slide 1 the medical therapy of prostatic symptoms (mtops) trial: results

Slide 1

The Medical Therapy Of Prostatic Symptoms (MTOPS) Trial: Results

Slide 2

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 specificto 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 3

Medical Treatment of Clinical BPH

Adapted from Chatelain C et al 5th International Consultation on BPH 2001:519-535.

Recommendations of the 5th International Consultation on BPH in 2001

Prevent complications

Minimize adverse effects of treatment

Preserve quality of life

Improve symptomsShort-term

Long-term

Overall

Slide 4

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.

Recommendations of the 5th International Consultation on BPH in 2001

Slide 5

Could Combination Therapy Be a Better Approach?

Two-Drug Therapy Activates Two Distinct and Complementary Mechanisms of Action

Adapted from Roehrborn CG Curr Opin Urol 2001;11:17-25; National Cancer Institute. NIH Publication No. 99-4303, 1999.

Alpha blockers 5-Alpha reductase inhibitors

Improve symptoms and increase urinary flow rate by relaxing prostatic and bladder-neck smooth muscle through sympathetic activity blockade

Improve symptoms, increase urinary flow rate, and prevent BPH outcomes by reducing prostate enlargement through hormonal mechanisms

Slide 6

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 7

Objective of MTOPS

Independently Conducted by the US National Institutes of Health (NIH)

Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243.

MTOPS (Medical Therapy Of Prostatic Symptoms)

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

Slide 8

Study Design: Overview

Double-blind, placebo-controlled, multicenter, randomized Average follow-up: 4.5 years

AUA=American Urological Association; Qmax=maximum urinary flow

Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243.

RandomizedN=3047

Entry Criteria

• Men 50 years of age• AUA symptom score 8–

30• Qmax 4–15 ml/sec• Voided volume 125 ml

Doxazosin(n=756)

PROSCAR™

(n=768)

PROSCAR +doxazosin

(n=786)

Placebo(n=737)

MTOPS (Medical Therapy Of Prostatic Symptoms)

Slide 9

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

Study Design: Outcomes

Primary outcome

AUA-SI=American Urological Association Symptom Index; AUR=acute urinary retention

Adapted from Bautista OM et al Control Clin Trials 2003;24:224-243.

Secondaryoutcome

MTOPS (Medical Therapy Of Prostatic Symptoms)

Slide 10

Characteristic Value*

Age (years) 62.0

AUA-SI score 17.0

TRUS Prostate volume (cc) 31.0

Postvoid residual urine volume (ml) 39.0

Qmax (ml/second) 10.6

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.

No significant differences between groups

Baseline Characteristics of Patients MTOPS (Medical Therapy Of Prostatic Symptoms)

Slide 11

Impact of Medical Therapy on Clinical Progression of BPH

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.

Cumulative incidence of BPH progression

66%risk

reduction(p<0.001)

25

20

15

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

Per

cen

tag

e w

ith

eve

nt

Years from randomization

Placebo (n=737)PROSCAR™ (n=768)Doxazosin (n=756)Combination (PROSCAR + doxazosin) (n=786)

MTOPS (Medical Therapy Of Prostatic Symptoms)

p=0.002

p<0.001

p<0.001

Slide 12

Most BPH Progression Events Were Due to Symptom Progression

Distribution of BPH progression events

MTOPS (Medical Therapy Of Prostatic Symptoms)

UTI=urinary tract infection

Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396.

>4-point AUA-SIincrease 80%

AUR12%

Incontinence 7%UTI/urosepsis 1%Renal insufficiency 0%

Slide 13

Impact of Medical Therapy on Symptom Control

*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.

MTOPS (Medical Therapy Of Prostatic Symptoms)

Cumulative incidence of 4-point increase in symptom score*

25

20

15

10

5

0

Per

cen

tag

e w

ith

eve

nt

Years from randomization

Placebo (n=737)PROSCAR™ (n=768)Doxazosin (n=756)Combination (PROSCAR + doxazosin) (n=786)

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5

64%risk

reduction(p<0.0001)

Slide 14

Effect of Medical Therapy on Prostate Volume

*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.

MTOPS (Medical Therapy Of Prostatic Symptoms)

Change from baseline in prostate volume

–20 –10 0 10 20

Median % change from baseline

–16%*

–13%*

+18%

+18%

Combination (PROSCAR™ + doxazosin) (n=786)

PROSCAR (n=768)

Placebo (n=737)

Doxazosin (n=756)

Slide 15

81%risk

reduction(p<0.001)

Impact of Medical Therapy on the Risk of AUR

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.

Cumulative incidence of AUR

3.5

3.0

2.5

2.0

1.5

1.0

0.5

00 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5

Per

cen

tag

e w

ith

eve

nt

Years from randomization

MTOPS (Medical Therapy Of Prostatic Symptoms)

Placebo (n=737)PROSCAR™ (n=768)Doxazosin (n=756)Combination (PROSCAR + doxazosin) (n=786)

p<0.001

p=0.009

Slide 16

Impact of Medical Therapy on the Need for Invasive BPH Therapy*

*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.

Cumulative incidence of BPH-related surgery

10

8

6

4

2

0

Per

cen

tag

e w

ith

eve

nt

Years from randomization

Placebo (n=737)PROSCAR™ (n=768)Doxazosin (n=756)Combination (PROSCAR + doxazosin) (n=786)

MTOPS (Medical Therapy Of Prostatic Symptoms)

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5

67%risk

reduction(p<0.001)

p<0.001

p<0.001

Slide 17

PROSCAR Placebo Doxazosin PROSCAR™ and doxazosin

Variable (n=737) (n=756) (n=768) (n=786)

*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.

Medical Monotherapy and Combination Therapy Demonstrated Long-Term Tolerability

MTOPS (Medical Therapy Of Prostatic Symptoms)

Ten most frequent adverse events among groups*

Adverse EventErectile dysfunction 3.3 3.6 4.5** 5.1**Dizziness 2.3 4.4** 2.3 5.4**Postural hypotension 2.3 4.0** 2.6 4.3**Asthenia 2.1 4.1** 1.6 4.2**Decreased libido 1.4 1.6 2.4** 2.5**Abnormal ejaculation 0.8 1.1 1.8** 3.1**Peripheral edema 0.7 0.9 0.7 1.3**Dyspnea 0.6 0.9 0.6 1.2**Allergic reaction 0.5 0.9** 0.6 0.7Somnolence 0.4 0.8** 0.4 0.8**

Total no. of person-years 3489 3652 3600 3832

Slide 18

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

MTOPS (Medical Therapy Of Prostatic Symptoms)

*vs. placebo at 4 years

Adapted from McConnell JD et al N Engl J Med 2003;349(25):2385-2396.

Slide 19

The Future of Combination Therapy for BPH

Adapted from NIH news release. Available at: http://www.nih.gov/news/pr/may2002/niddk-28.htm.

Leroy M. Nyberg Jr, PhD, MD Director, Urology ProgramNational Institute of Diabetes and Digestive and Kidney Diseases

“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.”

Slide 20

References

Please refer to notes page.

Slide 21

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

MTOPS: Medical Therapy Of Prostatic Symptoms

Before prescribing any of the products mentioned

in this slide presentation, please consult the manufacturers’

prescribing information.