Where have we been in the last 20 years? Diagnosis and Treatment of BPH and Prostate Cancer using Prostate Specific Antigen (PSA) Where have we been in the last 20 years? George T. Ho, MD October 27, 2007

Discovery of PSA Hara et al (Japanese J. Legal Medicine, 1971): 1st report of gamma seminoprotein from seminal plasma isolate.

Discovery of PSA Li et al (Fertility and Sterility, 1973): identification of Protein E1 from seminal plasma

Discovery of PSA Sensabaugh et al (J. Forensic Science, 1978): description of p30 in seminal plasma

Discovery of PSA Wang et al (Invest. Urology, 1979): identified seminal specific protein as PSA and developed assay for PSA

PSA Research Sensabaugh et al (1985): PSA is not found in the semen of bulls, rams, bears, and other mammals!

PSA Research Watt et al (PNAS 1988): PSA sequence at 237 amino acids at Cetus Corp

PSA hits prime time Stamey et al (NEJM 1987): 1st clinical evaluation of PSA in men with and without Prostate Cancer Levels of serum PSA correlated to prostate size/volume and stage of Prostate Cancer Serum PSA increases with sexual activity Serum PSA increases after DRE

Issues surrounding the use of PSA in Clinical Practice

PSA parameters: PSA Density PSA Velocity Age Specific PSA Free/Total PSA (PSAII)

PSA Density: PSA-D = serum PSA/prostate volume Normal range < 0.15

PSA Velocity: PSA-V = Change in PSA over time Normal Range < 0.75ng/cc/yr. Ng/

Age Specific PSA Age Range: PSA range: 40-49 <2.5ng/cc 50-59 60-69 <4.5ng/cc 70-79 <6.5ng/cc >79 ??? Should we be screening

Free/Total PSA: 90kDa 30kDa Mol. WT % Total PSA-ACT Free PSA 60-90% PSA is present in serum in various molecular forms. The two major forms recognized by commercial kits are: Mol. WT % Total PSA-ACT (bound PSA) 90kDa 60-90% Free PSA 30kDa 10-40%

Free/Total PSA: Percentage of Free PSA decreases as Total PSA increases in serum of men with prostate cancer (free/total PSA < 25% considered “abnormal”) Percentage of bound PSA (PSA-ACT) increases in serum of men with prostate cancer and prostatitis

Distribution of Free/Total PSA (PSAII): Based on ROC, the FDA agreed on NR of PSAII as >25% The AUA however suggests NR of PSAII as >20% to decrease number of unnecessary biopsies

Future PSA tests: B-PSA and C-PSA (Hybritech, La Jolla, CA)

Factors affecting serum PSA Sex DRE UTI Instrumentation of Lower GU tract Bicycle riding? Medications (Proscar and Avodart)

Prostate Cancer Chemoprevention Trial (PCPT) (Thompson, IM , et al Prostate Cancer Chemoprevention Trial (PCPT) (Thompson, IM , et al. NEJM, 2003: 349:215-224) 25% decrease in incidence of well-moderately diff. prostate cancers in men taking proscar vs. placebo Potential increase of poorly differentiated cancers in men taking proscar 28% men diagnosed with prostate cancer had normal PSA!

Problems in Early Diagnosis Does early detection really improve survival? What are the most accurate measures for early detection? How can clinically significant disease be distinguished? What are the most effective methods of treatment?

Early Detection Does Decrease Death Rate from Prostate Cancer Men who have a yearly PSA test are nearly three times less likely to die from prostate cancer than those who don’t have annual screening (3.6% vs. 11.3%). Jason Efstathiou, MD Annual Meeting of ASTRO Denver, CO 10/20/05

Best Use of PSA Following radical prostatectomy (Serum PSA should be nondetectable forever. Any detectable PSA may signal return of disease. No other monitoring modalities are necessary)

Legal Ramifications of PSA for PCP’s American Cancer Society recommends annual DRE and PSA, beginning at age 50 (age 40 in men with family history and in Afro-Americans). Beware of PSA velocity. Consider PSA II in young men and those at high risk, as well in those men with enlarged prostates and elevated total PSA’s. Always perform a DRE.

