1. Reappraisal of Published Randomized LUTS/BPH Clinical Trials –What Have We Learned and Where Do We Stand? 王炯珵 醫師 恩主公醫院泌尿科 Chung Cheng Wang, M.D. Ph.D Department of Urology, En Chu Kong Hospital, Taipei

2. Dr. Charles Sydney Burwell, Dean, Harvard Medical School 1935-49 Half of what we are going to teach you is wrong, and half of it is right Our problem is that we don't know which half is which 在十年內, 你們現在學習的知識有 一半會被證明是錯誤的, 更糟糕的 是我們不知道那一半是錯誤的

3. 請問蒲永孝教授講話比較有公信力 還是王炯珵醫師 ?

5. Guidelines Include Algorithms to Illustrate Medical Treatment Choices According to Evidence-based Medicine and Patients’ Profiles AUA 1 EAU 2

6. Recommendations for Treatment of Men with BPH Have Evolved in Line With Available Clinical Evidence VA Co-op 6 (finasteride + terazosin) ALFIN 7 (finasteride + alfuzosin) PREDICT 9 (finasteride + doxazosin) MTOPS 8 (finasteride + doxazosin) CombAT 2-year data 10 (dutasteride + tamsulosin) CombAT 4-year data 11 (dutasteride + tamsulosin) AUA and NICE 2010 guidelines 3,5 EAU 2011 guidelines 4 AUA 2003 guidelines 3 EAU 2004 guidelines 2 AUA 1994 guidelines 1 EAU 2001 guidelines 2 20052010 2000 2014 EAU 2014 guidelines 12

7. VACOOP study Terazosin + Finasteride N Engl J Med 1996;335:533–9 Prospective, randomized, double-blind 1229 patients enrolled Primary endpoint: AUA-SI & Qmax Follow up for 52 weeks Finasteride 和 Placebo 差不多 Terazosin 和 Combination 差不多

8. ALFIN Study Alfuzosin + Finasteride Eur Urol 1998; 34:169–75 Prospective, randomized, double-blind 1051 patients enrolled Primary endpoint: I-PSS & Qmax Follow up for 6 months 有沒有加 Finasteride 沒差 F A and A +F

9. What does the guidelines recommend? Eur Urol 2001; 40:256- 263 Based on the ALFIN and VACOOP Trial

10. PREDICT study Finasteride + Doxazosin Urology 2003;61:119–26 Prospective, randomized, double-blind 1095 patients enrolled Primary endpoint: I-PSS & Qmax Follow up for 52 weeks D F D+F P

11. MTOPS Study Finasteride + Doxazosin N Engl J Med 2003;349:2387–98 Prospective, randomized, double-blind 3047 patients enrolled Primary endpoint: clinical progression Follow up for 4.5 years(mean) 愛久見人心

12. Guideline Update EAU BPH Guidelines 2004 Eur Urol 46; 2004: 547-554

13. 事後諸葛亮很重要 Learning From Clinical Trial Experience

14. Prostate volume: Higher Baseline PV Associated With an Increase in BPH Progression Events in MTOPS Adapted from Crawford ED et al. J Urol 2006;175:1422–1427. 3.4 3.0 0.3 0.6 5.6 4.3 1.0 2.0 0.0 2.0 4.0 6.0 8.0 Overall BPH progression ≥4-point AUA SS progression AURInvasive therapy <31 ml p<0.0001p=0.001p=0.034 p=0.0005 Incidence rate (events per 100 Pyr) ≥31 ml Total prostate volume

15. PSA: Higher Baseline PSA Associated With an Increase in BPH Progression Events in MTOPS Adapted from Crawford ED et al. J Urol 2006;175:1422–1427. 3.1 2.8 0.3 0.8 5.9 4.5 1.0 1.8 0.0 2.0 4.0 6.0 8.0 p=0.0002p=0.0281p=0.029 p=0.018 Incidence rate (events per 100 Pyr) Overall BPH progression ≥4-point AUA SS progression AURInvasive therapy <1.6 ng/ml≥1.6 ng/ml PSA level

16. CombAT study is Designed to Investigate the Efficacy and Safety of Combination Therapy in Men with m-s Symptoms of BPH and at Risk of Clinical Progression Contemporary Clinical Trial 28; 2007:770-779

