Health and Prostate

Dutasteride (GlaxoSmithKline/Astellas’s Avodart) was the first marketed dual 5-ARI. In 1999, Glaxo Wellcome (now GlaxoSmithKline [GSK]) entered an agreement with Yamanouchi for this drug’s copromotion for benign prostatic hyperplasia in the United Kingdom. Approval in the United States was granted for the treatment of symptomatic benign prostatic hyperplasia in November 2001. In October 2002, the FDA approved a supplemental NDA for dutasteride for the treatment of symptomatic benign prostatic hyperplasia in men with an enlarged prostate. Subsequently, it was launched in the United States in January 2003 and in the United Kingdom in February 2003. In March 2003, GSK announced the launch of dutasteride in all major European markets.

As an inhibitor of both types 1 and 2 isoenzymes of 5-alpha-reductase, dutasteride is unique; finasteride inhibits only type 2. However, the type 2 isoenzyme is the dominant form; type 1 accounts for only 15% of the prostatic enzyme. The dual inhibition of the enzyme reduces dihydrotestosterone serum levels to less than 10% of normal, but there is no evidence that inhibition of both forms of the enzyme has any therapeutic benefit.

The foremost clinical study evaluating the efficacy and safety of dutasteride was published in 2002. The placebo-controlled study was conducted over the course of two years in three pooled Phase III trials. Dutasteride was evaluated in 4,325 benign prostatic hyperplasia patients with moderate to severe symptoms (AUASI score of 12 points or more) and an enlarged prostate of 30 grams or more. In all three trials, patients were randomized to 0.5 mg of dutasteride daily or placebo; 2,951 (68%) of the patients completed the study. Researchers reported the following results:

•  At two years, the serum dihydrotestosterone level in dutasteride-treated patients was reduced from baseline by a mean of 90.2% (placebo increased 9.6% from baseline), the total prostate volume by a mean of 25.7% (placebo increased 1.7%), and the symptom score on average by 4.5 points (placebo by 2.3 points).

•  The risk of acute urinary retention with dutasteride fell by 57%, and the risk associated with benign prostatic hyperplasia surgical intervention declined 48%, compared with placebo.

•  The number of discontinuations (717 placebo, 657 drug-treated) and reasons for not completing the study (e.g., adverse events, lack of efficacy) were not statistically different.

•  Drug-related adverse events were observed in 5% more of the patients treated with dutasteride than with placebo (19% versus 14%). They included impotence, decreased libido, ejaculation disorders, and gynecomastia (enlarged breasts), but most effects were transient, and new events declined significantly in the second year.

Patients who completed the Phase III trials with dutasteride were eligible for enrollment in a two-year, open-label extension. The trial consisted of two study groups: patients who continued dutasteride treatment and patients who switched to dutasteride from placebo. In this trial, as in the double-blind placebo phase, both AUASI and Qmax improved from baseline. Results were as follows:

•  Patients who continued dutasteride treatment for an additional two years had an overall reduction in AUASI of 6.1 points. Qmax increased 2.8mL/s. Patients who switched from placebo had a reduction in AUASI of 5.3 points, and Qmax increased 1.8mL/s.

•  After 24 months, researchers found that hormone levels were significantly affected by dutasteride. Both treatment arms had reduced serum dihydrotestosterone levels by more than 90% and serum testosterone levels by 25% from baseline.

•  The most commonly reported drug-related side effects were impotence, decreased libido, and abnormal ejaculation. Results from patients taking dutasteride for four years showed that sexual adverse events decreased over the course of long-term treatment.