Transcript Critical Highlights

The Medical Therapy
Of Prostatic Symptoms
(MTOPS) Trial: Results
Slide 1
Medical Treatment of BPH: The Challenge
BPH is the most common benign neoplasm in older
men
Clinical BPH involves benign prostatic enlargement,
lower urinary tract symptoms (LUTS), and bladder
outlet obstruction
BPH can interfere with daily activities and can
diminish health-related quality of life specific
to urinary symptoms
BPH=benign prostatic hyperplasia
Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243; Emberton M et al Urology 2003;61(2):267-273; Girman CJ et al Eur Urol
1999;35:277-284.
Slide 2
Recommendations of the 5th International Consultation on BPH in 2001
Medical Treatment of Clinical BPH
Short-term
Improve symptoms
Long-term
Prevent complications
Overall
Minimize adverse effects of treatment
Preserve quality of life
Adapted from Chatelain C et al 5th International Consultation on BPH 2001:519-535.
Slide 3
Recommendations of the 5th International Consultation on BPH in 2001
Medical Treatment of Clinical BPH
5-alpha reductase inhibitors and alpha blockers
are the only recommended medical treatments
of BPH
Recommendations for phytotherapy or polyene
derivatives require additional long-term data
Adapted from Chatelain C et al 5th International Consultation on BPH 2001:519-535.
Slide 4
Could Combination Therapy Be a Better Approach?
Two-Drug Therapy Activates Two Distinct
and Complementary Mechanisms of Action
Alpha blockers
Improve symptoms
and increase urinary
flow rate by relaxing
prostatic and
bladder-neck
smooth muscle
through sympathetic
activity blockade
5-Alpha reductase inhibitors
Improve symptoms,
increase urinary flow
rate, and prevent BPH
outcomes by reducing
prostate enlargement
through hormonal
mechanisms
Adapted from Roehrborn CG Curr Opin Urol 2001;11:17-25; National Cancer Institute. NIH Publication No. 99-4303, 1999.
Slide 5
Evidence on Combination Therapy
Most trials of 5-alpha reductase inhibitor + alpha-blocker
therapy were of short duration or lacked placebo controls
Two randomized, placebo-controlled, multicenter, 12-month
studies showed that combination therapy did not enhance the
efficacy of alpha-blocker monotherapy in terms of improving
symptoms or urinary flow rate
– VA COOP: Placebo vs. PROSCAR™ vs. terazosin vs.
combination in 1229 men with BPH in US VA system
– PREDICT: Placebo vs. PROSCAR vs. doxazosin vs.
combination in 1095 men with BPH in Europe
PROSCAR (finasteride) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
VA COOP=Veterans Affairs Cooperative; PREDICT=Prospective European Doxazosin and Combination Therapy
Adapted from Roehrborn CG Curr Opin Urol 2001;11:17-25; Debruyne FMJ et al Eur Urol 1998;34:169-175; Savage SJ et al Can J Urol
1998;5(3):578-584; Lepor H et al N Engl J Med 1996;335(8):533-539; Kirby RS et al Urology 2003;61(1):119-126.
Slide 6
MTOPS (Medical Therapy Of Prostatic Symptoms)
Objective of MTOPS
To determine whether long-term medical therapy
with PROSCAR™, the alpha blocker doxazosin,
or their combination would prevent or delay
the clinical progression of BPH
Independently Conducted by the US National
Institutes of Health (NIH)
Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243.
Slide 7
MTOPS (Medical Therapy Of Prostatic Symptoms)
Study Design: Overview
Double-blind, placebo-controlled, multicenter, randomized
Average follow-up: 4.5 years
Randomized
N=3047
Entry Criteria
•
•
•
•
Doxazosin
(n=756)
Men 50 years of age
AUA symptom score 8–30
Qmax 4–15 ml/sec
Voided volume 125 ml
PROSCAR™
(n=768)
PROSCAR +
doxazosin
(n=786)
Placebo
(n=737)
AUA=American Urological Association; Qmax=maximum urinary flow
Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243.
Slide 8
MTOPS (Medical Therapy Of Prostatic Symptoms)
Study Design: Outcomes
Primary
outcome
Secondary
outcome
Clinical progression of BPH
– Confirmed 4-point increase in AUA-SI
– AUR
– Recurrent urinary tract infections/
urosepsis
– Urinary incontinence
– Renal insufficiency
Natural history of BPH with respect to
–
–
–
–
–
BPH symptoms
Qmax
Prostate volume
Sexual function
Quality of life
AUA-SI=American Urological Association Symptom Index; AUR=acute urinary retention
Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243.
Slide 9
MTOPS (Medical Therapy Of Prostatic Symptoms)
Baseline Characteristics of Patients
Characteristic
Age (years)
AUA-SI score
TRUS Prostate volume (cc)
Postvoid residual urine volume (ml)
Qmax (ml/second)
Value*
62.0
17.0
31.0
39.0
10.6
No significant differences between groups
AUA=American Urological Association; TRUS=transrectal ultrasound
*Values are medians
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396.
Slide 10
MTOPS (Medical Therapy Of Prostatic Symptoms)
Impact of Medical Therapy on
Clinical Progression of BPH
Cumulative incidence of BPH progression
Placebo (n=737)
PROSCAR™ (n=768)
Doxazosin (n=756)
Combination (PROSCAR + doxazosin) (n=786)
Percentage with event
25
20
15
p=0.002
p<0.001
10
66%
risk
reduction
(p<0.001)
p<0.001
5
0
0
0.5
1.0
1.5 2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
Years from randomization
P values are for the comparison with placebo.
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396; Bautista OM et al Control Clin Trials 2003;24:224-243.
