CONDUCT study A step further in changing treatment paradigm in BPH

CONDUCT study A step further in changing treatment paradigm in BPH CLUJ,25.09.2015, Adriana Stoica, Medical Advisor GSK Toate informa,ile con,nute in aceasta prezentare sunt conforme cu Rezumatul caracteris,cilor produsului Acest material promoţional este des,nat profesioniş,lor din domeniul sănătăţiii

CONDUCT study Published on line in January 2015 online free access - Roehrborn CG et al, BJUInt 2015 doi:10.1111/bju.13033

CONDUCT study geography 1,2 Investigators from which countries contributed to the study 8 countries contributed to the study: 742 patients randomised France, Germany, Greece, Italy, Netherlands, Romania, Spain, United Kingdom 1. Roehrborn CG et al, BJUInt 2015 doi:10.1111/bju.13033; 2. CONDUCT study NCT01294592 Protocol summary https://clinicaltrials.gov/ct2/ show/nct01294592?term=conduct+and+dutasteride&rank=1 (accessed 4-6-2015)

CONDUCT study scheme 1,2 Fixed dose combination of dutasteride and tamsulosin + lifestyle advice Randomisation 1:1 Watchful Waiting with initiation of tamsulosin if symptoms did not improve from baseline (V2) + lifestyle advice V1 V2 (screening) (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 1. NCT01294592 Protocol summary: https://clinicaltrials.gov/ct2/show/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033..

CONDUCT study endpoints 1,2 Primary Endpoint Secondary Endpoints l Change in International prostate symptom score from baseline to Month 24 l Change in BPH Impact Index score from baseline l Change in Question 8 IPSS from baseline l Time to/proportion of subjects with clinical BPH progression l Improvements/change in questions 1 and 2 of the Patient Perception of Study Treatment (PPST) Questionnaire l Safety and tolerability 1. NCT01294592 Protocol summary: https://clinicaltrials.gov/ct2/show/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033..

CONDUCT study rationale: adds to existing evidence The CONDUCT study adds to the existing clinical information (CombAT study) on the prescription of combination treatment to patients with moderate BPH at risk of progression 1 CONDUCT 2,3 investigated several areas which benefited from further investigation: l Less symptomatic (moderate) patients l Treatment naive patients l Earlier (4 weeks) fixed dose combination of Dutasteride and Tamsulosin efficacy measurement l Comparison to Watchful Waiting with initiation of tamsulosin if symptoms did not improve 1. Roehrborn CG, Siami P, Barkin J, Damiăo R, Major-Walker K, Nandy I, et al. Eur Urol 2010 Jan;57(1):123-31; 2. NCT01294592 Protocol summary: https://clinicaltrials.gov/ct2/show/nct01294592?term=nct01294592&rank=1; 3. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033..

Entry criteria (CONDUCT vs CombAT) CONDUCT Eligibility Criteria 1 CombAT Eligibility Criteria 2,3 Age (years) 50 years 50 Total IPSS 8 19 12 Total prostate volume (ml) 30 (by TRUS) 30 Total serum PSA 4 (ng/ml) 1.5-10.0 1.5-10.0 Current or prior treatment related to BPH No current or prior treatment related to BPH Previous 5-ARI use 6 m prior to entry; Previous α-blocker use 2 w prior to entry 1. NCT01294592 Protocol summary: https://clinicaltrials.gov/ct2/show/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Siami P, Barkin J, Damiăo R, Becher E, Miňana B et al. Eur Urol 2009 Feb;55(2):461-71; 3. Roehrborn CG, Siami P, Barkin J, Damiăo R, Major-Walker K, Nandy I, et al. Eur Urol 2010 Jan;57(1):123-31.

Escalation to tamsulosin in Watchful Waiting with initiation of tamsulosin* group 1 More than a half of patients in Watchful Waiting with initiation of tamsulosin* arm escalated to tamsulosin, with initiation occurring in >50% of cases within the first 6 months 100% Initiation of 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 190 51% 183 49% 215 58% 158 42% 224 60% 149 40% 229 61% 144 39% Tamsulosin (if any IPSS measurement shown no improvement or worsening from baseline) No Initiation of Tamsulosin * if symptoms did not improve 1. Roehrborn CG, Warnack W, Perez IO, Roos E, Calomfirescu N, Brotherton B, et al. Eur Urol Suppl Apr 2014;13(1):LBA1, EAU Congress presentation.