Use of PSA in Benign Prostate Hyperplasia PSA increases as size of prostate enlarges Alpha Blockers are no better than placebo in preventing growth of prostate (MTOPS, NEJM, December 2003) Alpha Blockers do not alter the natural progression of BPH (ie, rate of urinary retention or need for surgery)

Stopping the Progression Of BPH Use of 5 alpha reductase inhibitors (5 ARI) Differences in the two available 5 ARI

Near Complete DHT Suppression Requires Inhibiting Both 5AR Isoenzymes AVODART Finasteride Type II 5AR Testosterone DHT Although the etiology of BPH is multifactorial and not yet definitively established, prostate growth is regulated by androgens, particularly DHT. DHT and other androgens bind to androgen receptors in the stromal and epithelial cells of the prostate. When DHT binds to the androgen receptor, this causes a cascade of intracellular events that leads to the expression of genes and production of growth factors that regulate cell division and proliferation in the prostate.1 DHT has approximately five times greater affinity for the androgen receptor than testosterone.2 Testosterone is converted to the more potent androgen DHT by the enzyme 5-reductase (5AR). Two isoenzymes, or isoforms, of 5AR exist in the body: type I and type II. Both type I and type II 5AR isoenzymes are found in the prostate and affect stromal and epithelial cells in the prostate.1 In BPH, both isoenzymes of 5AR are elevated.3 Near complete DHT suppression requires inhibition of both type I and type II 5AR isoenzymes. The 5ARIs suppress DHT by inhibiting the conversion of testosterone to DHT. AVODART® (dutasteride) is the only dual 5ARI  it selectively inhibits both type I and type II 5AR isoenzymes. In comparison, finasteride only inhibits the type II 5AR isoenzyme.1 Reference 1. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5α-reductase inhibition in human benign prostatic hyperplasia. Eur Urol. 2000;37:367–380. 2. Grino BB, Griffen JE, Wilson JD. Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone. Endocrinology. 1990;126:11651172. 3. Ielhe C, Radvanyi F, Gil Diez de Medina S, et al. Differences in steroid 5-reductase iso-enzymes expression between normal and pathological human prostate tissue. J Steroid Biochem Mol Biol. 1999;68:189195. Type I 5AR Prostate volume reduced AVODART Bartsch G et al. Eur Urol. 2000;37:367380.

Change in DHT from baseline (%) AVODART® (dutasteride) Provides More Complete and Reliable DHT Suppression than Finasteride* Finasteride 5.0 mg (n = 11) P < 0.001 AVODART 0.5 mg (n = 12) –20 Standard deviation (variability among patients) –40 Change in DHT from baseline (%) 93% vs 62% DHT suppression at 24 weeks –60 –62% –80 AVODART provides more complete DHT suppression than finasteride. In this randomized, double-blind, parallel-group study of men with BPH, inhibition of type I and type II 5AR by AVODART resulted in more complete DHT suppression compared with finasteride, which inhibits only type II 5AR. At the 0.5 mg/day dose, AVODART suppressed DHT by 93% at 24 weeks. In comparison, finasteride 5.0 mg/day suppressed DHT by 62% at study endpoint. AVODART also achieved more reliable suppression of DHT with less subject variability than finasteride. Reference Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs S. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5-reductase inhibitor. J Clin Endocrinol Metab. 2004;89:2179–2184. Data on file, GlaxoSmithKline. –93% –100 4 8 12 16 20 24 Time (weeks) *The clinical benefit of more complete and consistent DHT suppression has not been established. DHT suppression may vary. In another study finasteride reduced DHT by approximately 70%. Adapted from Clark RV et al. J Clin Endocrinol Metab. 2004;89:21792184. Data on file, GlaxoSmithKline.

AVODART® (dutasteride) Rapidly Reduces Prostate Volume as Early as 1 Month Mean Prostate Volume Reduction From Baseline to Year 4 (n = 796) 10 Double-blind phase Open-label phase 5 –5 –5.2 Mean change in prostate volume(%) –10 –15 –13.8 –20 AVODART was associated with a significantly greater mean percentage reduction from baseline in prostate volume at each time point beginning at 1 month and continuing through the end of the 24-month, double-blind phase. At month 24, the mean percentage reduction from baseline in prostate volume was 26.0% for the AVODART group compared with a 1.4% increase in the placebo group. During the 2-year, open-label phase, patients in both arms received AVODART. Reduction in prostate volume was maintained during the open-label phase in men who received AVODART for the entire 4-year study period. Men who were treated with AVODART during both the double-blind and open-label phases experienced a mean percentage reduction in prostate volume of 27.3%. Men who were switched from placebo during the double-blind phase to AVODART at the beginning of the open-label phase experienced a 21.7% mean reduction in prostate volume compared with baseline. Reference Debruyne F, Barkin J, van Erps P, et al. Efficacy and safety of long-term treatment with the dual 5-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol. 2004;46:488–495. –19.9 –25 –23.6 –26.0 –30 –27.3 1 3 6 12 24 48 Treatment month Debruyne F et al. Eur Urol. 2004;46:488494.

