The Management of BPH & The Impact of Combination Therapy Results Combination of Avodart and Tamsulosin (CombAT) Medical Therapy of Prostate Symptoms (MTOPS) Dr. Jack Barkin, md, fics, facs, dabu, Mcert HM, frcs(c) Clinical Professor: Dept. of Surgery-University of Toronto Chief of Staff: Humber River Regional Hospital Vice-Pres: Canadian Society for the Study of the Aging Male (CSSAM) US men eligible for BPH treatment * with projected population changes Number in millions 8 7 6 5 4 3 2 50 59 60 69 70 79 1 0 2000 2010 2020 *Based on 1994 AHCPR Guidelines and Olmsted County, Minnesota: IPSS >7 points and Q max <15 ml/s Jacobsen et al. Arch Intern Med 1995; 155: 477 481 The Evolution of Combination Therapy
Canadian Guidelines for the Management of BPH Treatment Algorithm: INITIAL PRESENTATION Typical man with LUTS 2 to BPH, No Surgical Indications Mild symptoms Moderate/ Severe Symptoms Small or Large Prostate Watchfu l Waiting Watchful Waiting Small prostat e No Significant Bother The Canadian Journal of Urology; 2005;12(3);2677-2683 Large prostate Watchful Waiting OR Consider 5ARI therapy Small prostate Alpha blocker Tx or Surgical Option Moderate-Severe Bother Large prostate Alpha blocker or 5ARI or Combo Tx or Surgical Option Medical Management of LUTS 2 to BPH Risk of Progression (Prostate Size) Conservative Measures Consider 5ARI Watchful Waiting Combination Therapy Alpha Blocker Symptom Severity (Degree of Bother) If a drug treatment that reduces the size of the prostate can be found, perhaps a combination of the two forms of medical treatment will have a place Caine. Urol Clin North Am 1990; 17: 641 9
Combining modes of action for BPH treatment 5α-reductase inhibition Decrease in DHT synthesis from testosterone Androgenic drive of prostate reduced Prostate volume reduced diminishing outflow obstruction Oncogenesis reduced α 1 -adrenergic blockade Blockade of α 1 -adrenergic receptors in prostate, urethra and bladder neck Relaxation of smooth muscle resulting in improved urinary flow Effects on spinal cord receptors? Benefit profile of 5α-reductase inhibitors and α 1 -blockers in BPH 5ARIs α-blockers Reduce PV Maintain reductions in PV Improve symptoms/flow Onset of symptom relief in 1 2 weeks Maintain symptom/flow improvements Prevent symptomatic progression Reduce longer-term risk of AUR and surgery Combination therapy: the best of both worlds? Key issues for Combination Therapy What are the benefits of combination therapy? Symptoms/flow: short and long-term benefits Prostate volume reduction Long-term outcomes: AUR and surgery Overall progression of BPH What is the combined adverse event profile? Diminished? Additive? Synergistic?