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 14 Mean IPSS 13 12 11 10 9 8 7 6 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 9.4 7.6 Moderate Mild 5 1 3 6 9 12 Months from randomisation *Last observation carried forward **Both treatment arms included lifestyle advice administered 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033.. 15 18 21 24

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 14 Mean IPSS 13 12 11 10 9 8 7 6 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 9.4 7.9 9.4 7.6 Moderate Mild 5 1 3 6 9 12 Months from randomisation *Last observation carried forward **Both treatment arms included lifestyle advice administered 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033.. 15 18 21 24

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 14 Mean IPSS 13 12 11 10 9 8 7 6 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 9.4 7.9 9.4 7.6 Moderate Mild 5 1 3 6 9 12 15 18 21 24 Months from randomisation Combination therapy resulted in shifting of BPH *Last observation carried forward **Both treatment arms included lifestyle advice administered symptom score from moderate to mild category from month 9 onwards 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033..

Study results: IPSS change Adjusted mean change from baseline in IPSS 0-1 -2-3 -4-5 -6-0.9-3.2 1-2.4-4.5 3 Fixed dose combination of dutasteride and tamsulosin (n=369)** Watchful Waiting with initiation of tamsulosin if symptoms did not improve (n=373)** 6 9 p<0.001-3.6-3.6-5.2 12 15 Months from randomisation 18 21-5.4 24 Patient assessment of improvement thresholds *,3 Slight -1.9 Moderate -4.0 Marked -7.4 Rapid *Improvement symptom thresholds were selected for the lower IPSS baseline score (8-19) improvement with **Both combination treatment therapy arms included lifestyle advice administered (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 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 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033. not ; improve 3. Barry MJ, Williford WO, Chang Y, Machi M, Jones KM, Walker-Corkery E, et al. J Urol 1995 Nov;154(5): 1770-4.

Efficacy: BPH clinical progression CONDUCT Clinical progression events were defined by 1 : A rise in IPSS of 3 points at any visit when compared to Visit 2 (baseline) AUR related to BPH Recurrent (more than one) UTI related to BPH Incontinence (overflow or urge) related to BPH Renal insufficiency related to BPH (a single 50% rise from baseline serum creatinine and a total value 1.5 mg/ dl) 1. NCT01294592 Protocol summary: https://clinicaltrials.gov/ct2/show/nct01294592?term=nct01294592&rank=1

Efficacy: BPH clinical progression 1 Subjects with progression, % 30 20 10 0 Fixed dose combination of dutasteride and tamsulosin** Watchful Waiting with initiation of tamsulosin if symptoms did not improve** 0 6 12 18 24 Months from randomisation 29% 18% 43.1% relative risk reduction at year 2; (p<0.001) 11.3% absolute risk reduction (risk difference) Number needed to treat: 9 Cumulative number of events/subjects at risk Year 1 Year 2 Fixed dose combination of dutasteride and tamsulosin 48/369 17/276 Watchful Waiting with initiation of tamsulosin if symptoms did not improve 94/373 14/251 *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. **Both treatment arms included lifestyle advice administered 1. Adapted from Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033.

Efficacy: BPH clinical progression components 1-3 Fixed dose combination of dutasteride and tamsulosin** (n=369) Watchful Waiting with initiation of tamsulosin*, ** (n=373) Symptom progression (deterioration of IPSS 3) % of subjects with any occurrence (95% CI) 16 (12.5, 20.0) 27 (22.8, 31.9) BPH-related AUR <1 (0.0, 1.7) 3 (1.0, 4.3) BPH-related urinary incontinence 1 (0.0, 2.1) <1 (0.0, 1.7) BPH-related UTI <1 (0.0, 1.3) 2 (0.3, 2.9) BPH-related renal insufficiency 0 <1 (0.0, 0.8) * if symptoms did not improve **Both treatment arms included lifestyle advice administered 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033. ; 3. Roehrborn CG, Warnack W, Perez IO, Roos E, Calomfirescu N, Brotherton B, et al. Eur Urol Suppl Apr 2014;13(1):LBA1, EAU Congress presentation.

