| The
Impact Of Dutasteride, a Novel 5-a- Reductase Inhibitor, on
the Hallmarks of BPH Progression and Outcomes
Boyle
Peter1 , Roehrborn Claus2, Andriole Gerald3, Nickel J Curtis4,
Hofner, Klaus5 , O'Leary, Michael 6
1Division
of Epidemiology and Biostatistics, European Institute of Oncology,
Milan, Italy, 2 The University of Texas Southwestern Medical
Center, Dallas, TX, USA; 3Division of Urology, Washington
University School of Medicine, St. Louis, MO, USA; 4Department
of Urology, Queen's University, Kingston, Ontario, Canada;
5 Urology Clinic, Oberhausen, Germany, 6Harvard Medical School,
Boston, USA.
INTRODUCTION
& OBJECTIVES: Benign Prostatic Hyperplasia (BPH) is
a progressive condition characterised by increasing deterioration
of symptoms, decreased urinary flow, increased prostate volume
(PV) as well as increased risk of acute urinary retention
(AUR) and BPH-related surgery. The objective of these clinical
studies was to demonstrate the impact of dutasteride, a novel
dual 5 ?-reductase inhibitor on the hallmarks of BPH progression
and outcomes.
MATERIALS
& METHODS: Three 2-year multi-center, double-blind,
placebo-controlled studies on dutasteride were conducted (n
= 4325 total). A 1-month placebo run-in period was followed
by randomisation to active treatment with dutasteride, 0.5
mg/day, or placebo. Inclusion criteria were: moderate to severe
symptoms (AUA-SI ³ 12), prostate volume ³ 30 cc;
prostate-specific antigen ³ 1.5 ng/ml and £ 10.0ng/ml;
and maximum flow rate (Qmax) £ 15 ml/sec. Symptoms were
assessed by the American Urological Association Symptom Index
Questionnaire (AUA-SI). BPH-specific health status and Qmax
were assessed at baseline and at 1, 3, 6, 12,18 and 24 months.
BPH-specific health status was measured using BPH Impact Index
(BII). Prostate volume (PV) was measured at screening (visit
1), 1 (one study), 3 (one study) 6, 12 and 24 months. Statistical
analyses were performed using two-sided tests of significance
at alpha = 0.05; At Visit results were analysed.
RESULTS:
Dutasteride significantly improved symptoms as early as 3
months in one study (-2.6 vs. -1.9 adjusted mean score change
from baseline for dutasteride vs. placebo groups [p = 0.016])
and at 6 months in the pooled analysis of the three studies
(-3.2 vs.-2.5 [p < 0.001]) with sustained improvement up
to 24 months (-4.5 vs. -2.3 [p < 0.001]). Qmax was improved
from 1 month in a pooled analysis of the three studies and
by 3 months in all studies with continuing improvement up
to 24 months (0.8 vs. 0.5 [p = 0.006], 1.3 vs. 0.6 [p <
0.001], 2.0 vs. 0.9 [p < 0.001] adjusted mean change from
baseline [ml/sec] dutasteride vs. placebo groups for 1,3 and
24 months respectively). Dutasteride statistically significantly
improved BPH-specific health status at 6 months in the pooled
analysis [-0.63 vs. -0.41 adjusted mean score change from
baseline for dutasteride vs. placebo groups (p = 0.003)],
with sustained significant improvement up to the end of the
study (24 months) [-1.0 vs. -0.26, adjusted mean score change
from baseline for dutasteride vs. placebo groups (p < 0.001)].
The reduction from baseline in PV was significant from 1 month
(-8.6 vs. - 2.9 adjusted mean % for dutasteride vs. placebo
groups [p < 0.001]) and sustained PV reduction was seen
up by to 2 years ( -28.5 % vs. -1.8% in the placebo group).
There was a 57% reduction in the risk of AUR and 48% reduction
of risk of BPH-related surgery compared with placebo over
2 years. A low withdrawal rate due to adverse events was reported
(9% for either group) with withdrawals due to drug-related
adverse events only slightly higher in the placebo group (4%
vs. 3% for the dutasteride and placebo groups, respectively).
CONCLUSIONS:
Dutasteride impacts all the key hallmarks of BPH: lower urinary
tract symptoms, Qmax, BII, PV, risk of AUR and the need for
BPH-related surgery. The drug was well tolerated with minimal
drug-related adverse events. These findings highlight dutasteride
as a potential therapy of choice for BPH management.
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