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Tim Hargreave Dept of Oncology, Edinburgh University

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

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  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 Difficulty with animal models of Human Prostate Disease

  5. 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

  6. 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 2000;37:367–380.

  7. Dutasteride – Phase II studyDutasteride 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)

  8. 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

  9. 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.

  10. 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 1.5and <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.

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

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

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

  14. 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 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

  15.  0.9 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

  16. 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

  17. Urinary flow improved from 1 month and onwards to 4 years 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

  18. 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)

  19. Placebo/dutasteride 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

  20. 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 50-59 60-69 40-49 Age (Years) Jacobsen et al (1997)

  21. Dutasteride: BPH-related SurgeryKaplan 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

  22. Drug-related adverse events in the first two years (DB period) Gerald L. Andriole and Roger Kirby. European Urology 44 (2003) 82-88

  23. 5-reductaseinhibitors 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

  24. Coincidence of urinary and sexual symptoms - cause or effect? From Hargreave and Stephenson Potency and Prostatectomy BJUrol 1977 49,683

  25. 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

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

  27. DT24 + D12 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.

  28. 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.

  29. SMART-1: primary endpoint question at 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.

  30. SMART-1: primary endpoint at 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.

  31. SMART-1: primary endpoint questionat 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.

  32. MTOPS 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

  33. 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 V1b+28d + 4 days V1a +7d + 2 days V2+13 Wks 26 Wks - 195 Wks 208 Wks V18 +16 wks Visit Window + 7 days

  34. 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

  35. 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

  36. 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

  37. 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

  38. Prostate Cancer Prevention

  39. 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%

  40. 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 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

  41. 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

  42. 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

  43. 80 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

  44. 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: 537–41 * reported as adverse events

  45. What about year 2-4?

  46. Dutasteride – Phase III BPH studiesFor-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

  47. 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/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

  48. 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 -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

  49. 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

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