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Tim Hargreave Dept of Oncology, Edinburgh University. The medical management of BPH. Dutasteride. Taipei July 16, 2005. My thanks to. Prof Alex Tong- Long Lin President of the Taiwan Continence Society Professor Han-Sun Chiang Dean of the College of Medicine, Fu-jen University

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Tim Hargreave

Dept of Oncology, Edinburgh University

The medical management of BPH

Dutasteride

Taipei July 16, 2005


My thanks to

Prof Alex Tong- Long Lin

President of the Taiwan Continence Society

Professor Han-Sun Chiang

Dean of the College of Medicine, Fu-jen University

Professor Guang-Huan Sun

Head of Department of Surgery, Tri-Service General Hospital NDMC

Prof Dah-Shyong Yu

President of the Taiwan Urological Association

Mr Jerry Wu GlaxoSmithKline


Content
Content

  • About 5 alpha reductase inhibition

  • Dutasteride phase 3 data and the open label continuation 4 year data

  • SMART study:- combination and subsequent withdrawal of alpha blocker after 6 months

  • COMBAT:- fixed dose combination

  • Prostate cancer prevention


BPH and CaP occurs in Humans and Dogs but not in other animals subject to the same environmental chemicals

Difficulty with animal models of Human Prostate Disease


Steroid 5 alpha-reductase deficiency in man: an inherited from of male psuedohermaphroditism Imperato – McGinley J Geurrero L Gautier T Petersen RE (1974) Science 186 : 1213


Dutasteride avodart dual inhibitor of dht production
Dutasteride (Avodart) from of male psuedohermaphroditism–dual inhibitor of DHT production

Dutasteride

5-ReductaseType 1

Testosterone

DHT

5-Reductase Type 2

Finasteride and Dutasteride

Bartsch G et al. Eur Urol 2000;37:367–380.


Dutasteride phase ii study dutasteride dose dht response n 399
Dutasteride – Phase II study from of male psuedohermaphroditismDutasteride dose – DHT response (n=399)

20

0

71% suppression

with finasteride

5 mg

-20

DHT (% change

from baseline)

-40

95% suppression

with dutasteride 0.5 mg

-60

-80

-100

Placebo

0.01

0.1

1

10

Dutasteride daily dose (mg)

Clark et al (1999)


Type 1 and type 2 5 alpha reductase in the prostate
Type 1 and Type 2 5 from of male psuedohermaphroditism-alpha reductase in the prostate

Type 1 mRNA

Type 2 mRNA

  • In normal tissue Type 1 and Type 2 were expressed similarly in all zones (PZ=peripheral zone; TZ=transition zone; CZ=central zone)

  • In BPH tissue, Type 1 and Type 2 were increased vs normal prostate

  • In prostate cancer (CaP) tissue, Type 1, but not Type 2, was increased vs normal prostate

Lehle C et al. J Ster Biochem Mol Biol 1999;68:189–195. My comment is that these potentially important data need confirmation in another laboratory


Dutasteride phase iii study design
Dutasteride: from of male psuedohermaphroditismPhase III Study Design

One month single-blind

24 months double-blind

24 months open-label

Dutasteride 0.5mg/day

Dutasteride 0.5mg/day

Placebo Run-in

Placebo

Dutasteride 0.5mg/day

Roehrborn C et al. J Urology 2003 169; 1292.


Dutasteride phase iii studies major entry criteria
Dutasteride - Phase III Studies from of male psuedohermaphroditismMajor Entry Criteria

  • Male aged  50 years

  • Diagnosis of BPH by history and DRE

  • AUA-SI  12 (moderate to severe symptoms)

  • Prostate volume  30 cc by transrectal ultrasound

  • Serum PSA 1.5and <10ng/mL

  • Two voids at screening with Qmax  15 ml/sec (moderate to severe impairment) and minimum voided volume of  125 ml

Roehrborn C et al. J Urology 2003 169; 1292.


