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XXIIIrd Annual Congress of the European Association of Urology

Milan, Italy / March 26-29, 2008

Using two compounds with complementary modes of action is a favoured strategy in many areas of medicine including hypertension, certain cancers and, increasingly, for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Alpha-blockers provide rapid symptom relief and improvement in flow rate by reducing smooth muscle tone in the prostate and bladder neck, while the 5a-reductase inhibitors (5ARIs) block the conversion of testosterone to dihydrotestosterone, reducing prostate volume and the risk of acute urinary retention (AUR) as well as the need for BPH-related surgery, confirmed Dr. Carlos Llorente, Chief of Urology, Fundación Hospital Alcorcón, Madrid, Spain. What has not been clear until now is how well men with symptomatic BPH and larger prostate volumes would fare over the short and the longer term when treated with the combination strategy consisting of the 5ARI dutasteride plus the alpha-blocker tamsulosin vs. either treatment alone.

The CombAT Study

The Combination of Avodart and Tamsulosin (CombAT) was an important study designed to determine whether men at higher risk for BPH progression, as predicted by both higher prostate volumes and higher prostate-specific antigen (PSA) levels, derive greater benefit from combination therapy with a 5ARI and an alpha-blocker than those treated with either drug alone.

For the first time, CombAT also evaluated the effect of dual or monotherapy on specific symptom end points, notably, change in the International Prostate Symptom Score (I-PSS) from baseline out to two years, the primary two-year end point. On randomization, men with a prostate volume of 30 cc or greater, a total serum PSA of between 1.5 ng/mL and 10 ng/mL and peak urinary flow between 5 and 15 mL/sec (minimum voided volume of 125 mL or more) received one of three daily regimens: 0.5 mg dutasteride, 0.4 mg tamsulosin or the combination of both, for a treatment interval of four years.

LUTS were assessed at baseline and every three months thereafter using the I-PSS questionnaire (which includes an evaluation of BPH-related health status), while Qmax measurements of flow rate were again carried out at baseline and every six months thereafter. A total of 3822 men were evaluable for analysis at 24 months. As reported here by CombAT lead investigator Dr. Claus Roehrborn, Chair, Department of Urology, University of Texas Southwestern Medical Center, Dallas, combination dutasteride/tamsulosin produced a significantly greater reduction in the I-PSS score than either agent alone.

At month 24, I-PSS had decreased by 6.2 points from baseline for those in the combination arm compared with 4.9 points for those on dutasteride and 4.3 points for those on tamsulosin, a significant difference between the combination vs. monotherapy arms (P<0.001). Investigators also observed that the decrease in I-PSS was significantly greater for men receiving the combination compared with dutasteride alone starting as early as the third month of treatment, and by nine months compared with tamsulosin.

Significant reductions in BPH-related health status scores were also reported for men receiving the combination strategy compared to either agent alone (P<0.001 for each comparison). Regarding changes in flow, investigators also observed significantly greater improvements in Qmax for men receiving both agents compared with either monotherapy, starting at month 6 and persisting out to 24 months, the difference at 24 months between combination vs. monotherapy strategies being significant at P<0.001.

Importantly as well, age had no statistically significant effect on treatment outcomes, nor did baseline prostate volume or PSA levels: the combination was consistently better than either agent alone, regardless of baseline age, prostate volume or PSA levels.

The total number of drug-related adverse events (AEs) was significantly greater in the combination arm but no more than 5% of men in any of the treatment groups withdrew from the study as a result of AEs, as investigators pointed out.

Prostate Size Can Affect Therapeutic Choice

As discussed here further by Dr. Roehrborn, larger glands in general typically respond better to combination therapy, as has been previously demonstrated by other studies. “CombAT’s two-year analysis demonstrates that when we go from the lowest to the highest prostate volumes, we see that the 5ARI has greater efficacy in the larger glands. With alpha-blockers, the efficacy decreases not only along the axis of volume, but also along the axis of time.” For example, in the smallest of the prostate glands in CombAT (between 30 cc and 41 cc), benefit was attributable only to the alpha-blocker until about month 9, after which the combination was more effective.

Among the larger prostates (42 cc to 58 cc), the 5ARI was less effective than tamsulosin until about month 12, after which dutasteride numerocally exceeded the efficacy of the alpha-blocker. That said, “The best efficacy is maintained by the combination,” as Dr. Roehrborn noted, concluding: “The larger the prostate, the greater the benefit if you choose combination therapy, even as early as three months. By comparison, the effect of the alpha-blocker is minimal in large prostates. The bulk of the therapeutic contribution is carried by the 5ARI in those glands.”

5ARIs and Risk Reduction Therapy

Prostate Cancer Prevention Trial (PCPT) findings provided unequivocal evidence that 5ARIs reduce the risk of prostate cancer. Yet, there is still considerable debate over which men should receive a 5ARI for prostate cancer prevention and which PSA level to use as a marker of risk. As discussed by Dr. Gerald Andriole, Division of Urologic Surgery, Washington University, St. Louis, Missouri, men who should be considered for 5ARI prophylaxis are those with moderate or severe LUTS and an enlarged prostate of at least 30 cc.

Several large clinical trials have shown that men with these eligibility criteria achieve significant symptomatic relief on 5ARI therapy. In addition, men with a PSA level in excess of 1.5 ng/mL are also at a high risk for prostate cancer and can be considered as reasonable candidates for prophylactic 5ARI therapy, as they are subject to repeated screening forprostate cancer.

“One would say that if a man is judged worthy of screening for cancer, with a PSA in the high 1.5 ng/mL range and above, he should also by definition be a candidate for risk reduction,” Dr. Andriole told delegates.

However, he cautioned, “A single negative biopsy in a man with an elevated PSA does not adequately eliminate a chance that he has prostate cancer.” For example, there was still a 28% risk of prostate cancer among men involved in the PCPT trial who had negative previous biopsies but a PSA of 4 ng/mL. Similarly, men with what would be considered relatively low PSAs levels but with a suspicious digital rectal exam and one negative biopsy have nearly an equivalent 25% chance of prostate cancer on a second biopsy, Dr. Andriole noted.

He concluded, “It appears that men who have a PSA of 1.5 ng/mL carry a significantly elevated future risk of cancer compared to the background population, which might involve 30% to 40% of patients. I think it is our job to rethink how we have been using PSA, not just as an indicator for present cancer, but also as a marker for future risk. Even though their PSA has not surpassed a threshold, like 4, patients definitely warrant a biopsy if it is greater than 1.5 ng/mL because they remain at significant four- to five-year risk [for prostate cancer] and warrant risk reduction therapy.”