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.

63rd Annual Meeting of the Canadian Urological Association

Edmonton, Alberta / June 22-25, 2008

The 5-alpha reductase inhibitors (5ARIs) could become the new statins in prostate cancer prevention, offering the same degree of protection as the statins do against cardiovascular events, regardless of a man’s baseline risk to develop prostate cancer or prostate-specific antigen (PSA) levels.

Several issues have plagued wider uptake of the 5ARI finasteride following publication of the NCI-funded PCPT (Prostate Cancer Prevention Trial), in which researchers showed that the sampling density adjusted risk of developing prostate cancer was 35% lower in men who took finasteride for seven years compared with placebo controls. Why these industry-independent findings did not immediately translate into larger demand for the agent hinged largely upon a single finding: namely, on the surface, it appeared that a very small minority of men taking finasteride (6.4%) were more likely to develop high-grade tumours—namely those with Gleason scores 7 to 10—than their placebo counterparts (5.1%).

Based on this observation alone, Dr. Peter Scardino, Chairman, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, initially cautioned healthy men not to take finasteride for prostate cancer prevention in an influential editorial when PCPT was first published. PCPT investigators were not convinced finasteride was implicated in high-grade disease and hypothesized rather that by shrinking the prostate, the compound made high-grade disease more readily detectable on biopsy. In analyses presented at the recent American Urological Association meeting and discussed here by several speakers, PCPT investigators set out to answer two key questions: Whether the 5ARIs suppress clinically significant disease; and was the increase in high-grade cancer in the finasteride arm real or not?

As discussed here by Dr. Neil Fleshner, Professor of Surgery, University of Toronto, Ontario, PCPT investigators first had to take into account several inherent biases in the study. Firstly, PSA levels were approximately 50% less in the 5ARI arm whereas PSA levels were “true” levels in the placebo arm, so results had to be adjusted for the improved sensitivity of PSA in the active treatment arm for cancer detection. The sensitivity of the digital rectal exam (DRE) was also improved for cancer detection in the finasteride arm. By shrinking the prostate, prostate cancer, particular high-grade cancer, was more likely to be detected on biopsy in men who were taking the 5ARI, as PCPT investigators hypothesized. To determine whether the cancers that it prevented were significant, investigators carried out a central review of all positive biopsies in PCPT for grade and extent of disease.

Depending on the definition used to define “insignificant” (and the group used two), 27.7% and 30.5% of specimens from placebo patients were judged to be insignificant, as were 19.9% and 21.4% of specimens from men on finasteride—in other words, approximately 75% of patients in PCPT had clinically significant cancer by conventional standards. This finding clearly supported the observation that finasteride does indeed suppress the very same type of prostate cancer that the majority of men in the US are having treated today. It also suppressed significant disease at all levels of PSA, even among men with PSA levels as low as 0 to -1.0 ng/mL, among whom almost half of the detected cancers were found to be clinically significant.

Investigators also had to adjust for differences in end-of-study biopsy, as only about 60% of men in PCPT consented to an end-of-study biopsy. This meant that investigators had to “impute” what the relative risk reduction would be in men who did not undergo end-of-study biopsy. When they compared observed vs. estimated rates of prostate cancer, they found that observed rates for prostate cancer overall were 22.9% in placebo patients vs. 16.6% for those in the treatment arm compared with estimated rates of 21.1% for placebo patients vs. 14.7% for those on the 5ARI.

For high-grade cancer, observed rates among placebo patients were 4.8% vs. 5.8% for the treatment cohort, whereas estimated rates were 4.2% and 4.8% for placebo and active therapy patients, respectively, a non-significant difference between the two groups.

High-grade Cancer

Indeed, reanalysis of estimates of high-grade cancer from radical prostatectomy specimens indicated that low-grade cancers occurred in 8.7% of men on finasteride vs. 12.9% of placebo controls, while high-grade cancers occurred in 6.0% of treated men vs. 8.2% of placebo controls. Thus, not only did the 5ARI not increase the risk of high-grade disease in PCPT, it reduced the risk of high-grade disease, clearly answering the question of whether finasteride increases the risk of high-grade disease relative to placebo.

Furthermore, Dr. Fleshner reminded delegates, the side-effect profile in the PCPT was largely in favour of finasteride, with meaningful reductions in urinary tract infections, prostatitis, urinary retention and urgency incontinence, symptomatic BPH, and rates of transurethral resection of the prostate (TURP). In contrast, sexual dysfunction complaints were higher among men on active therapy but the risk of sexual dysfunction was judged to be minor.

“We now know without a doubt that prostate cancer is a preventable disease using 5ARI therapy, and particularly finasteride, given the results of PCPT and that clinically significant disease is prevented,” Dr. Fleshner said. “Many of us have been using these compounds for many years with few problems, and I use them for patients at high risk or at high anxiety for prostate cancer. While I think some of the controversies have harmed the wide-scale adoption of these compounds in clinical practice, I think it is a matter of time for all of this to sink in.”

Canadian BPH Audit Study

As reported by Dr. Curtis Nickel, Professor of Urology, Queen’s University Kingston, Ontario, benign prostatic hyperplasia (BPH) still represents about one-fifth of out-patient urology practice, according to the CanBAS (Canadian BPH Audit Study) carried out in 2007. CanBAS investigators analyzed 5616 patients from 30 urology practices over a two-week interval. With an average PSA of 3.9, BPH patients seen in this survey were representative of men with lower urinary tract infections (LUTS) in Canada.

On initial visit, 45% of men with BPH received an alpha blocker alone, while 25% received a 5ARI and 11% received the combination. On repeat visit, more men were likely to receive the combination of an alpha blocker/5ARI at 19%, with current rates for TURPs and other surgery being very low on both initial and repeat visit. Forty-one percent of men with a small prostate (<30 cc) were treated with an alpha blocker, as were 37% of men with medium-sized prostates and 24% of those with a prostate >50 cc. Combination therapy for small, medium and large prostates was used in 10%, 14% and 31% of the practice sample, respectively.

As Dr. Nickel reminded delegates, two-year results from the ongoing CombAT (Combination of Avodart and Tamsulosin) study in men with moderate to severe LUTS and an enlarged prostate showed that the 5ARI dutasteride and the alpha blocker tamsulosin provided significantly greater and more sustained improvements in LUTS than either compound alone.

Importantly, this was previously confirmed by the NIH-conducted MTOPS (Medical Therapy of Prostatic Symptoms) trial using finasteride and doxazosin. Recent results from PROACT (Proscar and Alpha-blocker Combination Followed by Discontinuation Trial) showed that for most patients, the alpha blocker could be dropped after nine months on combination therapy in patients who were doing well on finasteride and an alpha blocker, as their BPH symptoms continued to be controlled as well as when on the combination. Most patients also showed no adverse consequences following discontinuation of the alpha blocker.

Dr. Nickel concluded that with these trials in mind, survey results from CanBAS suggest that Canadian urologists are, for the most part, managing BPH according to evidence-based strategies.