Dutasteride mean baseline data for open label population
Dutasteride: from of male psuedohermaphroditismMean Baseline Data for open label population

Baseline data for this subset no different from larger double-blind population

Data on File GlaxoSmithKline


Dutasteride phase iii subject accountability
Dutasteride: from of male psuedohermaphroditismPhase III Subject Accountability

Data on File GlaxoSmithKline


Dht reductions sustained over 4 years
DHT reductions sustained over 4 years from of male psuedohermaphroditism

Double-blind Open-label

12 24 36 48

Treatment Month

Placebo 2 years

Dutasteride 4 years

Open-label dutasteride after placebo

Roehrborn CGet al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495


Reductions in total prostate volume over 4 years with dutasteride
Reductions in total prostate volume from of male psuedohermaphroditismover 4 years with dutasteride

Placebo

Dutasteride

Open-label dutasteride after placebo

Mean change (%)

*

*

*

*

5

1.4

0.2

0

-0.6

-1.5

-2.1

-5

-5.2

-10

-15

-13.8

-20

-19.9

-21.7

-25

-23.6

-26.0

-27.3

-30

Treatment month

1

3

6

12

24

48

*p<0.001 for differences between treatment groups

†p<0.001 for change from Month 24 to Month 48

‡p=0.07 for change from Month 24 to Month 48

Roehrborn CGet al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495


Symptom improvements aua si from 6 months with continuing improvements over 4 years

 0.9 from of male psuedohermaphroditism

Placebo n=1152

Dutasteride n=1188

Symptom improvements (AUA-SI) from 6 months, with continuing improvements over 4 years

Double-blind Open-label

-2.5

p<0.001

-4.4

-5.6

-6.5

Roehrborn CGet al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495


How does dutasteride symptom improvement compare to published studies
How Does Dutasteride Symptom Improvement Compare to Published Studies?

Dutasteride 4 year - AUA-SI - 2 year DB, 2 year OL; data on file GlaxoSmithKline

PLESS 4 year - Quasi AUA-SI - 4 year DB placebo-controlled; McConnell et al. New Engl J Med, 1998

Finasteride 5 year OL - Quasi AUA-SI - 4 year OL after 1 year DB; Hudson et al., Urology 1999

Alfuzosin 1 year OL - IPSS - 9 month OL after 3 month DB at 10mg QD; van Kerrebroeck et al., Euro Urol 2002

Tamsulosin 4 year OL -Boyarsky index - 0.4mg OL extension of European DB studies; Schulman et al., J of Urol 2001

MTOPS Steering Committee. J Urol 2002;167:265 (AUA-SI)

All other data series: Meta-analysis data, AUA BPH Guidelines 2003. Chapter 3, Appendix 3.

Dutasteride

Finasteride

Alpha blockers

4 year data


Urinary flow improved from 1 month and onwards to 4 years
Urinary flow improved from 1 month and onwards to 4 years Published Studies?

Double-blind Open-label

p<0.01

2.7

2.2

 0.8

1.9

0.6

Placebo n=1152

Dutasteride n=1188

Roehrborn CGet al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495


Peak flow rate and voided volume decrease with increasing age olmsted county study
Peak flow rate and voided volume decrease with increasing age Olmsted County Study

25

20

15

10

5

0

Volume (mL)

Qmax (ml/sec)

400

350

300

250

200

150

100

50

Qmax

Volume

40–44

45–49

50–54

55–59

60–64

65–69

70–74

75+

Age groups

Girman et al (1993)


Dutasteride acute urinary retention kaplan meier estimates time to first event

Placebo/dutasteride age

Dutasteride/dutasteride

Dutasteride: Acute Urinary RetentionKaplan Meier Estimates: Time to First Event

7

Double-blind Open-label

6.7%

6

4.6%

5

4

Percent of Patients

3.3%

3

2

1

1.9%

0

0 6 12 18 24 30 36 42 48

Treatment Month

Treatment: Placebo in Double-Blind, dutasteride in Open-label

No. of Events (cumulative): 28 49 70 87 97 103 106 111

No. at Risk: 2158 2039 1919 1793 1557 1054 940 851

Treatment: dutasteride in Double-blind and Open-label

No. of Events (cumulative): 19 27 31 38 40 45 49 52

No. at Risk: 2167 2052 1928 1827 1633 1119 1025 919

Roehrborn CGet al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495


Cumulative risk of acute urinary retention olmsted county study
Cumulative risk of acute urinary retention age Olmsted County Study