Medical therapy for BPH Finasteride launched 1991 PREDICT 1999 2003 launched 2002 Phase IIIa dutasteride 2003 CombAT 2007 First alpha blocker for BPH launched 1990 PLESS 1996 1998 VA-COOP 1996 1998 MTOPS 2003 2006 4-year data 2004 Early, short-term combination studies Placebo-controlled Study n Duration Type Agents Veterans Affairs Cooperative Study Lepor (1996) 1229 1 year DB + R Fin, Ter, Fin + Ter, Pla Lepor (1998) PREDICT Kirby (1999) a, b 1089 1 year DB + R Fin, Dox, Fin + Dox, Pla Roehrborn (2000) a, b Kirby (2003) VA-COOP study Symptom score 17 16 15 14 13 12 11 10 9 8 Placebo Finasteride Terazosin Combination Entry 24 13 26 39 52 Week of study Lepor et al. NEJM 1996; 335: 533 9
PREDICT study Symptom reductions at 1 year 0-1 -2-3 -4-5 -6-7 Doxazosin (n=275) -8-9 -8.3 Change in symptom score Finasteride (n=264) -6.6 Combo (n=286) -8.5 Placebo (n=269) -5.7 Kirby et al. Urology 2003; 61: 119 26 Early studies: Conclusions Outcomes: Combination therapy no different from alpha-blocker monotherapy for symptoms by one year Finasteride no better than placebo Issues: Mean PV below 40 cc in both studies Duration only one year in both studies Did these factors limit the benefit of combination therapy over alpha-blocker monotherapy? Patterns of symptom deterioration Impact of PSA and time in Placebo-treated men from the PLESS study Change in IPSS 0.0-0.5-1.0-1.5-2.0 PSA (ng/ml) 0.1 1.3 1.4 3.2 3.3 10.0-2.5-3.0 0 4 8 12 16 20 24 28 32 36 40 44 48 Months Roehrborn et al. Urology 1999; 54: 662 9
VA-COOP and PREDICT vs. MTOPS Mean baseline PV Mean baseline AUA-SI VA-COOP 1 PREDICT 2 MTOPS 3 37 cc 36 cc 36 cc 16 17 17 n 1229 1089 3047 Study duration 1 year 1 year 4.5 years 1. Lepor et al. NEJM 1996; 335: 533 9; 2. Kirby et al. Urology 2003; 61:119 262 3. McConnell et al. NEJM 2003; 349: 2387 98
MTOPS: Most frequent adverse events Incidence 5% in 1 group Plac Dox Fin Comb Asthenia 7.1% 15.7% 5.3% 16.8% Postural hypotension 8.0% 16.7% 9.1% 17.8% Dizziness 8.1% 17.7% 7.4% 23.2% Libido decreased 5.7% 7.0% 10.0% 11.6% Abnormal ejaculation 2.3% 4.5% 7.2% 14.1% Impotence 12.2% 14.4% 18.5% 22.6% Merck & Co Inc. Proscar (finasteride) prescribing information. Whitehouse Station, New Jersey, USA (2007) CombAT Combination of Avodart and Tamsulosin
Screening Why CombAT? Need to examine effects of combination therapy a priori in men at-risk of BPH progression Optimal population for combination? MTOPS composite primary endpoint provided limited symptom data What are the patterns of effect on symptoms over time? DHT suppression: dutasteride > finasteride What effects does it have in combination therapy? How do dutasteride and tamsulosin compare in men at-risk of progression? CombAT major entrance criteria Male aged 50 years Diagnosis of BPH by History and DRE IPSS 12 (moderate to severe symptoms) Prostate volume 30 cc by TRUS Serum PSA 1.5 and 10.0 ng/ml Two voids at screening with Q max >5 and 15 ml/sec (moderate to severe impairment) and minimum voided volume of 125 ml Siami, Barkin et al. Contemp Clin Trials, Aug 07, 28(6), 770-79 CombAT study design 2 year-planned analysis Single-blind Double-blind Washout Placebo run-in Tamsulosin (0.4 mg daily) (0.5 mg daily) Safety followup phase Combination 4 wks Treatment period = 4 years 16 wks Baseline Siami, Barkin et al. Contemp Clin Trials, Aug 07, 28(6), 770-79
