tim hargreave dept of oncology, edinburgh university the medical management of bph dutasteride...

Tim HargreaveDept of Oncology, Edinburgh University

The medical management of BPH

DutasterideDutasteride

Taipei July 16, 2005

My thanks to Prof Alex Tong- Long Lin

President of the Taiwan Continence Society

Professor Han-Sun ChiangDean 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 YuPresident of the Taiwan Urological Association

Mr Jerry Wu GlaxoSmithKline

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

Species ProstateRat

and

Mouse

Distinct dorsal, ventral and lateral prostate lobes with separate functions

No BPH

Human

And

Dog

Prostate zones in an anatomically single organ BPH and Cancer of Prostate

Horse Prostate not subject to BPH or cancer

Cat Prostate not subject to BPH or cancer

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

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

TestosteroneTestosterone

55-Reductase-ReductaseType 1Type 1

55-Reductase-ReductaseType 1Type 1

55-Reductase -Reductase Type 2Type 2

55-Reductase -Reductase Type 2Type 2

Dutasteride (Avodart) – dual inhibitor of DHT production

DHTDHT

Finasteride and Dutasteride

Dutasteride

95% suppression with dutasteride

0.5 mg

Dutasteride – Phase II studyDutasteride dose – DHT response

(n=399)

Dutasteride daily dose (mg)

-100

-80

-60

-40

-20

0

20

0.01 0.1 1 10Placebo

DH

T (

% c

han

ge

fro

m b

asel

ine)

Clark et al (1999)

71% suppression with finasteride

5 mg

• 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

Type 1 mRNA Type 2 mRNA

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

Type 1 and Type 2 5-alpha reductase in the prostate

Dutasteride: Phase III Study Design

Placebo Run-in

Dutasteride 0.5mg/day Dutasteride 0.5mg/day

Dutasteride 0.5mg/dayPlacebo

One month single-blind

24 months double-blind 24 months open-label

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

Dutasteride - Phase III StudiesMajor 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 1.5 and <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 Placebo /

Dutasteride N=1152

Dutasteride /

Dutasteride N=1188

Age (years) 66.0 66.2

AUA-SI 16.9 16.6

Qmax (mL/ sec) 10.7 10.2

PSA (ng/ mL) 3.9 4.1

Prostate Volume (cc)

53.9 56.1

Transition Zone (cc)

26.9 28.6

Data on File GlaxoSmithKline

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

Dutasteride: Phase III Subject Accountability

C om pleted 48 m onthsn = 803(70% )

N ot com pletedn = 349(30% )

Entered open-labeln = 1152

C om pleted 24 m onthsn = 1441

(67% )


Placebon = 2158

N ot C om pletedn = 657(30% )


C om pleted 48 m onthsn = 864(73% )

Entered open-labeln = 1188

C om pleted 24 M onthsn = 1510

(70% )

A vodartn = 2167

R andom izedn = 4325


DHT reductions sustained over 4 years

-94.1 -93.7 -94.8 -95.3-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

Med

ian

% C

han

ge

Placebo 2 years Dutasteride 4 years Open-label dutasteride after placebo

12 24 36 48

Treatment Month

Double-blind Open-label

Roehrborn CG et 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

1 3 6 12 24 48Treatment month

-0.6

0.2

-2.1 -1.5

1.4

-21.7

-5.2

-13.8

-19.9-23.6

-26.0 -27.3-30

-25

-20

-15

-10

-5

0

5Mean change (%)

* * *† *‡

*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

Placebo Dutasteride Open-label dutasteride after placebo


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

4 years

-7

-6

-5

-4

-3

-2

-1

0

0 6 12 18 24 30 36 42 48

Treatment Month

Mea

n (

+/-

SE

) C

han

ge

Placebo n=1152

Dutasteride n=1188


-2.5

-4.4

-6.5

-5.6

p<0.001

0.9


How Does Dutasteride Symptom Improvement How Does Dutasteride Symptom Improvement Compare to Published Studies?Compare to Published Studies?

