BPH

1
Tim Hargreave Dept of Oncology, Edinburgh
University
The medical management of BPH
Dutasteride
Taipei July 16, 2005
2
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
3
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

4
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
5
(No Transcript)
6
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
7
Testosterone (T) , Dihydrotestosterone (DHT) and
the prostate

• T Produced by Leydig cells in the testis in
  response to LH
• Most circulating T is bound to SHBG or protein.
• T fat soluble
• (Adrenal androgens)

• In the prostate cell T converted into DHT
• 5 alphareductase isoforms
• DHT 5x more potent than T
• DHT relates to BPH
• Higher levels of T in CaP

• Androgen receptor uptakes both T and DHT to
  initiate protein synthesis
• ? Differences in steroid binding domain of
  androgen receptor relevant to DHT and T but none
  so far identified

8
Dutasteride (Avodart) dual inhibitor of DHT
production
Dutasteride
5?-ReductaseType 1
Testosterone
DHT
5?-Reductase Type 2
Finasteride and Dutasteride
Bartsch G et al. Eur Urol 200037367380.
9
Dutasteride Phase II studyDutasteride dose
DHT response (n399)
20
0
71 suppression with finasteride 5 mg
-20
DHT ( change from baseline)
-40
95 suppression with dutasteride 0.5 mg
-60
-80
-100
0.01
0.1
1
10
Placebo
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 (PZperipheral zone
  TZtransition zone CZcentral 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
199968189195. My comment is that these
potentially important data need confirmation in
another laboratory
11
Dutasteride Phase 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.
12
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 lt10ng/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.
13
DutasterideMean Baseline Data for open label
population
Baseline data for this subset no different from
larger double-blind population
Data on File GlaxoSmithKline
14
Dutasteride Phase III Subject Accountability
Data on File GlaxoSmithKline
15
DHT reductions sustained over 4 years
Double-blind
Open-label
12 24
36 48
Treatment Month
Placebo 2 years
Dutasteride 4 years
Open-label dutasteride after placebo
Roehrborn CG et al Urol 63709-15,2004 Debruyne
F et al, Euro Urol 200446 488-495
16
Reductions in total prostate volume over 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
1
3
6
12
24
48
Treatment month
plt0.001 for differences between treatment
groups plt0.001 for change from Month 24 to Month
48 p0.07 for change from Month 24 to Month 48
Roehrborn CG et al Urol 63709-15,2004 Debruyne
F et al, Euro Urol 200446 488-495
17
Symptom improvements (AUA-SI) from 6 months, with
continuing improvements over 4 years
Double-blind
Open-label
-2.5
plt0.001
-4.4
-5.6
-6.5
Roehrborn CG et al Urol 63709-15,2004 Debruyne
F et al, Euro Urol 200446 488-495
18
In fact one can expect great symptom improvement
in real life
20
Double-blind
Open-label
19
18
Clinical trial
Real Life
17
16
Mean Score (AUA-SI units)
15
-9
14
13
12
11
10
-3
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
Treatment Month
Placebo n1152 Dutasteride n1188
Placebo run-in
Roehrborn CG et al Urol 63709-15,2004 Debruyne
F et al, Euro Urol 200446 488-495
19
Correct shifting in the proportion of patients
from severe to mild
Mild
45
Severe
40
35
30
25
of Patients
20
15
10
5
0
Screening
Baseline
Month 12
Month 24
Month 36
Month 48
Mild AUA-SI 0-7 Severe AUA-SI 20-35
Roehrborn CG et al Urol 63709-15,2004 Debruyne
F et al, Euro Urol 200446 488-495
20
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 2002167265 (AUA-SI) All other data series
Meta-analysis data, AUA BPH Guidelines 2003.
Chapter 3, Appendix 3.
Dutasteride
Finasteride
Alpha blockers
4 year data
21
Urinary flow improved from 1 month and onwards to
4 years
Double-blind
Open-label
plt0.01
2.7
2.2
? 0.8
1.9
0.6
Placebo n1152 Dutasteride n1188
Roehrborn CG et al Urol 63709-15,2004 Debruyne
F et al, Euro Urol 200446 488-495
22
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
4044
5054
4549
5559
6064
6569
7074
75
Age groups
Girman et al (1993)
23
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 CG et al Urol 63709-15,2004 Debruyne
F et al, Euro Urol 200446 488-495
24
Cumulative risk of acute urinary
retentionOlmsted County Study
40 30 20 10 0
No Mild symptoms
Moderate Severe symptoms
Incidence/ 1,000 person-years
70-79
40-49
50-59
60-69
Age (Years)
Jacobsen et al (1997)
25
Dutasteride BPH-related SurgeryKaplan Meier
Estimates Time to First Event
6
Double-blind
Open-label
5.6
4.4
5
Placebo/Dutasteride Dutasteride/dutasteride
4
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 CG et al Urol 63709-15,2004 Debruyne
F et al, Euro Urol 200446 488-495
26
Drug-related adverse events in the first two
years (DB period)
Gerald L. Andriole and Roger Kirby. European
Urology 44 (2003) 82-88
27
5?-reductase inhibitors and sexual AEsDut vs Fin
Roehrborn et al. Urology 2002 60
434-441 McConnell et al. NEJM 1998 338
557-563 includes breast tenderness or
enlargement
28
Coincidence of urinary and sexual symptoms -
cause or effect? From Hargreave and Stephenson
Potency and Prostatectomy BJUrol 1977 49,683
29
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
30
SMART1

