1. Medical Therapy of Prostate Symptoms (MTOPS) Jeannette Y. Lee, Ph.D. University of Alabama at Birmingham

2. Benign Prostatic Hyperplasia (BPH) Common cause of morbidity among older men Characterized by bothersome lower urinary tract symptoms (LUTS) Men with BPH and larger prostates due to BPH are at increased risk of complications such as acute urinary retention

3. Prevalence Clinical Significant BPH –AUA symptom score > 7 points (moderate to severe lower urinary tract symptoms) –Depressed peak uroflow (< 15 mL/sec) Prevalence by age group –17% in men from 50-59 yrs of age –27% in men from 60-69 yrs of age –35% in men from 70-79 yrs of age

4. MTOPS Trial Design Randomized, double blind, 2 x 2 factorial Two-year enrollment period Minimum four-year follow-up period Objective: to determine if doxazosin or finasteride, alone or in combination delayed or prevented clinical progression of BPH

5. Inclusion Criteria Men > 50 yrs of age AUA symptom score of 8-35 Peak urinary flow rate of 4-15 ml/sec Voided volume > 15 ml

6. Exclusion Criteria Prior medical or surgical intervention for BPH Supine blood pressure < 90/70 mmHg PSA > 10 ng/ml

7. Factorial Design Finasteride + Doxazosin Finasteride DoxazosinPlacebo

8. Treatments 5 -  reductase inhibitor Finasteride dose: 5 mg Alpha blocker Doxazosin dose doubled weekly starting with 1 mg daily until daily dose of 8 mg reached.

9. Follow-up Evaluations Vital signs AUA symptom score Urinary flow rate Adverse Events DRE, serum PSA< urinalysis Prostate volume (TRUS)

10. Follow-up Questionnaire AUA Symptom Score QOL Short Form-36 (SF-36) Sexual function questionnaire Prostatitis Questionnaire

11. Primary Endpoints Primary endpoint: time to BPH progression defined as –> 4 point increase in AUA symptom score –Acute urinary retention –Renal insufficiency –Recurrent urinary tract infection –Urinary incontinence

12. Secondary Endpoints Changes over time –AUA symptom score –Maximal urinary flow rate –PSA level –Prostate volume Cumulative incidence of invasive treatments for BPH

13. Results 3047 men randomized Baseline characteristics –Mean age: 62.6 yrs –White: 82% –Mean AUA symptom score: 16.9 –Mean prostate volume: 36.3 ml –Mean Max urinary flow rate: 10.5 ml/min –Mean post void residual volume: 68.1 ml –Mean serum PSA: 2.4 ng/ml –Mean serum creatinine: 1.1 mg/dl

14. Clinical Progression of BPH Rate per 100 PYs Placebo (N=737) Doxazosin (N=756) Finasteride (N=768) Combination (N=786) Clinical Prog. 4.52.72.91.5 > 4 pt rise AUASS 3.61.92.51.3 AUR0.60.40.20.1 Incont.0.3 0.1

15. Clinical Progression of BPH Events Placebo (N=737) Doxazosin (N=756) Finasteride (N=768) Combination (N=786) Clinical Prog. 122737842 > 4 pt rise AUASS 97556536 AUR18964 Incont.6771 UTI1201

16. Cumulative Incidence of Progression (N Engl J Med 2003: 349 (25): 2387-97)

17. Rate of Progression per 100 PYs Placebo: 4.5 BPH Progressors Doxazosin: 2.7 BPH Progressors Finasteride: 2.9 BPH Progressors Combination: 1.5 BPH Progressors

18. Invasive Therapy due to BPH CumulativePlacebo (N=737) Doxazosin (N=756) Finasteride (N=768) Combination (N=786) Rate per 100 PY 1.3 0.50.4 Events37261412

19. Adverse Events – Sexual Function (Rate per 100 PYs) Placebo (N=737) Doxazosin (N=756) Finasteride (N=768) Combination (N=786) Erectile dysfunction 3.323.564.53*5.11* Decreased libido 1.41.562.36*2.51* Abnormal ejaculation 0.831.101.78*3.05* * p<0.05 compared to placebo

20. Adverse Events – Hypotension (Rate per 100 PYs) Placebo (N=737) Doxazosin (N=756) Finasteride (N=768) Combination (N=786) Dizziness2.294.41*2.335.35* Postural hypotension 2.294.03*2.564.33* Asthenia2.064.08*1.564.20* * p<0.05 compared to placebo

21. MTOPS Summary Combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression more than each drug alone. Finasteride containing regimens reduced the long-term risk of AUR and need for invasive therapy. McConnell et al, N Engl J Med 2003.

22. Methods papers Study Design –Bautista et al, Controlled Clinical Trials 2003 Recruitment –Kusek et al, Controlled Clinical Trials 2002

23. Secondary Analyses Placebo patients – baseline factors associated with clinical progression * –Total prostate volume –PSA –Peak flow rate –Post residual volume –Age * Crawford et al, J Urol 2006

24. Secondary Analyses Combination therapy is better than either agent alone (finasteride, doxazosin) in decreasing the risk of clinical BPH progression in those with higher prostate volumes* Kaplan et al, J Urol 2006

25. MPSA MTOPS Prostatic Sample Analysis Consortium – evaluate biomarkers associated with BPH (Mullins et al, J Urol 2008).

26. Analyses in Progress Longitudinal analyses of sexual function Risk of prostate cancer

27. MTOPS Data Available Uroflow Measurements (quarterly) Compliance/pill counts (quarterly) PSA measurements (semi-annually) PE, CBC, serum chemistry, urinalysis (annually) TRUS and Biopsy (Screening, 12 mos, end of study)

28. MTOPS Questionnaires AUA Symptom Questionnaire (quarterly) Sexual Function Questionnaire (screening and end of study) Medical Outcomes Study (MOS) – Short Form 36 (SF-36) (annually) Prostatitis Questionnaire (annually)

29. MTOPS Data from Diagnostic Center PSA (ng/ml) LH (mIU/ml) Testosterone (ng/dl) % Free PSA Total PSA

30. MTOPS Samples in NIDDK Repository Type of Specimen NumberNumber of participants Serum102,916 (0.5 ml aliquots) 4127 Frozen tissue7001 Bx samples 1449 Fixed tissue14,416 Bx blocks 1449