17. CombAT Study Dutasteride + Tamsulosin Eur Urol 2009;55:461–71. 4838 patients enrolled 450 centers in 34 countries worldwide p< 0.001 Primary end point at 2 and 4 years Pivotal trial Tamsulosin 0.4 mg + dutasteride-matched placebo Dutasteride 0.5 mg + tamsulosin-matched placebo Combination (dutasteride 0.5 mg + tamsulosin 0.4 mg) Placebo run-in Screening Double-blind Single-blind Safety follow up Pre- screen \ScreenBaselineM48Follow-up (End of treatment +16 weeks) M24 Visits every 3 months, QD dosing IPSS Time to AUR or surgery

18. Combination Therapy Significantly Reduces the Relative Risk of AUR and/or BPH-related Surgery at 4 years Eur Urol. 2010;57:123– 131 For combination versus tamsulosin at Year 4: Relative risk reduction = 65.8%, Absolute risk reduction = 7.7% NNT: 13 patients 5ARI >> Alpha blocker

19. Combination Therapy Reduces Risk of AUR, BPH-related Surgery and BPH Clinical Progression Eur Urol. 2010;57:123–131

20. Dutasteride Plus Tamsulosin Provided Significantly Greater Symptom Benefit Than Either Monotherapy Eur Urol 2010;57:123–131 Alpha blocker 越吃越沒效

21. Drug Adherence Nichol MB et al. J Urol. 2009;181:2214-21. Time to non-adherence with medication Combination 5ARI Alpha blocker

22. 找對人很重要 ! Choose the Right Population for Study

23. Entry Criteria for CombAT Included a BPH Population at Higher Risk of Progression Than MTOPS Plo, placebo; Dox, doxazosin; Fin, finasteride; Comb, combination; Tam, tamsulosin; Dut, dutasteride 1. McConnell J et al. N Engl J Med. 2003;349:2387–2398; 2. Roehrborn C et al. Eur Urol. 2010;57:123–131.. MTOPS 1 Plo Dox. 4–8 mg Fin. 5 mg Comb. Age ≥50 years IPSS 8–30 PSA ≤10 ng/ml Median: serum PSA 1.6 ng/ml PV 31 cc 3047 patients 4.5 years mean follow up CombAT 2 Tam. 0.4 mg Dut. 0.5 mg Comb. Entry criteria: serum PSA ≥1.5 ng/ml PV ≥30 cc Median: PV 48.9 cc 71% of moderate BPH symptoms Age ≥50 years IPSS ≥12 PSA 1.5–10 ng/ml PV ≥30 cc 4844 patients 4 years LOCF

24. Differences between MTOPS and CombAT in the population under study Mean ± S.D.CombAT (n=4844) MTOPS (n=3047) Age (years)66.1 ± 7.0162.6 ± 7.3 Caucasian4259 (88%)2509 (82%) Total IPSS16.4 ± 6.1616.9 ± 5.9 Total prostate volume (cc) 55.0 ± 23.5836.3 ± 20.1 Serum PSA (ng/ml)4.0 ± 2.082.4 ± 2.1 Qmax (mL/sec)10.7 ± 3.6210.5 ± 2.6 Post-void residual volume (ml) 67.7 ± 64.8768.1 ± 82.9 CombAT and MTOPS: different patient populations

