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. SpeciesProstate 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 HorseProstate not subject to BPH or cancer CatProstate 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

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. T DHT Testosterone (T), Dihydrotestosterone (DHT) and the prostate TT Produced by Leydig cells in the testis in response to LH TMost circulating T is bound to SHBG or protein. TT fat soluble (Adrenal androgens) T DHTIn the prostate cell T converted into DHT 5 alphareductase isoforms DHT TDHT 5x more potent than T DHTDHT relates to BPH THigher levels of T in CaP DHTAndrogen receptor uptakes both T and DHT to initiate protein synthesis DHTT? Differences in steroid binding domain of androgen receptor relevant to DHT and T but none so far identified

8. Bartsch G et al. Eur Urol 2000;37:367–380. Testosterone 5  -Reductase Type 1 5  -Reductase Type 2 Dutasteride (Avodart) – dual inhibitor of DHT production DHT Finasteride and Dutasteride Dutasteride

9. 95% suppression with dutasteride 0.5 mg Dutasteride – Phase II study Dutasteride dose – DHT response (n=399) Dutasteride daily dose (mg) -100 -80 -60 -40 -20 0 20 0.010.1110 Placebo DHT (% change from baseline) Clark et al (1999) 71% suppression with finasteride 5 mg

10. 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 mRNAType 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

11. Dutasteride: Phase III Study Design Placebo Run-in Dutasteride 0.5mg/day Placebo One month single-blind 24 months double-blind 24 months open-label Roehrborn C et al. J Urology 2003 169; 1292.

12. 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 Q max  15 ml/sec (moderate to severe impairment) and minimum voided volume of  125 ml Roehrborn C et al. J Urology 2003 169; 1292.

13. Dutasteride: Mean Baseline Data for open label population Data on File GlaxoSmithKline Baseline data for this subset no different from larger double-blind population

14. Dutasteride: Phase III Subject Accountability Data on File GlaxoSmithKline

15. DHT reductions sustained over 4 years Placebo 2 yearsDutasteride 4 yearsOpen-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

16. Reductions in total prostate volume over 4 years with dutasteride 136122448 Treatment 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 5 Mean 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 PlaceboDutasterideOpen-label dutasteride after placebo Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495

17. Symptom improvements (AUA-SI) from 6 months, with continuing improvements over 4 years Placebo n=1152 Dutasteride n=1188 Double-blind Open-label -2.5 -4.4 -6.5 -5.6 p<0.001  0.9 Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495

18. In fact one can expect great symptom improvement in “real life” 10 11 12 13 14 15 16 17 18 19 20 -3036912151821242730333639424548 Treatment Month Mean Score (AUA-SI units) Double-blind Open-label Placebo n=1152 Dutasteride n=1188 Placebo run-in -9 Clinical trial Real Life Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495

19. Correct shifting in the proportion of patients from severe to mild 0 6 23 28 33 39 42 30 18 16 11 8 0 5 10 15 20 25 30 35 40 45 ScreeningBaselineMonth 12Month 24Month 36Month 48 % of Patients Mild Severe Mild = AUA-SI 0-7; Severe = AUA-SI 20-35 Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 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 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

21. Urinary flow improved from 1 month and onwards to 4 years Placebo n=1152 Dutasteride n=1188 Double-blind Open-label 2.7 1.9 0.6 2.2 p<0.01  0.8 Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495

22. Peak flow rate and voided volume decrease with increasing age Olmsted County Study Q max (ml/sec) Volume (mL) 25 20 15 10 5 0 400 350 300 250 200 150 100 50 Age groups 40–4450–5445–4955–5960–6465–6970–7475+ Q max Volume Girman et al (1993)

23. Dutasteride: Acute Urinary Retention Kaplan 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. of Events (cumulative): 19 27 31 38 40 45 49 52 No. at Risk: 2167 2052 1928 1827 1633 1119 1025 919 0 6 12 18 24 30 36 42 48 Percent of Patients Treatment Month 0 1 2 3 4 5 6 7 Placebo/dutasteride Dutasteride/dutasteride Double-blind Open-label 4.6% 1.9% 6.7% 3.3% Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495

24. Cumulative risk of acute urinary retention Olmsted County Study Jacobsen et al (1997) 40 30 20 10 0 Incidence/ 1,000 person-years 40-49 50-5960-69 70-79 Age (Years) No– Mild symptoms Moderate – Severe symptoms

25. Dutasteride: BPH-related Surgery Kaplan Meier Estimates: Time to First Event 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 Placebo/Dutasteride Dutasteride/dutasterid e 0 6 12 18 24 30 36 42 48 Treatment Month Percent of Patients 0 1 2 3 4 5 6 Double-blind Open-label 4.4% 2.4% 5.6% 3.3% Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 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 AE’s Dut 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 Data on File GlaxoSmithKline Patients who received dutasteride in both the double-blind and open-label phases. *Includes breast enlargement and breast/nipple tenderness

