra often leads to bladder outlet obstruction. “As a consequence of these multiple changes, BPH has a wide-ranging impact on the patient,” indicated Dr. Roehrborn. “The condition and associated symptoms adversely affect quality of life, lead to concern about the risk of acute urinary retention [AUR] and the need for surgery, and cause substantial bother that affects many aspects of a patient’s life.”

Mechanism of Action

Recent studies have also provided conclusive evidence that BPH is a progressive condition. That evidence has led to increased recognition of AUR and the need for surgery if disease progression remains unchecked. The incidence of AUR increases with age from <1% of men aged 45 to 49 years to about 12% of men aged 80 to 83 years. Accumulating clinical experience has shown that the two most common BPH medical therapies, alpha-blockers and 5-alpha-reductase inhibitors (5ARIs), have differing effects on prostatic enlargement. Progression of enlargement appears more likely in patients treated with alpha-blockers (Boyle et al. J Urol 2004;46:620-6). Moreover, recent studies have shown that 5ARIs reduce the risk of invasive therapy and AUR in BPH but this is not the case with alpha-blockers (McConnell et al. N Engl J Med 2003;349:2387-98, Roehrborn et al. AUA Annual Meeting 2006, Abst. 1633, 1641).

The 5ARIs differ in their effects on the underlying processes of BPH. Finasteride blocks only type 2 5AR, which predominates in BPH. In contrast, dutasteride blocks type 1 5AR as well as the type 2 isoform, Dr. Roehrborn noted. Type 1 has less of a role in BPH compared to type 2 but is the predominant isoform associated with prostate cancer.

As he explained, both 5ARIs work by preventing the conversion of testosterone to dihydrotestosterone (DHT), which interacts with the androgen receptor to influence both cell growth and cell death. However, dutasteride suppresses serum DHT by more than 90%, compared to about 70% with finasteride (Roehrborn et al. Urology 2002;60:431-41). This dual inhibition of 5AR1 and 5AR2 results in greater and more consistent suppression of DHT than inhibition of 5AR2 alone. Dutasteride is effective in reducing prostate volume and symptoms as well as diminishing the risk of AUR.

Findings from Previous and Ongoing Studies

The ongoing Combination of Avodart and Tamsulosin (CombAT) trial should help clarify the role of combination therapy in BPH management. Patients with symptomatic BPH will be randomized to tamsulosin, dutasteride or the combination of the two and followed for four years. In the similarly designed Medical Therapy of Prostatic Symptoms (MTOPS) trial involving use of finasteride,doxazosin or both, the combination therapy provided the best overall outcomes. Of note, in BPH trials of 5ARIs, dutasteride was associated with statistically significant reduction in prostate cancer incidence compared to placebo.

To date, the best evidence for chemoprevention has emerged from the Prostate Cancer Prevention Trial (PCPT), which showed a 25% reduction in prostate cancer incidence among cancer-free men treated for up to seven years with finasteride vs. placebo (Thompson et al. N Engl J Med 2003;349:215-24). However, patients treated with the 5ARI had a higher incidence of high-grade cancers compared to the placebo group. Dr. Gerald Andriole, Chairman of Urologic Surgery, Siteman Cancer Center and Professor, Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri, suggested that possible explanations include an inhibitory specificity of finasteride for low-grade tumours, finasteride promotion of high-grade disease or a sampling artifact (biopsy) caused by finasteride-induced gland shrinkage (Mellon JK. Eur J Cancer 2005;41:2016-22). He noted that the sampling artifact is indicated as the most plausible reason for the higher rate of high-grade cancer in the active treatment group.

The ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial will likely determine whether dutasteride can prevent the development of prostate cancer in a higher-risk patient population compared to that of the PCPT. For example, entry criteria allow enrolment of men with prostate-specific antigen (PSA) values as high as 10 ng/mL, whereas PCPT limited enrolment to men with PSA values <3 ng/mL (Gomella LG. Curr Opin Urol 2005;15:29-32). The results of this study may offer a clearer picture of risk reduction in a high-risk population.

In Dr. Andriole’s opinion, available data demonstrate that “dutasteride is, in fact, both biochemically and clinically a better drug than finasteride, both for treating BPH and potentially for preventing prostate cancer.”

Role of Inflammation

Canadian investigators reported an association between baseline prostate inflammation and severity of LUTS symptoms in REDUCE patients. The degree of biopsy-proven inflammation at study entry correlated significantly with the severity of symptoms, irritation, obstruction (P<0.0001 for all) and nocturia (P=0.0003), according to Dr. J. Curtis Nickel, Professor of Urology, Queen’s University, Kingston, Ontario.

Recognition of this relationship will afford an opportunity to determine the extent to of the role of inflammation in LUTS. “Data from the MTOPS trial suggested that inflammation plays an important role in progression of BPH/LUTS,” reported Dr. Nickel. “With this data from the REDUCE trial, we can now prospectively determine whether baseline inflammation can be used to predict the risk of progression and whether it plays a role in the development of prostate cancer. We will also be able to see if dutasteride affects progression.”

Another analysis of baseline data from REDUCE revealed an association between BPH and components of the metabolic syndrome. BPH correlated significantly with obesity, hypertension, higher body mass index, higher glucose levels, and lower levels of HDL-C, reported Dr. Steven Kaplan, Professor of Urology, Cornell University, New York. The association between BPH and the metabolic syndrome warrants further investigation, he added, given recent evidence that metabolic syndrome may help fuel prostate growth (Ozden et al. Eur Urol 2007;51:199-203).

Dr. Roehrborn and colleagues reported an association between baseline symptom scores and subsequent symptom improvement during the placebo run-in phase of the CombAT and REDUCE trials. A combined analysis of baseline data from both trials revealed a positive association between screening symptom scores and improvement in symptoms during the placebo phase that preceded randomized therapy. The REDUCE population enriched the dataset with men who had low symptom scores, affording the opportunity to gather valuable information about BPH-related parameters in men who have small prostates and mild symptoms, stated Dr. Roehrborn.

Summary

Recent studies have provided a better understanding of the pathophysiology of BPH. The MTOPS trial provided information that combination therapy might be a treatment option for BPH. It was also suggested that the 5ARI finasteride in combination therapy delays disease progression of BPH. Dutasteride, the other 5-ARI, with its dual inhibitory action of two types of isoenzymes, reduces prostate volume and is currently being studied in prostate cancer chemoprevention. Follow-up of emerging evidence from the CombAT trial in early September will likely prove to be of interest.