25. Long-term Benefit of 5-ARI and α 1 -Blocker Combination Therapy 1,2,3 1. Füllhase C et al. Eur Urol. (2013), doi: 10.1016/j.eururo.2013.01.018; 2. Roehrborn C et al. Eur Urol. 2010;57:123–131. 3. Roehrborn CG et al. BJU Int 2015 doi:10.1111/bju.13033 The only [5ARI + α 1 -blocker] combinations assessed for efficacy and safety in long-term RCTs ALFIN 1 0.5 year 1051 patients Alfuzosin 2x5 mg/ Finasteride 5 mg ALFIN 1 0.5 year 1051 patients Alfuzosin 2x5 mg/ Finasteride 5 mg MTOPS 1 6 year 3047 patients Doxazosin 4-8 mg/ Finasteride 5 mg MTOPS 1 6 year 3047 patients Doxazosin 4-8 mg/ Finasteride 5 mg VA-COOP 1 1 year 1229 patients Terazosin 10 mg/ Finasteride 5 mg VA-COOP 1 1 year 1229 patients Terazosin 10 mg/ Finasteride 5 mg PREDICT 1 1 year 1095 patients Doxazosin 4–8 mg/ Finasteride 5 mg PREDICT 1 1 year 1095 patients Doxazosin 4–8 mg/ Finasteride 5 mg CombAT 2 2–4 year 4844 patients Tamsulosin 0.4 mg/ Dutasteride 0.5 mg CombAT 2 2–4 year 4844 patients Tamsulosin 0.4 mg/ Dutasteride 0.5 mg 1995 1996 2001 2003 2010 2yrs change in IPSS from baseline 4yrs Time to first AUR or BPH related surgery CONDUCT 3 2 year 742 patients *Fixed-dose DUT+TAM combination vs. WW with initiation of tamsulosin if symptoms did not improve CONDUCT 3 2 year 742 patients *Fixed-dose DUT+TAM combination vs. WW with initiation of tamsulosin if symptoms did not improve 2015 Primary endpoint AUA-SS/IPSS and Qmax 2yrs change in IPSS from baseline Clinical progression Evidence from CombAT resulted in changes to the guidelines [DUT + TAM] CombAT, CONDUCT [FIN + DOX] MTOPS study *Fixed-dose combination therapy (dutasteride + tamsulosin) vs.Watchful Waiting with initiation of tamsulosin if symptoms did not improve Both treatment arms included lifestyle advice administered

26. Lifestyle advice ? 真的有嗎 ? 40mL

27. Create More Benefits by Designing Following Study to Fill the Data Gap

28. Understanding the Study Patient Populations MTOPS vs. CombAT vs. CONDUCT MTOPS IPSS range (8‒30) MTOPS 1 (4.5 years mean follow up) Combination therapy vs. Placebo and Doxazocin 4–8 mg and Finasteride 5 mg 3047 pts Entry criteria: Age ≥ 50, PSA ≤10 ng/mL Baseline: Mean PSA: 2.4 ng/mL, Median PV: 31.0 mL International Prostate Symptom Score (IPSS) Mean IPSS 16.9 812193530 Mean IPSS 16.6 ModerateSevere CONDUCT* IPSS range (8‒19) CONDUCT 4,5 (2y) Fixed-dose combination therapy (dutasteride + tamsulosin) vs. Watchful Waiting with initiation of tamsulosin if symptoms did not improve 742 pts 100% treatment naive, PSA 1.5- 10.0 ng/mL PV ≥30 mL Baseline, : Mean PSA: 3.9 ng/mL Mean PV: 51.0 mL Mean IPSS 13.2 71% patients with moderate symptoms 2 CombAT IPSS range (12‒35) CombAT 2,3 (4y LOCF) Combination therapy (dutasteride + tamsulosin) vs. dutasteride 0.5 mg and tamsulosin 0.4 monotherapy 4844 pts Entry criteria: Age ≥50, PSA 1.5‒10 ng/mL, PV ≥30 mL Baseline: Mean PSA: 4.0 ng/mL Median PV: 48.9 mL, 38% treatment naïve *Both treatment arms included lifestyle advice administered

29. Rationale for the CONDUCT Study Adds to existing evidence CONDUCT 1,2 investigated several areas which would benefit from further investigation: Less symptomatic (moderate) patients All Treatment-naive patients Earlier (4 weeks) fixed-dose combination of dutasteride and tamsulosin efficacy measurement Comparison to a recognised clinical approach for some patients at risk of progression – Watchful Waiting with initiation of tamsulosin if symptoms did not improve

30. Randomisation 1:1 V1 (screening) V2 (baseline) V3 (W4) V4 (W13) V9 (W78) V10 (W91) V11 (W104) IPSS, BII score, Patient Perception of Study Treatment measured at each visit If initiated, escalation to tamsulosin 0.4 mg once daily at any visit after Visit 2 would be continued for the remainder of the study unless the subject elected to withdraw prematurely Fixed-dose combination of dutasteride and tamsulosin + lifestyle advice Watchful Waiting with initiation of tamsulosin if symptoms did not improve from baseline (V2) + lifestyle advice CONDUCT: Study Design 1.Protocol Summary : http://clinicaltrials.gov/ct2/show/NCT01294592?term=NCT01294592 &rank=1 (Accessed 5 April 2015) 2.Roehrborn CG et al. BJU Int 2015 doi:10.1111/bju.13033