0

1

2

3

4

5

6

7

8

9

Sym

ptom

impr

ovem

ent f

rom

bas

elin

e

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

0

0.5

1

1.5

2

2.5

3

3.5

0 6 12 18 24 30 36 42 48

Treatment Month

Mea

n C

hang

e (m

L/se

c)

Placebo n=1152

Dutasteride n=1188


2.7

1.9

0.6

2.2

p<0.01

0.8


Peak flow rate and voided volume decrease with increasing age

Olmsted County Study

Qmax (ml/sec) Volume (mL)

25

20

15

10

5

0

400

350

300

250

200

150

100

50

Age groups

40–44 50–5445–49 55–59 60–64 65–69 70–74 75+

Qmax

Volume

Girman et al (1993)

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

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. at Risk: 2167 2052 1928 1827 1633 1119 1025

919

0 6 12 18 24 30 36 42 48

Per

cen

t o

f P

atie

nts

Treatment Month

0

1

2

3

4

5

6

7

Placebo/dutasteride

Dutasteride/dutasteride


4.6%

1.9%

6.7%

3.3%


Cumulative risk of acute urinary retention

Olmsted County Study

Jacobsen et al (1997)

40

30

20

10

0

Inci

den

ce/

1,00

0 p

erso

n-y

ears

40-49 50-59 60-69 70-79Age (Years)

No– Mild symptoms

Moderate – Severe symptoms

Dutasteride: BPH-related SurgeryKaplan Meier Estimates: Time to First Event

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


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

Treatment: Dutasteride in Double-blind and Open-label


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

Placebo/Dutasteride

Dutasteride/dutasteride

0 6 12 18 24 30 36 42 48

Treatment Month

Per

cen

t o

f P

atie

nts

0

1

2

3

4

5

6 Double-blind Open-label

4.4%

2.4%

5.6%

3.3%


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

Placebo(n=2,158)

(% of patients)

Dutasteride(n=2,167)

(% of patients)

Adverse event Study month

0–6 7–12 13–18 19–24 0–6 7–12 13–18 19–24

Gynaecomastia 0.2 0.3 0.3 0.1 0.5 0.8 1.1 0.6

Erectile dysfunction 1.7 1.5 0.5 0.9 4.7 1.4 1.0 0.8

Decreased libido 1.4 0.6 0.2 0.1 3.0 0.7 0.3 0.3

Ejaculation disorders 0.5 0.3 0.1 0.0 1.4 0.5 0.5 0.1

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

5-reductase inhibitors and sexual AE’s

Dut vs FinType I & II 5ARI: Year 1

(Roehrborn et al*)Type II 5ARI: Year 1(McConnell et al**)

PlaceboN=2158

DutasterideN=2167

p PlaceboN=1376

FinasterideN=1384

p

Impotence 3.0% 6.0% P<0.001 3.7% 8.1% P<0.001

Decreased libido 1.9% 3.7% P<0.001 3.4% 6.4% P<0.001

Gynaecomastia*** 0.5% 1.3% P=0.009 0.2% 0.9% P=0.04

DecreasedEjaculate

NA NA - 0.8% 3.7% P<0.001

Ejaculationdisorder

0.7% 1.8% P<0.001 0.1% 0.8% P=0.003

* 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

No of Patients withdrawing

n=2167

% of Patients

Impotence 27 1%

Decreased Libido 23 1%

Ejaculation Disorder

6 <1%

Gynaecomastia* 24 1%


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

SMART1

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

Placeb

o

1 weekSingleblind

Combination

dutasteride 0.5mg dutasteride 0.5mg + placebo+ placebo

tamsulosintamsulosinCombination

dutasteride 0.5mg + tamsulosin 0.4mg

once daily

SMART-1: study design

Placebo run-in

4 weeksSingleblind

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

24 weeksSingleblind

12 weeksDouble blind

DT24 + D12

DT36

Wk 30 Wk 36

SMART-1: study endpointsPrimary 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


77%

91%

SMART-1: primary endpoint question at week 30 (at visit)

Pat

ien

ts (

%)


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

100

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

% patients better/same

80

60

40

20

0

Some pts miss their A Blockers


96% 93%

% p

atie

nts

bet

ter/

sam

e

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

100

*For patients responding same/better at week 30

SMART-1: primary endpoint at week 36 (nine months)

80

60

40

20

0

Differences no longer that apparent

SMART-1: primary endpoint question

at week 30 by baseline IPSS


100

80

60

40

20

0

Moderate(baseline IPSS <20)

(n=220)

% p

atie

nts

Bet

ter/

Sam

e

DT36 DT24 + D12 DT36 DT24 + D12

Severe(baseline IPSS 20)

(n=82)93%

84% 86%

58%

Severe pts need longer AB treatment

MTOPS

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

Cumulative incidence of BPH progression

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

% w

ith

even

t

Years from randomisation

Placebo (n=737)Finasteride (n=768)Doxazosin (n=756)Combination (n=786)

Combination vs. Placebo

66% risk reduction

(P=0.002)

(P<0.001)

(P<0.001)

• Risk reduction with finasteride and doxazosin was significantly greater than with either drug alone• Finasteride alone vs. placebo: 34% risk reduction• Doxazosin alone vs. placebo: 39% risk reduction.