40

30

20

10

0

No– Mild symptoms

Moderate – Severe symptoms

Incidence/ 1,000 person-years

70-79

50-59

60-69

40-49

Age (Years)

Jacobsen et al (1997)


Dutasteride bph related surgery kaplan meier estimates time to first event
Dutasteride: BPH-related Surgery age Kaplan Meier Estimates: Time to First Event

6

Double-blind Open-label

5.6%

4.4%

5

4

Placebo/Dutasteride

Dutasteride/dutasteride

3.3%

3

Percent of Patients

2

2.4%

1

0

0 6 12 18 24 30 36 42 48

Treatment Month

Treatment: Placebo in Double-Blind, dutasteride in Open-label

No. of Events (cumulative): 13 40 59 85 90 95 96 98

No. at Risk: 2158 2057 1944 1823 1587 1070 956 866

Treatment: Dutasteride in Double-blind and Open-label

No. of Events (cumulative): 12 25 39 47 50 52 56 57

No. at Risk: 2167 2064 1944 1846 1651 1125 1033 930

Roehrborn CGet al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495


Drug related adverse events in the first two years db period
Drug-related adverse events in the first two years (DB period)

Gerald L. Andriole and Roger Kirby. European Urology 44 (2003) 82-88


5 reductase inhibitors and sexual ae s dut vs fin
5-reductase period)inhibitors and sexual AE’sDut vs Fin

* Roehrborn et al. Urology 2002; 60: 434-441

**McConnell et al. NEJM 1998; 338: 557-563

***includes breast tenderness or enlargement


Coincidence of urinary and sexual symptoms - cause or effect?

From Hargreave and Stephenson Potency and Prostatectomy

BJUrol 1977 49,683


Withdrawals due to sexual function and gynaecomastia adverse events over 4 years is relatively few
Withdrawals Due to Sexual Function and Gynaecomastia Adverse Events over 4 years is relatively few

Patients who received dutasteride in both the double-blind and open-label phases. *Includes breast enlargement and breast/nipple tenderness

Data on File GlaxoSmithKline


Smart1

SMART1 Events over 4 years is relatively few

When can you withdraw alpha blocker from a dutasteride-alpha blocker combination?


Smart 1 study design

DT24 + D12 Events over 4 years is relatively few

SMART-1: study design

DT36

dutasteride 0.5mg

+ placebo

tamsulosin

Combination

dutasteride 0.5mg

+ tamsulosin 0.4mg

once daily

Placebo

Placebo run-in

Combination

4 weeks

Single

blind

24 weeks

Single

blind

12 weeks

Double blind

1 week

Single

blind

Wk 30

Wk 36

J Barkin et al. European Urology (2003): 44; 461-466.


Smart 1 study endpoints
SMART-1: Events over 4 years is relatively few study endpoints

Primary endpoint

  • At 30 weeks post-baseline (e.g. 6 weeks post-withdrawal of tamsulosin in one group)

    ‘over the past 2 weeks, on average have you felt better, worse or the same, with respect to your urinary symptoms, than at your last visit?’

    Secondary endpoint

  • IPSS – changes from baseline and changes relative to withdrawal point

J Barkin et al. European Urology (2003): 44; 461-466.


Smart 1 primary endpoint question at week 30 at visit
SMART-1: primary endpoint question Events over 4 years is relatively fewat week 30 (at visit)

100

80

60

Patients (%)

40

Some pts miss their A Blockers

20

0

DT36 (n=154) DT24 + D12 (n=149)

% patients better/same

DT36 = combination dutasteride+ tamsulosin for 36 weeksDT24 + D12 = combination dutasteride+ tamsulosin for 24 weeksfollowed by dutasteride+ placebo for 12 weeks

J Barkin et al. European Urology (2003): 44; 461-466.


