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61st Annual Meeting of the Canadian Urological Association

Halifax, Nova Scotia / June 25-28, 2006

Predicting Benign Prostatic Hyperplasia Progression

In an interview given by Dr. Gerald Andriole, Director, Prostate Study Center, Barnes-Jewish Hospital, Professor and Chief of Urologic Surgery, Washington School of Medicine, St. Louis, Missouri, US, indicated “Dihydrotestosterone [DHT] is the androgen that is driving prostate growth: benign prostate enlargement, and maybe even the development of prostate cancer. The 5 alpha-reductase (5AR) inhibitors, which can selectively block the production of DHT, should be able to fundamentally alter these two diseases.”

Identifying who is considered to be a high-risk patient remains controversial. According to Dr. Andriole, “the high-risk population for benign prostatic hyperplasia [BPH] progression comprises men who have trouble urinating and whose serum prostate-specific antigen [PSA] levels are >1.4 ng/mL. Those men have a 30% to 40% four-year probability of having meaningful side effects from BPH, so they represent the perfect target to receive 5AR inhibitors. The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study is looking at a high-risk group of men with elevated PSA (2.4 ng/mL)—which most people would say represents a meaningful kind of prostate cancer.”

As BPH progresses, it can lead to worsening symptoms, acute urinary retention (AUR), and need for surgery. Disease prevention, as opposed to treatment, is a new concept for most urologists. For some medical conditions, physicians may need to treat as many as 100 patients to prevent one event. The Medical Therapy of Prostatic Symptoms (MTOPS) trial data showed that urologists would have to treat between 30 and 40 high-risk BPH patients to prevent AUR or surgery.

Program chair Dr. Neil Fleshner, Head of Urology, Department of Surgery, University Health Network, and Associate Professor, University of Toronto asked the audience to select the most important predictor of BPH progression. The response was split among prostate volume (37%), PSA level (27%), degree of bother (15%), symptom score (12%), and urine flow rate (9%).

“I think everybody is right and everything matters,” Dr. Andriole stated, “but volume and PSA are probably the two biggest drivers of BPH progression.” In the MTOPS trial, there were significant differences in BPH progression rates depending on patients’ baseline PSA tertiles of <1.4, 1.4 to 3.9, or ³4 ng/mL (McConnell et al. N Engl J Med 2003;349:2387-98). Prostate growth was shown to be more than three times greater in patients in the high PSA tertile compared to those in the low tertile (3.3 vs 0.7 mL/year; Roehrborn et al. J Urol 2000:163:13-20). “I think that findings are indicative of a 1.4 cut-off point,” Dr. Andriole concluded.

5AR inhibitors Are Not All Equal

There are several differences between the two 5AR inhibitors agents. While finasteride inhibits type 2 of the 5AR enzyme, whereas dutasteride inhibits type 1 and 2. The latter reduces serum DHT by 90% vs.70% and it has a substantially longer half-life of five weeks vs. eight hours. There is also more variability in a given man’s response to both 5AR inhibitors. Finasteride does not inhibit a number of different genetic variations of the 5AR type 2 enzyme, which is very important element for African American patients.

Dr. Andriole presented data that showed 50% of the men on finasteride experienced a 70% reduction of serum DHT, whereas 100% of men on dutasteride experienced at least a 70% reduction. Findings indicated a reduction of intraprostatic DHT > 90% in men who had taken dutasteride.

There has really never been the perfect comparative trial over the long-term comparing finasteride and dutasteride, but the entry criteria and treatment evaluations of the relevant studies were very similar. The prostate volume reduction with finasteride at four and six years is in the 25% range, which is what you see after two years of therapy with dutasteride. “These were non-comparative studies, but they can give us some rough guidance to say that enhanced DHT suppression looks like it probably does matter,” Dr. Andriole said.

Chemoprevention in 2006

Dr. Luc Valiquette, Urologist, CHUM-Hôpital Saint-Luc and Professor, Department of Surgery, Université de Montréal offered the following case study to examine chemoprevention. A 40-year-old, concerned black male whose father died at age 72 due to prostate cancer presented with a PSA of 1.6, a normal digital rectal examination (DRE), and a prostate volume of 30 mL. Dr. Valiquette asked the audience what treatment strategy they would use. Most audience members would monitor the patient (61%), but some would do a biopsy (25%), and a few would initiate 5AR inhibitor without a biopsy (14%). Dr. Valiquette, Dr. Fleshner, and Dr. Andriole all agreed that this patient has multiple risk factors and would warrant a biopsy.

In a follow-up case, this same patient underwent a 10-core biopsy and the results were negative. Most audience members (60%) replied that they would still closely monitor this patient, but 5% would repeat the biopsy, and 35% would initiate 5AR inhibitor. Dr. Valiquette indicated that he would just monitor this patient. Dr. Fleshner stated that with his degree of concern, this patient probably represents the ideal man for prevention therapy. Dr. Andriole agreed, saying that the REDUCE trial is looking at this type of high-risk men who had a negative biopsy. “He’s, in my opinion, high-risk enough, and I’m willing to give dutasteride the benefit of the doubt, because it’s a safe drug. I’d prescribe it.”

“As much as I like screening with PSA levels and doing radical prostatectomies, the reality is that early diagnosis and aggressive treatment is of unknown efficacy,” Dr. Andriole commented. “We know that it puts our patients at significant risk of overtreatment. We know that it’s extraordinarily costly. We’re very fortunate that prostate cancer has a very long natural history with several discreet steps in its biogenesis where we may be able to intervene.”

Summary

According to Dr. Andriole, “a PSA cut-off point >1.4 is perhaps the best predictor of BPH progression; dutasteride and finasteride differ in many ways including DHT suppression; and dutasteride clearly reduces prostate cancer volume and other cancer-related markers.”

Candidates for therapy are men at high-risk for cancer or for BPH progression. “We have to find the right group of people to benefit from this treatment. In the REDUCE study which is treating high-risk patients, the two-year biopsies should be completed by early next year,” concluded Dr. Andriole.