Transcript BPH - 台灣泌尿科醫學會

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
• 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
Species
Prostate
Rat
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
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
5-Reductase
Type 1
Testosterone
5-Reductase
Type 2
Finasteride and Dutasteride
Bartsch G et al. Eur Urol 2000;37:367–380.
DHT
Dutasteride – Phase II study
Dutasteride dose – DHT response
(n=399)
20
DHT (% change
from baseline)
0
71% suppression
with finasteride
5 mg
-20
-40
95% suppression
with dutasteride
0.5 mg
-60
-80
-100
Placebo
0.01
0.1
1
Dutasteride daily dose (mg)
Clark et al (1999)
10
Type 1 and Type 2 5-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
One month
single-blind
24 months double-blind
Placebo
Run-in
Dutasteride 0.5mg/day
Placebo
Roehrborn C et al. J Urology 2003 169; 1292.
24 months open-label
Dutasteride 0.5mg/day
Dutasteride 0.5mg/day
Dutasteride - Phase III Studies
Major 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
Age (years)
Placebo /
Dutasteride
N=1152
66.0
Dutasteride /
Dutasteride
N=1188
66.2
AUA-SI
16.9
16.6
Qmax (mL/sec)
10.7
10.2
3.9
4.1
53.9
56.1
26.9
28.6
PSA (ng/mL)
Prostate Volume
(cc)
Transition Zone
(cc)
Baseline data for this subset no different from larger double-blind population
Data on File GlaxoSmithKline
Dutasteride:
Phase III Subject Accountability
Randomized
n = 4325
Placebo
n = 2158
Completed 24 months
n = 1441
(67%)
Avodart
n = 2167
Not completed
n = 717
(33%)
Entered open-label
n = 1152
Completed 48 months
n = 803
(70%)
Data on File GlaxoSmithKline
Not completed
n = 349
(30%)
Not Completed
n = 657
(30%)
Completed 24 Months
n = 1510
(70%)
Entered open-label
n = 1188
Not completed
n = 324
(27%)
Completed 48 months
n = 864
(73%)
DHT reductions sustained over 4 years
10
Double-blind
Open-label
0
Median % Change
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
-94.1
12
-93.7
-94.8
24
36
Treatment Month
Placebo 2 years
Dutasteride 4 years
Open-label dutasteride after placebo
Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495
-95.3
48
Reductions in total prostate volume
over 4 years with dutasteride
Placebo
Mean change (%)
5
0
-5
Dutasteride
Open-label dutasteride after placebo
* *
1.4
0.2
-0.6
-2.1
*† *‡
-1.5
-5.2
-10
-15
-13.8
-20
-19.9
-25
-30
Treatment month 1
-21.7
-23.6
-26.0
3
6
12
*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 CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495
24
-27.3
48
Symptom improvements (AUA-SI) from 6
months, with continuing improvements over
4 years
0
Mean (+/- SE) Change
Double-blind
-1
Open-label
-2.5
-2
-3
p<0.001
-4
-5
-4.4
-5.6
 0.9
-6
-6.5
-7
0
6
12
18
24
30
36
Treatment Month
Placebo n=1152
Dutasteride n=1188
Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495
42
48
Dutasteride
9
Finasteride
8
Alpha blockers
7
6
Dutasteride 4 year - AUA-SI
- 2 year DB, 2 year OL; data
on file GlaxoSmithKline
PLESS 4 year - Quasi AUASI - 4 year DB placebocontrolled; 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
5
4
Alfuzosin 1 year OL - IPSS
- 9 month OL after 3 month
DB at 10mg QD; van
Kerrebroeck et al., Euro Urol
2002
3
2
1
1
y
PL
ES r
S
4y
M
TO
r
PS
Ta
m
4y
la
r
be
5y
Ta
l1
rO
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3w
L
la
ks
be
tu
l1
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3w
1
ks
tu
dy
Al
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f1
ra
yr
zo
O
s in
L
AU
A
Do
1y
x
AU r
Do
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x
-4
1y
r
yr
M
T
Ta
OP
m
S
-5
yr
O
L
L
O
AU
A
4y
r
DB
yr
2
yr
DB
0
1
Symptom improvement from baseline
How Does Dutasteride Symptom Improvement
Compare to Published Studies?