Smart 1 primary endpoint at week 36 nine months
SMART-1: primary endpoint Events over 4 years is relatively fewat week 36 (nine months)

100

80

60

Differences no longer

that apparent

% patients better/same

40

20

0

DT36 (n=139) DT24 + D12 (n=115)

*For patients responding same/better at week 30

J Barkin et al. European Urology (2003): 44; 461-466.


Smart 1 primary endpoint question at week 30 by baseline ipss
SMART-1: primary endpoint question Events over 4 years is relatively fewat week 30 by baseline IPSS

Severe

(baseline IPSS 20)

(n=82)

Moderate

(baseline IPSS <20)

(n=220)

93%

100

80

60

40

20

0

84%

86%

58%

% patients Better/Same

Severe pts need longer AB treatment

DT36 DT24 + D12 DT36 DT24 + D12

J Barkin et al. European Urology (2003): 44; 461-466.


Mtops
MTOPS Events over 4 years is relatively few

Cumulative incidence of BPH progression

25

20

15

10

5

0

Combination vs. Placebo

66%

risk reduction

Placebo (n=737)

Finasteride (n=768)

Doxazosin (n=756)

Combination (n=786)

(P=0.002)

% with event

  • Risk reduction with finasteride and doxazosin was significantly greater than with either drug alone

  • Finasteridealone vs. placebo: 34% risk reduction

  • Doxazosin alone vs. placebo: 39% risk reduction.

(P<0.001)

(P<0.001)

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 randomisation

Adapted from McConnell J et al. N Engl J Med 2003;349:2387-2398


Combat study schematic
CombAT Study Schematic Events over 4 years is relatively few

Single-blind

Double-blind

Tamsulosin 0.4mg od

Safety Follow up phase

Placebo run-in

Dutasteride 0.5 mg od

Screening

Combination

V1a

V1b

V2

V3

V4 - V17

V18

V19

Baseline

V1b+28d

+ 4 days

V1a +7d

+ 2 days

V2+13 Wks

26 Wks - 195 Wks

208 Wks

V18 +16 wks

Visit Window + 7 days


Combat primary objective
CombAT Primary Objective Events over 4 years is relatively few

  • To demonstrate superior efficacy of combination therapy compared to each monotherapy for:

    • symptom improvement (IPSS) at 2 years of treatment

    • clinical outcomes of AUR or BPH-related surgery at 4 years of treatment


Combat secondary objectives
CombAT Secondary Objectives Events over 4 years is relatively few

  • To demonstrate superior efficacy of combination therapy compared to each monotherapy for:

    • overall risk of BPH clinical progression

    • health outcome measures

    • safety and tolerability


Combat inclusion criteria
CombAT Inclusion Criteria Events over 4 years is relatively few

  • Males, aged  50 years

  • BPH clinical diagnosis (by history and DRE)

  • IPSS  12 points at screening

  • Prostate Volume  30 cc by TRUS

  • Total PSA  1.5ng/mL at screening


Combat inclusion criteria1
COMBAT Inclusion Criteria Events over 4 years is relatively few

  • Maximum Flow Rate

    • Qmax > 5 mL/sec and 15 mL/sec with minimum voided volume of  125mL at screening (based on 2 voids)

  • Others

    • Willing/able to give Informed Consent and comply with study procedures

    • Literate and able to comprehend and record information on questionnaires

    • Able to swallow oral medications

    • Willing/able to participate in study for 4 years


Prostate cancer prevention

Prostate Cancer Prevention Events over 4 years is relatively few


Finasteride prevention study (PCPT) Events over 4 years is relatively fewN Eng J Med 2003;349:213-22National Cancer Institute (with SWOG & ECOG)Headline effect Prostate cancer prevalence reduced by 24.8% i.e. from 24.4% to 18.4%


PCPT – cumulative incidence of prostate cancer Events over 4 years is relatively few

Probability of prostate cancer

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0.00

Placebo

Finasteride

0

1

2

3

4

5

6

7

Years after randomisation

Placebo group Biopsy rate (%) 3.0 2.8 2.2 2.9 2.8 2.6 7.1

Total no. of cancers diagnosed 48 71 60 80 92 96 124

No. of grade 7–10 cancers 5 6 15 35 24 24 38

Finasteride group

Biopsy rate (%) 3.3 2.0 2.1 2.5 2.1 2.2 7.0

Total no. of cancers diagnosed 42 35 39 68 78 51 122

No. of grade 7–10 cancers 11 11 17 31 28 26 64

Thompson et al. NEJM 2003; 349: 215–24


Pcpt what does it tell us
PCPT Events over 4 years is relatively fewWhat does it tell us?