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

31
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.
32
SMART-1 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.
33
SMART-1 primary endpoint question at week 30
(at visit)
100
80
60
Patients ()
40
Some pts miss their A Blockers
20
0
DT36 (n154) DT24 D12 (n149)
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.
34
SMART-1 primary endpoint at week 36 (nine
months)
100
80
60
Differences no longer that apparent
patients better/same
40
20
0
DT36 (n139) DT24 D12 (n115)
For patients responding same/better at week 30
J Barkin et al. European Urology (2003) 44
461-466.
35
SMART-1 primary endpoint questionat week 30 by
baseline IPSS
Severe (baseline IPSS ?20) (n82)
Moderate (baseline IPSS lt20) (n220)
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.
36
MTOPS
Cumulative incidence of BPH progression
25 20 15 10 5 0
Combination vs. Placebo 66 risk reduction
Placebo (n737) Finasteride (n768) Doxazosin
(n756) Combination (n786)
(P0.002)
with event

• 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.

(Plt0.001)
(Plt0.001)
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
20033492387-2398
37
CombAT Study Schematic
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 V1b28d 4 days
V1a 7d 2 days
V213 Wks
26 Wks - 195 Wks
208 Wks
V18 16 wks
Visit Window 7 days
38
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

39
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

40
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

41
COMBAT Inclusion Criteria

• Maximum Flow Rate
• Qmax gt 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

42
Prostate Cancer Prevention
43
Finasteride prevention study (PCPT) N Eng J Med
2003349213-22National Cancer Institute (with
SWOG ECOG) Headline effect Prostate cancer
prevalence reduced by 24.8 i.e. from 24.4 to
18.4
44
PCPT cumulative incidence of prostate cancer
Probability of prostate cancer
0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0.00
Placebo Finasteride
2
1
0
4
3
6
5
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 8
0 92 96 124 No. of grade 710 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 710 cancers 11 11 17 31 28 26 64
Thompson et al. NEJM 2003 349 21524
45
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

46
PCPTWhat 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

47
Type 1 and 2 5?-reductase expression in prostate
cancer Increased expression of Type 1
5?-reductase in PCa
Mean Area of Moderate High Intensity Staining
( of Total Epithelial/Tumor Area)
1
0
1
3
5
7
9
11
2
4
6
8
10
BPH
PIN
Primary
Recurrent
BPH
PIN
Primary
Recurrent
Mets
Mets
5?R1
5?R2
Thomas et al. The Prostate 2004 Epub
48
Dutasteride BPH studies Prostate 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 53741
reported as adverse events
49
What about year 2-4?
50
Dutasteride Phase III BPH studiesFor-cause PCa
detection
Probability of prostate cancer
1.2 versus 2.5, p0.002
0.05
n55
0.04
0.03
0.02
n27
Treatment Placebo Dutasteride
0.01
0
0
6
12
18
24
30
36
42
48
Time (months)
Andriole et al. Urology 2004 64 53741
51
REduction by DUtasteride of prostate Cancer
Events (REDUCE) study

• Men aged 5075 years with
• One negative prostate biopsy within 6 months of
  study entry
• PSA ?2.5 and ?10 ng/mL
• IPSS lt25 and Qmax ?5 mL/sec
• Prostate volume ?80 mL

1 month placebo run-in
Dutasteride 0.5 mg/day4 years
Placebo4 years
Randomisation aim n8,000
2- and 4-year biopsies and biopsies for-cause
as indicated clinically
Andriole et al. J Urol 2004 172 13147
52
REDUCE (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
0
24
48
-1
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
53
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
  21524)
• The REDUCE study will further clarify the Gleason
  issue

54
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

55
EAU Guidelines5- alpha reductase inhibitors

• Men with small prostates (lt40ml) 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)

56
EAU Guidelines5- 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

57
EAU Guidelines5- 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

58
EAU Guidelines5- 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

59
EAU Guidelines5- alpha reductase inhibitors

• Side effects of finasteride are minimal
• Side effects of dutasteride similar to those seen
  with finasteride

60
EAU Guidelines5- 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.

61
The Future

• Total medical management of AUR
• Clarification of the effect of 5 alpha reductase
  treatment on prostate cancer