4 year data
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: Metaanalysis data, AUA BPH
Guidelines 2003. Chapter 3,
Appendix 3.
Urinary flow improved from 1 month and
onwards to 4 years
3.5
Mean Change (mL/sec)
Double-blind
Open-label
p<0.01
3
2.7
2.2
2.5
 0.8
2
1.9
1.5
0.6
1
0.5
0
0
6
12
Placebo n=1152
18
24
30
Treatment Month
Dutasteride n=1188
Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495
36
42
48
Peak flow rate and voided volume
decrease with increasing age
Olmsted County Study
Qmax (ml/sec)
25
Qmax
Volume
20
Volume (mL)
400
350
300
15
250
200
10
150
5
0
100
40–44 45–49 50–54 55–59 60–64 65–69 70–74 75+
Age groups
Girman et al (1993)
50
Dutasteride: Acute Urinary Retention
Kaplan Meier Estimates: Time to First Event
7
Double-blind
6.7%
Open-label
6
4.6%
5
Placebo/dutasteride
Dutasteride/dutasteride
4
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
No. at Risk:
2158
49
70
87
97
103
106
111
2039
1919
1793
1557
1054
940
851
27
31
38
40
45
49
52
2052
1928
1827
1633
1119
1025
919
Treatment: dutasteride in Double-blind and Open-label
No. of Events (cumulative): 19
No. at Risk:
2167
Roehrborn CG et 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
40
Incidence/ 1,000 person-years
No– Mild symptoms
Moderate – Severe symptoms
30
20
10
0
40-49
Jacobsen et al (1997)
50-59
60-69
Age (Years)
70-79
Dutasteride: BPH-related Surgery
Kaplan Meier Estimates: Time to First Event
6
Double-blind
Open-label
5
Percent of Patients
5.6%
4.4%
4
Placebo/Dutasteride
Dutasteride/dutasteride
3
3.3%
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
No. at Risk:
2158
40
59
85
90
95
96
98
2057
1944
1823
1587
1070
956
866
25
39
47
50
52
56
57
2064
1944
1846
1651
1125
1033
930
Treatment: Dutasteride in Double-blind and Open-label
No. of Events (cumulative): 12
No. at Risk:
2167
Roehrborn CG et 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)
Dutasteride
(n=2,167)
(% of patients)
Placebo
(n=2,158)
(% of patients)
Study month
Adverse event
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 Fin
Type I & II 5ARI: Year 1
(Roehrborn et al*)
Type II 5ARI: Year 1
(McConnell et al**)
Placebo
N=2158
Dutasteride
N=2167
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
Decreased
Ejaculate
NA
NA
-
0.8%
3.7%
P<0.001
Ejaculation
disorder
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
Placebo Finasteride
N=1376
N=1384
p
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
27
% of Patients
Decreased Libido
23
1%
Ejaculation
Disorder
6
<1%
Gynaecomastia*
24
1%
Impotence
1%
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
When can you withdraw alpha
blocker from a dutasteride-alpha
blocker combination?
SMART-1: study design
DT24 + D12
DT36
Placebo
Placebo
run-in
Combination
dutasteride 0.5mg
+ tamsulosin 0.4mg
once daily
dutasteride 0.5mg
+ placebo
tamsulosin
Combination
4 weeks
Single
blind
24 weeks
Single
blind
12 weeks
Double blind
Wk 30
J Barkin et al. European Urology (2003): 44; 461-466.
1 week
Single
blind
Wk 36
SMART-1: study endpoints
Primary endpoint
• At 30 weeks post-baseline (e.g. 6 weeks postwithdrawal 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)
100
91%
77%
Patients (%)
80
60
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 weeks
DT24 + D12 = combination dutasteride + tamsulosin for 24 weeks
followed 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)
100
96%
93%
% patients better/same
80
60
40
Differences no longer
that apparent
20
0
DT36 (n=139)
*For patients responding same/better at week 30
J Barkin et al. European Urology (2003): 44; 461-466.