30. SMART1 When can you withdraw alpha blocker from a dutasteride-alpha blocker combination?

31. Placebo 1 week Single blind Combination dutasteride 0.5mg + placebo tamsulosin Combination dutasteride 0.5mg + tamsulosin 0.4mg once daily SMART-1: study design Placebo run-in 4 weeks Single blind J Barkin et al. European Urology (2003): 44; 461-466. 24 weeks Single blind 12 weeks Double blind DT24 + D12 DT36 Wk 30 Wk 36

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) Patients (%) J Barkin et al. European Urology (2003): 44; 461-466. DT36 (n=154)DT24 + D12 (n=149) 100 DT36 = combination dutasteride + tamsulosin for 36 weeks DT24 + D12 = combination dutasteride + tamsulosin for 24 weeks followed by dutasteride + placebo for 12 weeks % patients better/same 80 60 40 20 0 Some pts miss their A Blockers

34. J Barkin et al. European Urology (2003): 44; 461-466. % patients better/same 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

35. SMART-1: primary endpoint question at week 30 by baseline IPSS J Barkin et al. European Urology (2003): 44; 461-466. 100 80 60 40 20 0 Moderate (baseline IPSS <20) (n=220) % patients Better/Same DT36DT24 + D12DT36DT24 + D12 Severe (baseline IPSS  20) (n=82) 93% 84%86% 58% Severe pts need longer AB treatment

36. 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 0.51.0 1.5 2.02.5 3.03.5 4.04.5 5.0 5.5 % with event 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) 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.

37. CombAT Study Schematic Tamsulosin 0.4mg od Dutasteride0.5 mg od Combination Placebo run-in Safety Follow up phase Visit Window + 7 days Screening V1aV1bV2V3 V1a +7d + 2 days Baseline V1b+28d + 4 days V2+13 Wks V4 - V17 V18V19 26 Wks - 195 Wks208 Wks V18 +16 wks Single-blind Double -blind

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 > 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 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%

44. PCPT – cumulative incidence of prostate cancer 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0.00 21043657 Years after randomisation Probability of prostate cancer Placebo Finasteride Placebo group Biopsy rate (%)3.02.82.22.92.82.67.1 Total no. of cancers diagnosed487160809296124 No. of grade 7–10 cancers561535242438 Finasteride group Biopsy rate (%)3.32.02.12.52.12.27.0 Total no. of cancers diagnosed423539687851122 No. of grade 7–10 cancers11111731282664 Thompson et al. NEJM 2003; 349: 215–24

45. 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

46. 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 PCPT What does it not tell us?

47. Type 1 and 2 5  -reductase expression in prostate cancer Increased expression of Type 1 5  -reductase in PCa 1357911246810 0 20 30 40 50 60 70 80 Mean Area of Moderate + High Intensity Staining (% of Total Epithelial/Tumor Area) BPHPINPrimaryRecurrentBPHPINPrimaryRecurrent 5  R15  R2 1 Mets Thomas et al. The Prostate 2004: Epub

48. Dutasteride BPH studies Prostate cancer detection* - Year 0-2 Number of subjects Tx Day when diagnosed placebo dutasteride 50% reduction in PCa incidence overall* 61% reduction in PCa incidence starting month 13* Andriole et al. Urology 2004; 64: 537–41 * reported as adverse events Andriole et al. Urology 2004; 64: 537–41 * reported as adverse events

49. What about year 2-4?

50. Dutasteride – Phase III BPH studies For-cause PCa detection Time (months) 0612182430364248 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

51. 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 Q max  5 mL/sec Prostate volume  80 mL 1 month placebo run-in Randomisation aim: n=8,000 Dutasteride 0.5 mg/day 4 years Placebo 4 years 2- and 4-year biopsies and biopsies ‘for-cause’ as indicated clinically Andriole et al. J Urol 2004; 172: 1314–7

52. REDUCE (REduction by DUtasteride of prostate Cancer Events) : Study Design 2 year biopsy (Visit 6) 4 year biopsy (Visit 10) Randomization (Visit 2) -702448 Entry biopsy 4-year Treatment period Placebo run-in month: 4-month Follow- up 52 Study Entry (Screen Visit 1) For-cause biopsies may occur here Interim analysis following 2 years Follow-up of premature withdrawals for clinical events 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: 215–24) The REDUCE study will further clarify the Gleason issue

54. 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

55. 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)

56. 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 plab- dut patients

57. 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

58. EAU Guidelines 5- 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 Guidelines 5- alpha reductase inhibitors Side effects of finasteride are minimal Side effects of dutasteride similar to those seen with finasteride

60. 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.

61. The Future Total medical management of AUR Clarification of the effect of 5 alpha reductase treatment on prostate cancer