  • Intervention can alter the prevalence of prostate cancer

  • Finasteride 5 mg daily will reduce the prevalence of biopsy proven prostate cancer by approximately 25%

  • Considering for cause biopsies this represents an absolute risk reduction from 8.7 to 6.3 ie 2.4%

  • Such treatment will be associated with the expected increase in sexual related adverse events, and beneficial effects on BPH related urinary symptoms


Pcpt what does it not tell us
PCPT Events over 4 years is relatively fewWhat does it not tell us?

  • Whether this is prevention, or treatment (delay in progression) of occult disease

  • Whether the reduced prevalence affects the incidence of clinical prostate cancer

  • If finasteride can reduce prostate cancer deaths

  • At what age prophylactic treatment should be started

  • Whether there are men at risk for whom prophylaxis treatment is indicated


80 Events over 4 years is relatively few

70

60

50

40

30

20

10

Type 1 and 2 5-reductase expression in prostate cancerIncreased expression of Type 1 5-reductase in PCa

Mean Area of Moderate + High Intensity Staining

(% of Total Epithelial/Tumor Area)

1

0

BPH

1

PIN

3

Primary

5

Recurrent

7

9

11

BPH

2

PIN

4

Primary

6

Recurrent

8

10

Mets

Mets

5R1

5R2

Thomas et al. The Prostate 2004: Epub


Dutasteride bph studies prostate cancer detection year 0 2
Dutasteride BPH studies Events over 4 years is relatively fewProstate cancer detection* - Year 0-2

50% reduction in PCa

incidence overall*

placebo

61% reduction in PCa

incidence starting month 13*

Number of subjects

dutasteride

Tx Day when diagnosed

Andriole et al. Urology 2004; 64: 537–41

* reported as adverse events


What about year 2 4

What about year 2-4? Events over 4 years is relatively few


Dutasteride – Phase III BPH studies Events over 4 years is relatively fewFor-causePCa detection

Probability of prostate cancer

1.2% versus 2.5%, p=0.002

0.05

n=55

0.04

0.03

0.02

n=27

Treatment

Placebo

Dutasteride

0.01

0

0

6

12

18

24

30

36

42

48

Time (months)

Andriole et al. Urology 2004; 64: 537–41


Reduction by dutasteride of prostate cancer events reduce study
REduction by DUtasteride of prostate Cancer Events Events over 4 years is relatively few (REDUCE) study

  • Men aged 50–75 years with:

  • One negative prostate biopsy within 6 months of study entry

  • PSA 2.5 and 10 ng/mL

  • IPSS <25 and Qmax5 mL/sec

  • Prostate volume 80 mL

1 month placebo run-in

Dutasteride 0.5 mg/day4 years

Placebo4 years

Randomisation aim: n=8,000

2- and 4-year biopsies and biopsies ‘for-cause’ as indicated clinically

Andriole et al. J Urol 2004; 172: 1314–7


REDUCE Events over 4 years is relatively few

(REduction by DUtasteride of prostate Cancer Events) :

Study Design

Randomization

(Visit 2)

2 year biopsy

(Visit 6)

4 year biopsy

(Visit 10)

Study Entry (Screen Visit 1)

-7

-1

0

24

48

52

month:

4-year Treatment period

Placebo

run-in

Entry biopsy

4-month Follow-up

For-cause biopsies may occur here

Interim analysis following 2 years

Follow-up of premature withdrawals for clinical events


Conclusions
Conclusions Events over 4 years is relatively few

  • The PCPT provides strong evidence that 5ARIs can reduce the risk of prostate cancer.