CombAT Study Schematic

Tamsulosin 0.4mg odTamsulosin 0.4mg od

Dutasteride 0.5 mg odDutasteride 0.5 mg od

Combination

Placebo run-in

Safety Follow up

phase

Visit Window + 7 days

Scr

een

ing

V1aV1a V1bV1b V2V2 V3V3

V1a +7d + 2 days

BaselineV1b+28d+ 4 days

V2+13 Wks

V4 - V17V4 - V17 V18V18 V19V19

26 Wks - 195 Wks 208 Wks V18 +16 wks

Single-blind Double-blind

CombAT Primary Objective

• 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

• 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

• 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 Criteria

• 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

Finasteride prevention study (PCPT)

N 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

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0.00210 43 65 7

Years after randomisation

Probability of prostate cancer

PlaceboFinasteride

Placebo group Biopsy rate (%) 3.0 2.8 2.2 2.9 2.8 2.6 7.1Total no. of cancers diagnosed 48 71 60 80 92 96 124No. of grade 7–10 cancers 5 6 15 35 24 24 38Finasteride groupBiopsy rate (%) 3.3 2.0 2.1 2.5 2.1 2.2 7.0Total no. of cancers diagnosed 42 35 39 68 78 51 122No. of grade 7–10 cancers 11 11 17 31 28 26 64

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

PCPTWhat 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

• 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

PCPTWhat does it not tell us?

Type 1 and 2 5-reductase expression in prostate cancer

Increased expression of Type 1 5-reductase

in PCa

1 3 5 7 9 11 2 4 6 8 100

10

20

30

40

50

60

70

80

Me

an

Are

a o

f M

od

era

te +

Hig

h I

nte

ns

ity

Sta

inin

g(%

of

To

tal

Ep

ith

eli

al/T

um

or

Are

a)

BPH PIN Primary Recurrent BPH PIN Primary Recurrent

5R1 5R2

1

Mets Mets

Thomas et al. The Prostate 2004: Epub

Dutasteride BPH studies Prostate cancer detection* - Year

0-2

0

10

20

30

40

50

60

0 200 400 600 800 1000

Num

ber

of

subj

ects

Tx Day when diagnosed

placebo

dutasteride

50% reduction in PCa 50% reduction in PCa incidence overall*incidence overall*

61% reduction in PCa 61% reduction in PCa incidence starting month 13*incidence starting month 13*

Andriole et al. Urology 2004; 64: 537–41* reported as adverse eventsAndriole et al. Urology 2004; 64: 537–41* reported as adverse events

What about year 2-4?

Dutasteride – Phase III BPH studiesFor-cause PCa detection

Time (months)

0 6 12 18 24 30 36 42 48

Probability of prostate cancer 1.2% versus 2.5%, p=0.002

Treatment Placebo Dutasteride

0

0.01

0.02

0.03

0.04

0.05

n=55

n=27

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

REduction by DUtasteride of prostate Cancer Events (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

Randomisation aim: n=8,000

Dutasteride 0.5 mg/day

4 years

Placebo4 years

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

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

REDUCE(REduction by DUtasteride of prostate Cancer Events) :

Study Design

2 year biopsy(Visit 6)

4 year biopsy(Visit 10)

Randomization(Visit 2)

-7 0 24 48

Entry biopsy

4-year Treatment period

Placeborun-in

month: -1

4-month Follow-up

52

Study Entry (Screen Visit 1)

For-cause biopsies may occur here

Interim analysis following 2 yearsFollow-up of premature withdrawals for clinical eventsInterim analysis following 2 yearsFollow-up of premature withdrawals for clinical events

Conclusions• 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 Guidelines5- 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


• 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)


• 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


• 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


• 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


• Side effects of finasteride are minimal

• Side effects of dutasteride similar to those seen with finasteride


• 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

• Total medical management of AUR

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

tim hargreave dept of oncology, edinburgh university the medical management of bph dutasteride...

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