Health outcomes results: BPH Impact Index BPH Impact Index (BII, bother score) decreased in both groups over time and the decrease was significantly greater (p<0.001) at all post-baseline visits in fixed dose combination of dutasteride and tamsulosin treatment arm 1,2,** Adjusted mean change from baseline (LOCF) 0-0.5-1 -1.5-2 -2.5-3 -0.4 1-1.3 Fixed dose combination of dutasteride and tamsulosin (n=369) Watchful Waiting with initiation of tamsulosin if symptoms did not improve (n=373) 3-1.0-1.8-1.3-1.9-1.5-2.1 *Improvement thresholds were selected for the lower BII baseline scores (<5) **Both treatment arms included lifestyle advice administered 6 9 12 15 Months from randomisation -1.4-2.2 18 21-1.6-2.4 24 Patient assessment of improvement thresholds *,3 Moderate -0.7 Marked -1.4 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Adapted from Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033; 3. Barry MJ, Williford WO, Chang Y, Machi M, Jones KM, Walker-Corkery E, et al. J Urol 1995 Nov;154(5):1770-4.

Health outcomes results: Question 8 of IPSS Question 8 of IPSS score decreased in both groups over time and the decrease was significantly greater (p<0.001) at all post-baseline visits in fixed dose combination of dutasteride and tamsulosin treatment arm 1,2 Adjusted mean change from baseline (LOCF) 0-0.5-1 -1.5-2 -0.3-0.8 1 3 Fixed dose combination of dutasteride and tamsulosin (n=369)* Watchful Waiting with initiation of tamsulosin if symptoms did not improve (n=373)* -0.7-1.1 6 Months from randomisation -1.1-1.1-1.3 *Both treatment arms included lifestyle advice administered 9 12 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033.. 15 18 21-1.5 24

Extent of exposure and summary of adverse events (AEs) after randomisation CONDUCT 1 Safety was monitored in all subjects Fixed dose combination of dutasteride and tamsulosin (n=369)** Watchful Waiting with initiation of tamsulosin (n=229)** Subjects, n (%) Years of subject exposure* 615 349 Any AE 190 (51) 95 (41) Drug-related AE 87 (24) 23 (10) Any serious AE (SAE) 38 (10) 19 (8) AE leading to discontinuation of study drug AE leading to withdrawal from study 27 (7) 11 (5) 27 (7) 11 (5) Any fatal AE 0 2 (<1) * *Fatal SAEs were not related to treatment **Both treatment arms included lifestyle advice administered 1. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033..

Drug-related AEs (in 2% subjects) CONDUCT 1 Fixed dose combination of dutasteride and tamsulosin (n=369)* Watchful Waiting with initiation of tamsulosin (n=229)* Subjects, n (%) Any drug-related AE 87 (24) 23 (10) Erectile dysfunction 29 (8) 0 Retrograde ejaculation 18 (5) 9 (4) Dizziness 9 (2) 4 (2) Decreased libido 9 (2) 0 Ejaculation disorder 6 (2) 0 Loss of libido 6 (2) 0 Vertigo 6 (2) 0 Drug-related AEs affecting sexual function were reported by subjects during the first 6 months of therapy then incidence of sexual adverse events diminished over the course of treatment. 1. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033.. *Both treatment arms included lifestyle advice administered

Non-fatal SAEs (reported in 2 subjects) CONDUCT 1 Fixed dose combination of dutasteride and tamsulosin (n=369)* Watchful Waiting with initiation of tamsulosin (n=229)* Subjects, n (%) Any non-fatal SAE 38 (10) 19 (8) Atrial fibrillation 4 (1) 2 (<1) Respiratory tract infection 1 (<1) 2 (<1) Cellulitis 2 (<1) 0 Diverticulitis 0 1 (<1) Inguinal hernia 2 (<1) 0 Presyncope 2 (<1) 0 Prostatitis 1 (<1) 1 (<1) Colon cancer 0 2 (<1) Prostate cancer 0 1 (<1) 1. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033.. *Both treatment arms included lifestyle advice administered

CONDUCT study: safety profile of Duodart was consistent with previous evidence 1,2 The safety profile of Duodart remained consistent with other studies and post-marketing experience. The most frequently reported AEs in both primary treatment groups were erectile dysfunction and retrograde ejaculation No subject in the DUODART group was diagnosed with prostate cancer No breast cancer cases were reported Cardiovascular events: The overall proportion of subjects with any cardiovascular AEs of special interest was similar between the DUODART and the Watchful Waiting with initiation of tamsulosin if symptoms did not improve groups (1.9% vs. 1.6%) No unexpected adverse events No fatal SAEs were reported in the DUODART group. Three subjects experienced fatal SAEs in the Watchful Waiting with initiation of tamsulosin if symptoms did not improve group* *Both treatment arms included lifestyle advice administered 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033..