DT24 + D12 (n=115)
SMART-1: primary endpoint question
at week 30 by baseline IPSS
100
Moderate
(baseline IPSS <20)
(n=220)
Severe
(baseline IPSS 20)
(n=82)
93%
84%
86%
80
60
58%
40
20
0
Severe pts need longer AB treatment
DT36
J Barkin et al. European Urology (2003): 44; 461-466.
DT24 + D12
DT36
DT24 + D12
MTOPS
Cumulative incidence of BPH progression
% with event
25
Combination vs.
Placebo
66%
risk reduction
Placebo (n=737)
Finasteride (n=768)
Doxazosin (n=756)
Combination (n=786)
20
15
(P=0.002
)
(P<0.001)
10
(P<0.001)
5
0
0
0.5
1.0
1.5 2.0
2.5
3.0
3.5
4.0
4.5
Years from randomisation
Adapted from McConnell J et al. N Engl J Med 2003;349:2387-2398
5.0
5.5
• 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
Double-blind
Single-blind
Tamsulosin 0.4mg od
Safety
Follow up
phase
Placebo
run-in
Dutasteride
0.5 mg od
Combination
V1a
V1b
V1a +7d
+ 2 days
V2
Baseline
V1b+28d
+ 4 days
V3
V2+13 Wks
V4 - V17
26 Wks - 195 Wks
Visit Window + 7 days
V18
208 Wks
V19
V18 +16 wks
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;349:213-22
National 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
Probability of prostate cancer
0.08
Placebo
Finasteride
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0.00
0
Placebo group
Biopsy rate (%)
Total no. of cancers diagnosed
No. of grade 7–10 cancers
Finasteride group
Biopsy rate (%)
Total no. of cancers diagnosed
No. of grade 7–10 cancers
Thompson et al. NEJM 2003; 349: 215–24
1
2
3
4
5
Years after randomisation
6
7
3.0
48
5
2.8
71
6
2.2
60
15
2.9
80
35
2.8
92
24
2.6
96
24
7.1
124
38
3.3
42
11
2.0
35
11
2.1
39
17
2.5
68
31
2.1
78
28
2.2
51
26
7.0
122
64
PCPT
What 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?
• 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
Increased expression of Type 1 5-reductase in PCa
80
(% of Total Epithelial/Tumor Area)
Mean Area of Moderate + High Intensity Staining
Type 1 and 2 5-reductase
expression in prostate cancer
70
60
50
40
30
1
20
10
0
1
BPH
3
PIN
5
7
9
Primary Recurrent Mets
5R1
Thomas et al. The Prostate 2004: Epub
11
2
BPH
4
PIN
6
8
10
Primary Recurrent Mets
5R2
Dutasteride BPH studies
Prostate cancer detection* - Year 0-2
60
50% reduction in PCa
incidence overall*
Number of subjects
50
placebo
61% reduction in PCa
incidence starting month 13*
40
30
dutasteride
20
10
0
0
200 Tx Day when
400 diagnosed
600
Andriole et al. Urology 2004; 64: 537–41
* reported as adverse events
800
1000
What about year 2-4?
Dutasteride – Phase III BPH studies
For-cause PCa detection
Probability of
prostate cancer
1.2% versus 2.5%, p=0.002
0.05
n=55
0.04
0.03
n=27
0.02
Treatment
Placebo
Dutasteride
0.01
0
0
6
12
18
24
30
Time (months)
Andriole et al. Urology 2004; 64: 537–41
36
42
48
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
Dutasteride
0.5 mg/day
4 years
Randomisation
aim: n=8,000
Placebo
4 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
Randomization
(Visit 2)
Study Entry
2 year biopsy
4 year biopsy
(Visit 6)
(Visit 10)
(Screen Visit
1)
month: -7
-1
0
24
48
52
4-year Treatment period
Placebo
Entry biopsy run-in
For-cause biopsies may occur here
Interim analysis following 2 years
Follow-up of premature withdrawals for clinical events
4-month
Followup
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 Guidelines
5- 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 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 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 plabdut patients
EAU Guidelines
5- 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 inhibitors
• The combination of finasteride with an alphablocker 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 inhibitors
• Side effects of finasteride are minimal
• Side effects of dutasteride similar to
those seen with finasteride
EAU Guidelines
5- 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
• Total medical management of AUR
• Clarification of the effect of 5 alpha
reductase treatment on prostate cancer