Comparison of CombAT and MTOPS Treatment groups CombAT 1 MTOPS 2 monotherapy Tamsulosin monotherapy and tamsulosin combination therapy n 4844 3047 Location International US only Entry criteria Age PV (cc) PSA (ng/ml) IPSS Primary endpoints 2-year 4-year 50 30 1.5 and 10 12 Improvement in IPSS Reduction in risk of AUR/surgery Finasteride monotherapy Doxazosin monotherapy Finasteride and doxazosin combination therapy Placebo 50 NA 10 8 30 NA Composite endpoint of BPH clinical progression 1 Siami, Barkin et al. Contemp Clin Trials; 2 McConnell et al. NEJM 2003; 349: 2387 98 Age and Serum PSA can Help Identify Patients with Enlarged Prostates* * Each prediction is subject to an error of approximately ± 5 ml. These results are based on the trial population studied, and estimate the average prostate volume for a given age and PSA level. Adapted from Roehrborn CG et al. Entered single-blind phase n=5052 Randomized to double-blind phase n=4844 Combination n=1610 n=1623 Tamsulosin n=1611 Completed 24-month visit n=1267 (79%) Adverse event n=154 (9.6%) Consent withdrawn n=71 (4.4%) Lack of efficacy n=36 (2.2%) Other n=82 (5.1%) Not completed 24-month visit n=343 (21%) Completed 24-month visit n=1301 (80%) Adverse event n=108 (6.7%) Consent withdrawn n=95 (5.9%) Lack of efficacy n=45 (2.8%) Other n=74 (4.6%) Not completed 24-month visit n=322 (20%) Completed 24-month visit n=1254 (78%) Adverse event n=136 (8.4%) Consent withdrawn n=74 (4.6%) Lack of efficacy n=53 (3.3%) Other n=94 (5.8%) Not completed 24-month visit n=357 (22%) Roehrborn et al. J Urol (In Press); Roehrborn et al. SIU, 2007, MP-20.28, POD-06.02
Baseline demographics and patient characteristics (mean ± SD) Combination (n=1610) (n=1623) Tamsulosin (n=1611) Age (years) 66.0 ± 7.05 66.0 ± 6.99 66.2 ± 7.00 Caucasian ethnicity 1421 (88%) 1433 (88%) 1405 (87%) Total mean IPSS score (points) 16.6 ± 6.35 16.4 ± 6.03 16.4 ± 6.10 Time since first lower urinary tract symptoms (years) 5.4 ± 5.07 5.3 ± 4.69 5.4 ± 4.76 Total prostate volume (cc) Median TPV (cc) Transition zone volume (cc)* 54.7 ± 23.51 48.9 27.7 ± 20.20 54.6 ± 23.02 48.4 30.3 ± 21.02 55.8 ± 24.18 49.6 30.5 ± 24.47 Serum PSA (ng/ml) 4.0 ± 2.05 3.9 ± 2.06 4.0 ± 2.08 Qmax (ml/sec) 10.9 ± 3.62 10.6 ± 3.57 10.7 ± 3.66 Post-void residual volume (ml) 68.1 ± 66.01 67.4 ± 63.49 67.7 ± 65.14 Sexually active 1176 (73%) 1189 (73%) 1164 (72%) Previous alpha blocker use 805 (50%) 820 (51%) 819 (51%) Previous 5ARI inhibitor use 171 (11%) 188 (12%) 172 (11%) *Sub-group of 656 men CombAT 4 year endpoints Primary Time to event/proportion of subjects with AUR or BPH related surgery Secondary Time to BPH related clinical progression First of: Symptom deterioration by IPSS 4 points Acute urinary retention Incontinence Recurrent UTI or urosepsis Renal insufficiency related to BPH All primary and secondary endpoints evaluated at Year 2 are secondary endpoints at Year 4 Siami, Barkin et al. Contemp Clin Trials 2007;28:770 28:770 9 32 CombAT: Time to first AUR or BPH related surgery Patients with AUR/surgery (%) 16 14 12 10 8 6 4 2 0 Risk reduction estimate comb vs.. tamsulosin = Combination 65.8% (95% CI: 54.7, 74.1%) p<0.001 Tamsulosin Risk reduction estimate comb vs.. dutasteride = 19.6% (95% CI: 10.9, 41.7%) p = 0.18 0 12 24 36 48 Study month Roehrborn, Barkin et al. In press with Eur Urol 33