31. CONDUCT 最偉大的地方 : 30min 衛教

33. **Both treatment arms included lifestyle advice administered Efficacy: Mean IPSS at Each Visit Mean IPSS at visit (LOCF*) demonstrates the effect of study treatment arms** on the symptom category (moderate vs mild) throughout the study course 1,2 24 21 1815129631 Combination therapy resulted in shifting of BPH symptom score from moderate to mild category from month 9 onwards 9.4 7.6 Moderate Mild *Last observation carried forward Fixed dose combination of dutasteride and tamsulosin (n=369) Watchful Waiting with initiation of tamsulosin if symptoms did not improve (n=373) 9.4 7.9

34. *Improvement thresholds were selected for the lower IPSS baseline score (8-19) **Both treatment arms included lifestyle advice administered Study Results: IPSS Change Fixed dose combination of dutasteride and tamsulosin (n=369)** Watchful Waiting with initiation of tamsulosin if symptoms did not improve (n=373)** p<0.001 Patient assessment of improvement thresholds *,3 Adjusted mean change from baseline in IPSS Slight -1.9 Moderate -4.0 Marked -7.4 -0.9 -2.4 -3.6 -5.2 -4.5 -3.2 24 21 1815129631 Rapid symptom improvement with combination therapy (measured at month 1) Superior symptom improvement with combination therapy at each post-baseline visit (p<0.001) vs. Watchful Waiting with initiation of tamsulosin if symptoms did not improve Sustained superiority of fixed dose combination in symptom improvement over 2 years of treatment vs. Watchful Waiting with initiation of tamsulosin if symptoms did not improve -5.4

35. Efficacy: BPH Clinical Progression 1 *Overall clinical progression events defined by a rise in IPSS of ≥3 points at any visit when compared to Visit 2 (baseline), AUR related to BPH, UTI related to BPH, Incontinence related to BPH, Renal insufficiency related to BPH. Fixed dose combination of dutasteride and tamsulosin** Watchful Waiting with initiation of tamsulosin if symptoms did not improve** 29% 18% Cumulative number of events/Subjects at riskYear 1Year 2 Fixed dose combination of dutasteride and tamsulosin48/36917/276 Watchful Waiting with initiation of tamsulosin if symptoms did not improve 94/37314/251 43.1% relative risk reduction at year 2; (p<0.001) 11.3% absolute risk reduction (risk difference) Number needed to treat: 9

36. CONDUCT Results: Summary 1,2 1. Study Results Summary at http://clinicaltrials.gov/ct2/show/results/NCT01294592?term=NCT01294592&ra nk=1 accessed on 13 January 2015, 2. Roehrborn CG et al. BJUInt 2015 doi:10.1111/bju.1303310.1111/bju.13033 CONDUCT Study Supports first line use Consistent safety profile Rapid symptom improvement Compliments CombAT data

37. Dig Out Useful Evidence Beyond Studies by Post-hoc Analysis

38. 5ARI Prostate Cancer Risk Reduction Studies 1. Thompson I et al. Prostate 1997;33:217–221; 2. Thompson I et al. N Engl J Med 2003;349:215–224; 3. Andriole G et al. J Urol 2004;172:1314–1317; 4. Andriole GL et al. N Engl J Med 2010;362:1192–1202. 20102014 19942003 PCPT: results published (finasteride versus placebo) Increased incidence of high-grade tumors with finasteride 2 PCPT initiated (finasteride versus placebo) 1 REDUCE initiated (dutasteride versus placebo) 3 REDUCE: results published (dutasteride versus placebo) Increased incidence of high- grade tumors with dutasteride 4

39. Prostate Cancer Prevention Trial

41. Reduction of Dutasteride of Prostate Cancer Event (REDUCE)

42. Figure out the purpose Improve the study design by lessons Choose the right population Fill the data gap Post-hoc analysis Take Home Messages