  • The primary PCPT publication demonstrated an elevated risk of high-grade tumours in the finasteride arm compared with the placebo arm but this is now thought to reflect study bias:

    • Most significantly the effect of finasteride in reducing prostate volume (Thompson et al 2005)

    • No evidence of dose effect (If finasteride induces high grade CaP then the rate of high grade disease should have increased over time but it did not).

    • Gleason grading more difficult to interpret after hormonal treatment

    • No difference in proportion of high grade tumours in end of study biopsies. The higher biopsy rate at one year was likely to be the result of PSA doubling rule (Thompson et al. NEJM 2003; 349: 215–24)

  • The REDUCE study will further clarify the Gleason issue


Eau guidelines 5 alpha reductase inhibitors
EAU Guidelines Events over 4 years is relatively few5- alpha reductase inhibitors

  • It has been shown in numerous randomised, placebo controlled trials that finasteride is capable of reducing prostate volume and improving symptom scores and flow rates. Maximum benefits are seen at a mean period of 6 months

  • There is now evidence that dutasteride is at least as effective as finasteride in reducing prostate volume


Eau guidelines 5 alpha reductase inhibitors1
EAU Guidelines Events over 4 years is relatively few5- alpha reductase inhibitors

  • Men with small prostates (<40ml) are less likely to benefit from finasteride

  • Data from MTOPS indicates that most men will respond to finasteride in the longer term irrespective of prostate size and the indications for finasteride have been extended.

  • Dutasteride trial data indicates that dutasteride is very effective in men with prostates greater than 30ml (trial entry criterion)


Eau guidelines 5 alpha reductase inhibitors2
EAU Guidelines Events over 4 years is relatively few5- alpha reductase inhibitors

  • Finasteride can alter natural history of symptomatic BPH by influencing prostatectomy and acute urinary retention rates. The costs of such protocols, however, should be further evaluated.

  • Evidence indicates that dutasteride is at least as effective as finasteride. Significant reduction in AUR (57%) and BPH-related surgery (48%) risks compared to placebo in first 2 years

    • From year 2-4, continued protection for Dut-Dut patients.

    • From year 2-4 adoption of dutasteride protection / slope for plab-dut patients


Eau guidelines 5 alpha reductase inhibitors3
EAU Guidelines Events over 4 years is relatively few5- alpha reductase inhibitors

  • The long term (up to 6 years) effects of finasteride are substantial

  • We do not have 6 year data for dutasteride. The 4 year data from the phase 3 study show that dutasteride has a substantial effect at least as great as that from finasteride

    • 6.5 point AUA-SI (from run in baseline)

    • 9.0 point AUA-SI (from screening baseline)

    • 10.1 point AUA-SI improvement in patients with severe symptoms

    • sustained and durable reduction in prostate volume


Eau guidelines 5 alpha reductase inhibitors4
EAU Guidelines Events over 4 years is relatively few5- alpha reductase inhibitors

  • The combination of finasteride with an alpha-blocker is of no benefit according to the data currently available

  • MTOPs demonstrates that the combination of finasteride and doxazosin is superior to either medication alone

  • We do not have data equivalent to the MTOPS study for dutasteride. Data from the Smart study indicates that most men can stop combination therapy after 6 months but those with severe symptoms should continue with combination therapy of dutasteride and tamsulosin for one year


Eau guidelines 5 alpha reductase inhibitors5
EAU Guidelines Events over 4 years is relatively few5- alpha reductase inhibitors

  • Side effects of finasteride are minimal

  • Side effects of dutasteride similar to those seen with finasteride


Eau guidelines 5 alpha reductase inhibitors6
EAU Guidelines Events over 4 years is relatively few5- alpha reductase inhibitors

  • Finasteride treatment does not mask the detection of prostate cancer. By doubling the PSA serum levels an accurate estimation can be expected

  • For Dutasteride treatment there is the same recommendation i.e. PSA should not be measured within the first 6 months because the results cannot be interpreted but thereafter the results should be double to make comparison with pretreatment readings.


The future
The Future Events over 4 years is relatively few

  • Total medical management of AUR

  • Clarification of the effect of 5 alpha reductase treatment on prostate cancer


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