CombAT 4-year combination therapy reduces incidence of clinical progression Risk reduction estimates: Combination vs.. dutasteride = 31.2% (95% CI: 17.7, 42.5%) Combination vs.. tamsulosin = 44.1% (95% CI: 33.6, 53.0%) Incidence of clinical progression (%) * * Roehrborn, Barkin et al. In press with Eur Urol Cumulative incidence based on ITT population *p<0.001 vs. combination 34 CombAT IPSS Adjusted mean change from baseline (LOCF) Study month Adjusted mean IPSS change from baseline p < 0.001 combination vs. tamsulosin p < 0.001 combination vs. dutasteride (n = 1610) (n = 1623) (n = 1611) Roehrborn, Barkin et al. In press with Eur Urol 35 IPSS Q8 IPSS comprises 7 questions about the nature and frequency of problems with urination 1 overall QOL question: Q8: If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that? 6 point response scale (0 = delighted to 5 = terrible)
Secondary endpoint: Mean change in BPH Health Status (QOL Q8) Adjusted mean change in Q8 score from baseline (ITT, LOCF) 0.0 p<0.001 combo vs. dut p<0.001 combo vs. tam -0.5-0.6-1.0-1.5-0.8-0.9-0.9-0.9-1.1-1.0-1.0-1.1-1.0-1.1-1.2-1.0-1.1-1.1-1.1-1.1-1.1-1.1-1.1-1.3-1.4-1.4-1.4 0 3 6 9 12 15 18 21 24 Treatment month Tamsulosin Combination Barkin J. Siami P.et al, BJU 2008,103919-26 Prostate specific antigen Median percentage change from baseline Median change (%) 20 12.5% 10 0.0 0-10 -20-30 -40-50 -53.7% -55.0% -60-55.6% -55.7% -70 0 12 24 Treatment month Tamsulosin Combination Roehrborn, Barkin et al, J Urol, 2009 179(2): 616-21 CombAT 4 year overall adverse event profile Combination Tamsulosi (n=1610) (n=1623) n Adverse events (AE) 73% 73% (n=1611) 72% Serious AEs 19% 21% 22% Drug related related AEs 28% 21%* 19%* Serious drug related related AEs <1% <1% <1% AEs leading to study withdrawal 13% 12% 14% Drug related related AEs leading to study withdrawal 6% 4% 4% *p 0.01 vs. combination Roehrborn, Barkin et al. In press with Eur Urol 39
CombAT 4 year 4 drug related related AEs in 1% of subjects Combination (n=1610) (n=1623) Tamsulosin (n=1611) Erectile dysfunction 9% 7% 5% Retrograde ejaculation 4% <1% 1% Altered (decreased) libido 4% 3% 2% Ejaculation failure 3% <1% <1% Semen volume decreased 2% <1% <1% Loss of libido 2% 1% 1% Dizziness 2% <1% 2% Gynecomastia 2% 2% <1% Nipple pain 1% <1% <1% Breast tenderness 1% 1% <1% Roehrborn, Barkin et al. In press with Eur Urol 40 Summary In CombAT, combination therapy was superior to tamsulosin but not to dutasteride in reducing the risk of AUR and BPH related surgery Symptom improvement was superior with combination therapy compared with both monotherapies, with the level of benefit maintained from Year 2 The rate of BPH clinical progression was significantly reduced with combination therapy compared with both monotherapies Safety and tolerability of combination therapy was consistent with previous experience with dutasteride and tamsulosin monotherapies The incidence of the composite cardiac failure adverse event in the tamsulosin and combination treatment groups, although low, was slightly elevated compared with the dutasteride group Although drug related AEs were more frequent with combination they rarely led to discontinuation of therapy 41 Patterns of symptom effect Impact of prostate volume and time PV (cc) 10 20 30 40 50 60 70 80+ 5ARIs Short Long term ABs Short Long term In men with prostate enlargement, 5ARIs offer better long-term symptom benefits than alpha blockers