Mean AUA-SI score change from baseline AVODART® (dutasteride) Significantly Improves Urinary Symptoms Out to 4 Years Time (months) 1 3 6 12 24 36 48 –1 –1.4 4-year symptom improvement (n = 860) –2 Mean AUA-SI score change from baseline –3 –2.7 –3.4 –4 –3.8 AVODART provided a significant and clinically meaningful 6.5-point decrease in AUA-SI score at 4 years.1 According to Barry et al, a decrease of 3 points on the AUA-SI would be perceptible to patients,2 so the magnitude of the improvement in patients treated with AVODART would be clinically meaningful. At 48 months, 73% of patients experienced at least a 3-point improvement in AUA-SI from baseline.1 While some men have fewer problems and symptoms after 3 months of treatment with AVODART, a treatment period of 6 months is usually necessary to see if AVODART will improve symptoms. References 1. Debruyne F, Barkin J, van Erps P, et al. Efficacy and safety of long-term treatment with the dual 5-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol. 2004;46:488–495. 2. Barry MJ, Williford WO, Chang Y, et al. Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients? J Urol. 1995;154:17701774. –4.4 –5 –6 –5.6 –6.5 –7 Double-blind phase Open-label phase Debruyne F et al. Eur Urol. 2004;46:488494.

AVODART® (dutasteride) Reduced the Risk of AUR by 57% at 2 Years Placebo 4.2% 4 57% risk reduction 3 Patients (%) AVODART 1.8%* 2 1 AUR is one of the most significant negative outcomes of LUTS and BPH, both from the patient and health economic perspectives.1 Men with a prostate volume > 30 mL have a three-fold higher risk for AUR compared with those men who have a prostate volume  30 mL.2 (In this group, due to small sample size relative risk estimate was not adjusted for age, AUA-SI score, and Qmax.) In 2-year, placebo-controlled studies, the percentage of patients developing AUR was 4.2% in the placebo group and 1.8% in the AVODART group. The cumulative number of events at year 2 in the AVODART group was 39 compared with 90 in the placebo group. AVODART reduced the risk of AUR by 57% compared with placebo over the 2-year double-blind phase.1 AUR occurred in a small percentage of men over the entire 4-year study period (including the 2-year, open-label phase). Out to 4 years, the incidence of AUR was maintained at rates consistent with those observed in the double-blind phase.3 References 1. Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60:434441. 2. Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Natural History of prostatism: risk factors for acute urinary retention. J Urol. 1997;158:481487. 3. Data on file, GlaxoSmithKline. 6 12 18 24 Month Out to 4 years, the incidence of AUR was maintained at rates consistent with those during the double-blind phase *P < 0.001 vs placebo. Results of three combined, double-blind, pivotal studies of 4325 men with BPH. Roehrborn CG et al. Urology. 2002;60:434–441; Data on file, GlaxoSmithKline.

AVODART® (dutasteride) Reduced the Risk of BPH-Related Surgery by 48% At 2 Years 5 Placebo 4.1% 4 48% risk reduction 3 Patients (%) AVODART 2.2%* 2 1 BPH-related surgery is considered another significant, negative outcome of LUTS and BPH, both from the patient and health economic perspectives.1 Among men aged 60 years or older with an enlarged prostate, the 20-year probability of surgery is 39%.2 In 2-year, placebo-controlled studies, the percentage of patients undergoing BPH-related surgery was 4.1% in the placebo group and 2.2% in the AVODART group. The cumulative number of events in the AVODART group was 47 compared with 89 in the placebo group. AVODART reduced the risk of undergoing BPH-related surgery by 48% compared with placebo over the 2-year, double-blind phase.1 BPH-related surgery occurred in a small percentage of men over the entire 4-year study period (including the open-label phase). Out to 4 years, the incidence of BPH-related surgery was maintained at rates consistent with those during the double-blind phase. During the 2-year, open-label phase only a small percentage of subjects (0.6%, both treatment groups) underwent BPH-related surgery.3 References 1. Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60:434441. 2. Arrighi HM, Metter EJ, Guess HA, Fozzard JL. Natural history of benign prostatic hyperplasia and risk of prostatectomy. The Baltimore Longitudinal Study of Aging. Urology. 1991;38:48. 3. Data on file, GlaxoSmithKline. 6 12 18 24 Month Out to 4 years, the incidence of BPH-related surgery was maintained at rates consistent with those during the double-blind phase *P < 0.001 vs placebo. Results of three combined, double-blind, pivotal studies of 4325 men with BPH. Roehrborn CG et al. Urology. 2002;60:434–441; Data on file, GlaxoSmithKline.

Questions? Feel free to call me at (614) 222-3369 Or email at gthomd@yahoo.com