CONDUCT results: summary 1,2 Duodart is superior vs. Watchful Waiting with initiation of tamsulosin if symptoms did not improve* in symptom reduction Duodart resulted in greater (p<0.001) symptom improvement from 1st month out to 2 years in BPH patients with moderate symptoms and at risk of progression 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033.. *Both treatment arms included lifestyle advice administered 29

CONDUCT results: summary 1,2 Duodart is superior vs. Watchful Waiting with initiation of tamsulosin if symptoms did not improve* in improving QoL outcomes Duodart provided a superior improvement in QoL outcomes (BPH Impact Index and IPSS Q8) at all post-baseline visits (p<0.001) 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033.. *Both treatment arms included lifestyle advice administered

CONDUCT results: summary 1,2 Duodart is superior vs. Watchful Waiting with initiation of tamsulosin if symptoms did not improve* in reducing clinical progression Duodart significantly reduced the risk of BPH clinical progression over a 2-year period (p<0.001) 43.1% relative risk reduction 11.3% absolute risk reduction Number needed to treat: 9 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033.. *Both treatment arms included lifestyle advice administered

CONDUCT results: summary 1,2 CONDUCT Study Compliments CombAT data Evaluated BPH patients at risk of progression with only moderate symptoms and naïve to treatment 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033..

CONDUCT results: summary 1,2 CONDUCT Study Consistent safety profile The safety profile of Duodart was consistent with other studies and post-marketing experience 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033..

CONDUCT results: summary 1,2 CONDUCT Study Supports first line use CONDUCT data supports first line use of Duodart in BPH patients with moderate symptoms and at risk of progression 1. NCT01294592 Study results: https://clinicaltrials.gov/ct2/show/results/nct01294592?term=nct01294592&rank=1; 2. Roehrborn CG, Oyarzabal Perez I, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. BJU Int 2015 Jan doi: 10.1111/bju.13033..

EAU LUTS Guidelines support first-line medical treatment decision based on patient s symptoms and risk of BPH progression Male LUTS (without indications for surgery) No Bothersome symptoms? Yes No Nocturnal polyuria predominant Yes No Storage symptoms predominant Yes No Prostate volume >40 ml? Yes Education + lifestyle advice with or without α 1 -blocker No Long-term treatment? Residual storage symptoms Yes Watchful waiting with or without education + lifestyle advice Add muscarnic receptor antagonist Education+ lifestyle advice with or without 5-ARI ± α 1 -blocker/ PDE5I Education + lifestyle advice with or without muscarinic antagonist Gravas et al. Guidelines on management of male LUTS, incl. BPO (2014). http://uroweb.org/fileadmin/guidelines/ Guidelines_2014_30_April_2014.pdf (Accessed February 2015) Education + lifestyle advice with or without vasopressin analogue

CONDUCT study results: new evidence to support initial treatment with combination dutasteride and tamsulosin in patients with moderate BPH symptoms at risk of progression

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International prostate symptom score (IPSS) Patient assessment of improvement thresholds Clinical significance (patient global ratings of improvement) of changes in IPSS: Pt. Assessment of Improvement 0 35 Baseline Score Mean Absolute Change Scores ± SEM 8 19 (Moderate) Baseline Score Mean Absolute Change Scores ± SEM 20 35 (Severe) Baseline Score Mean Absolute Change Scores ± SEM Marked -8.8 ± 0.34-7.4 ± 0.29-15.3 ± 0.76 Moderate -5.1 ± 0.29-4.0 ± 0.29-8.7 ± 0.62 Slight -3.0 ± 0.27-1.9 ± 0.29-6.1 ± 0.54 None -0.7 ± 0.31-0.2 ± 0.35-2.0 ± 0.62 Worse +2.7 ± 0.93 +3.3 ± 1.09 +1.2 ± 1.79 Thresholds relevant to CombAT study Adapted from Barry MJ et al. J Urol 1995;154(5):1770 4 Thresholds relevant to CONDUCT study