Slide 11
MTOPS (Medical Therapy Of Prostatic Symptoms)
Most BPH Progression Events Were
Due to Symptom Progression
Distribution of BPH progression events
Incontinence 7%
UTI/urosepsis 1%
Renal insufficiency 0%
AUR
12%
>4-point AUA-SI
increase 80%
UTI=urinary tract infection
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396.
Slide 12
MTOPS (Medical Therapy Of Prostatic Symptoms)
Impact of Medical Therapy on Symptom Control
Cumulative incidence of 4-point increase in symptom score*
Percentage with event
25
Placebo (n=737)
PROSCAR™ (n=768)
Doxazosin (n=756)
Combination (PROSCAR + doxazosin) (n=786)
20
15
64%
risk
reduction
(p<0.0001)
10
5
0
0
0.5
1.0
1.5 2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
Years from randomization
*AUA-SI score
Adapted from McConnell JD. Presentation at AUA Annual Meeting, Orlando, Florida, USA, May 2002; Bautista OM et al Control Clin Trials
2003;24:224-243.
Slide 13
MTOPS (Medical Therapy Of Prostatic Symptoms)
Effect of Medical Therapy on Prostate Volume
Change from baseline in prostate volume
Combination
(PROSCAR™ + doxazosin)
–13%*
(n=786)
PROSCAR
–16%*
(n=768)
Doxazosin
+18%
(n=756)
Placebo
+18%
(n=737)
–20
–10
0
10
20
Median % change from baseline
*p<0.001 vs. baseline
Adapted from McConnell JD. Presentation at AUA Annual Meeting, Orlando, Florida, USA, May 2002; Bautista OM et al Control Clin Trials
2003;24:224-243.
Slide 14
MTOPS (Medical Therapy Of Prostatic Symptoms)
Impact of Medical Therapy on the Risk of AUR
Cumulative incidence of AUR
Placebo (n=737)
PROSCAR™ (n=768)
Doxazosin (n=756)
Combination (PROSCAR + doxazosin) (n=786)
Percentage with event
3.5
3.0
2.5
2.0
81%
1.5
p=0.009
1.0
0.5
risk
reduction
(p<0.001)
p<0.001
0
0
0.5
1.0 1.5
2.0
2.5 3.0
3.5
4.0 4.5
5.0
5.5
Years from randomization
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396; Bautista OM et al Control Clin Trials 2003;24:224-243.
Slide 15
MTOPS (Medical Therapy Of Prostatic Symptoms)
Impact of Medical Therapy on the Need
for Invasive BPH Therapy*
Cumulative incidence of BPH-related surgery
Percentage with event
10
Placebo (n=737)
PROSCAR™ (n=768)
Doxazosin (n=756)
Combination (PROSCAR + doxazosin) (n=786)
8
6
67%
4
p<0.001
risk
reduction
(p<0.001)
2
p<0.001
0
0
0.5
1.0 1.5
2.0
2.5 3.0
3.5
4.0
4.5
5.0
5.5
Years from randomization
*Endoscopic (e.g., transurethral prostatectomy) or open surgeries primarily; other therapies were minimally invasive (e.g., transurethral
microwave therapy)
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396; Bautista OM et al Control Clin Trials 2003;24:224-243.
Slide 16
MTOPS (Medical Therapy Of Prostatic Symptoms)
Medical Monotherapy and Combination
Therapy Demonstrated Long-Term Tolerability
Ten most frequent adverse events among groups*
Variable
Placebo
(n=737)
Total no. of person-years
3489
Adverse Event
Erectile dysfunction
Dizziness
Postural hypotension
Asthenia
Decreased libido
Abnormal ejaculation
Peripheral edema
Dyspnea
Allergic reaction
Somnolence
3.3
2.3
2.3
2.1
1.4
0.8
0.7
0.6
0.5
0.4
Doxazosin
(n=756)
3652
3.6
4.4**
4.0**
4.1**
1.6
1.1
0.9
0.9
0.9**
0.8**
PROSCAR™
(n=768)
3600
4.5**
2.3
2.6
1.6
2.4**
1.8**
0.7
0.6
0.6
0.4
PROSCAR
and doxazosin
(n=786)
3832
5.1**
5.4**
4.3**
4.2**
2.5**
3.1**
1.3**
1.2**
0.7
0.8**
*The numbers shown are the rates per 100 person-years of follow-up (incidence density) as of September 30, 2002; **p<0.05 vs. placebo
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396; Bautista OM et al Control Clin Trials 2003;24:224-243.
Slide 17
MTOPS (Medical Therapy Of Prostatic Symptoms)
Conclusions
Combination therapy is the most effective form of medical
therapy for BPH
– 66% reduction in risk of BPH progression (p<0.001*)
– 64% reduction in worsening symptoms (p<0.001*)
– 81% reduction in risk of AUR (p<0.001*)
– 67% reduction in need for invasive BPH therapy (p<0.001*)
Long-term monotherapy and combination therapy were
well tolerated and effective
*vs. placebo at 4 years
Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396.
Slide 18
The Future of Combination Therapy
for BPH
“The evidence supporting combination therapy [for BPH]
in selected patients is so strong that I expect to see
major changes in medical practice in the near future.”
Leroy M. Nyberg Jr, PhD, MD
Director, Urology Program
National Institute of Diabetes and
Digestive and Kidney Diseases
Adapted from NIH news release. Available at: http://www.nih.gov/news/pr/may2002/niddk-28.htm.
Slide 19
References
Please refer to notes page.
Slide 20
MTOPS: Medical Therapy Of Prostatic
Symptoms
Before prescribing any of the products mentioned
in this slide presentation, please consult the
manufacturers’ prescribing information.
Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved.
3-05
PSC 2004-W-14295-SS
Printed in USA
VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com
Slide 21