43 Conclusions Benefits of combination therapy over monotherapy in improving QoL were significant within first 12 months and sustained through Month 24 Baseline PV had little impact on the QoL measures studied CombAT is the first study to demonstrate significant superiority of the combination of a 5ARI and an α-blocker over each monotherapy in improving patient-reported QoL 4-year CombAT results will provide further information on long-term effects on patient-reported health outcomes Questions?? Prostate Cancer Risk Reduction Jack Barkin, MD University of Toronto
Burden of Prostate Cancer in Canada Cost to society Number one diagnosed cancer in Canadian men Cost of screening Cost of treatment Cost to patient and his partner Psychosocial: impact of diagnosis Impact of treatment Number two cancer killer of Canadian men Prostate cancer mortality reduction Recent screening trials Canadian prostate cancer mortality reduction Morbidity of Diagnosis and Treatment Psychological Diagnosis can lead to anxiety but can vary 30% of PCa patients met criteria for general distress 1 38% of PCa patients met criteria for severe psychological distress 2 ED and Incontinence Significant distress reported by Most patients who suffer from these common complications 44% of partners of patients with prostatectomy 1.Carlson L. Br J Cancer 2004;90:2297 2.Balderson N. Br J Health Psychol 2003;8:125 Manda M. NEJM 2008;358:1250
REDUCE: Study Design Study entry Study Randomization 2-year 10-core biopsy month: -7-1 0 24 48 Entry Matching placebo biopsy 0.5 mg daily Placebo run-in 4-year 10-core biopsy Protocol-independent biopsies could occur as indicated Andriole et al. J Urol 2004; 172: 1314 7
REDUCE: Baseline demographics Placebo (n=4126) (n=4105) Number Age (years) of Canadian Sites 62.7 ± 6.08 40 62.8 ± 6.04 Number White of Canadian Men 91% 751 91% Screened Family history of PCa 13% 13% Number Total PSA of Canadian (ng/ml) Men 5.9 ± 2.00 476 5.9 ± 1.97 Randomized Prostate volume (cc) 45.7 ± 18.78 45.7 ± 18.20 Number of cores at baseline biopsy 8.8 ± 2.44 8.8 ± 2.48 Men at high risk of prostate cancer Mean standard deviation Andriole G. AUA Annual Meeting, 2009 REDUCE: Primary endpoint reduced the relative risk of prostate cancer over 4 years by 23% p<0.0001 REDUCE: Drug-related Adverse Events Occurring in 1% Subjects in Either Treatment Group Placebo (n=4126) (n=4105) Decreased libido 1.6% 3.3% Loss of libido 1.3% 1.9% Erectile dysfunction 5.7% 9.0% Decreased semen volume 0.2% 1.4% Gynecomastia 1.0% 1.9% Any CV event* 8% 7% Composite cardiac failure* 0.4% 0.7% p<0.05 for all between-treatment group comparisons * GSK data on file Andriole G. AUA Annual Meeting, 2009
BPH Progression Events REDUCE: Time to first BPH-related surgery 7 Placebo: 5.1% 6 : 1.4% 73% risk reduction 5 p<0.0001 4 REDUCE patients were mild to moderately 3 2 symptomatic for BPH: 1 % subjects % subjects 0 0 12 24 36 48 Time (months) REDUCE: Time to First AUR Placebo 9 Placebo: 6.7% 8 : 1.6% 77% risk reduction 7 p<0.0001 6 5 4 3 2 1 0 0 12 24 36 48 Time (months) 73% Mean IPSS score at baseline 8.6 8.7 Mean PV at baseline 45.8 45.7 Number needed to treat 16 77% Andriole G. AUA Annual Meeting, 2009 REDUCE Summary AVODART reached its primary endpoint with a 23% RRR of prostate cancer detection (32% in men with a family history of the disease) Men with mean IPSS scores of 8.7 achieved a 73% RRR in BPH-related surgery and 77% RRR in AUR Side effect profile predictable with events subsiding over time 5ARI--Value Added?? In a man with moderate symptoms,moderate bother and an enlarged prostate>>>>> 5ARI: Prevent progression Reduce risk of AUR Reduce risk of the need for surgery 23-25% Reduced risk of detecting prostate cancer