Prostate Cancer: Current Challenges and Advances in Treatment

1. Prostate Cancer An Update Mohamed Abdulla (M.D.) Prof. of Clinical Oncology Kasr El-Aini School of Medicine Cairo University Khartoum, 05/12/2009

2. Challenging Issues: Increased Incidence; AGING. Better Understanding of Molecular Events. Higher Prevalence of Early Localized Disease; (Screening & Early Detection). Watchful Strategies. Androgen Deprivation Strategies. Evolution of High Precision Radiation Therapy Treatment. Improvements of Surgical Skills & Technology.

3. Molecular Events No Major Predisposition Genes. A wide Number of Susceptibility Loci are Identified Heterogeneity of Disease Behavior & Resistance to Treatment. Dominant Inherited Susceptibility Genes (30-40% of Early Onset Disease).

4. Molecular Events Normal Prostate Gland Intraepithelial Neoplasia Prostate Cancer Advanced Stage Metastatic Disease Androgen Resistant Disease Hereditary Factors Hormonal Factors Receptor Polymorphism 1 2 Early Oncogene Activation Loss of Tumor Suppressor Gene 3 Late Oncogene Activation Loss of Tumor Suppressor Gene 4 Stromal Factors 5 Androgen Receptor Mutation ++ Growth Factors & Receptors Rb Gene P53 & ras E-Cadherin

5. Androgen Synthesis & Receptor: Hypothalamus Pituitary Testis Adrenals Testosterone LHRH LH ACTH Hormonal Deprivation Therapy

6. Androgen Synthesis & Receptor: Testosterone 5Reductase DHT DHT AR HSP AR DNA Specific Sequence PSA IGF-1 VEGF Differentiation Metastases Angiogenesis

7. Proposed Risk Factors: Possible: 1. Age. 2. Race. 3. Premalignant PIN. 4. Affected Relatives. 5. Carnivorous Diet. 6. Dietary Fat. 7. Vitamin D. 8. Sexual Habits. Controversial: 1. BPH. 2. Sexually Transmitted Diseases. 3. Cigarette. 4. Alcohol Intake. 5. Cadmium Exposure. Morton RA Jr. Racial differences in adenocarcinoma of the prostate in North American men. Urology 1994;44(5):637645.

8. Therapeutic Opportunities Through Prostate Cancer Progression: Time Tumor Burden Expectant Treatment Biochemical Progression Androgen Depletion Hormone Refractory Stage D3

9. Chemopreventive Studies: Testosterone 5Reductase DHT AR HSP AR DNA Specific Sequence PSA IGF-1 VEGF DHT Dutasteride (Avodart Caps 0.5 mg)

10. Chemopreventive Studies: Mostaghel E, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 1. Men with clinically localized PCa aged 45-80 yrs; Gleason sum 7.0; PSA 2.5-10.0 ng/dL (N = 75) Dutasteride 7.0 mg loading dose, 0.5 mg daily (n = 26) No therapy (n = 25) Dutasteride 3.5 mg daily (n = 24)

11. of Intra-prostatic DHT. Tissue Testosterone. 32 Genes; (ILGF). 98 Genes; ( Trefoil factor 3 protein). Overall incidence of Prostate Cancer. Higher Incidence of High Grade Lesions. Better of DHT (98.8%) at 3.5 mg/day. Chemopreventive Studies: Mostaghel E, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 1.

12. Insignificant Prostate Cancer: Active Treatment Can Be Deferred = Active Surveillance Serum PSA. Prostate Volume. Clinical Stage. Gleason Grade. Systematic Biopsy Results. Kattan et al. J Urol. 2003;170:17921797.

13. Insignificant Prostate Cancer: Active Treatment Can Be Deferred = Active Surveillance DRE PSA Stage Gleason Grade Extremes of Biological Behavior & Natural History

14. The Concept of PSA Velocity: Ref. Indication Age PSA Level Velocity Threshold 1 Biopsy -- > 4 ng/ml 0.75 ng/ml/Year 1 Biopsy -- < 4 ng/ml 0.3-0.5 ng/ml/Year 2 Biopsy < 60 -- 0.2-0.4 ng/ml/Year PSA Velocity > 2.0 ng/ml/Year Shorter Time to Biochemical Recurrence & Disease Specific Mortality No A.S. 1. Loeb S, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 2. 2. Connolly DJ, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 6.

15. The Concept of PSA Velocity: 1. Loeb S, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 2. 2. Connolly DJ, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 6.

16. The Concept of PSA Velocity:

17. Active Surveillance Program: DRE. Free & Total PSA. Endo-rectal MRI with Spectroscopy (TRUS). TRUS Systematic Needle Biopsies. 6 Months 12-18 Months 2 3 Years

18. Patel MI, DeConcini DT, Lopez-Corona E, Ohori M, Wheeler T, Scardino PT. An analysis of men with clinically localized prostate cancer who deferred definitive therapy. J Urol. 2004;171:1520-1524. Importance of Strict Protocol:

19. Controversy & Debate: Potential Hazards Of Deferring Treatment Less Hormone Sensitive on Progression Local Progression Needs Intervention Reduce Survival Catastrophic Events Masking of Symptoms Chronic Toxicity of Prolonged Androgen Deprivation

20. Localized Disease: Risk of Recurrence Low T1-2a. Gleason Score 2-6 PSA < 10 ng/ml Intermediate T2b-c. Gleason Score 7 PSA 10-20 ng/ml High T3a Gleason Score 8-10 PSA > 20 ng/ml Very High T3b-T4

21. Localized Disease Medical Imaging Androgen Deprivation Therapy Therapy Surgery Radiation Therapy Ablative Therapies

22. Imaging Modalities: Limitations & New Arrivals: L.Ns. Size Does not Correlate with The Presence of Prostate Cancer Metastases (CT & MRI). (1) FDG-PET Scan is not Ideal in Staging of Prostate Ca 1. Relatively Slow Growth Of Prostate Cancer Cells. (2) 2. Excretion of FDG into Adjacent Bladder. ( 3) 3. Equal Sensitivity with Bone Scan. ( 4) 1. Tiguert R, Gheiler EL, Tefilli MV, et al. Lymph node size does not correlate with the presence of prostate cancer metastasis. Urology. 1999;53:367-371. 2. Price DT, Coleman RE, Liao RP, Robertson CN, Polascik TJ, DeGrado TR. Comparison of [18 F]fluorocholine and [18 F]fluorodeoxyglucose for positron emission tomography of androgen dependent and androgen independent prostate cancer. J Urol. 2002;168:273-280. 3. Kwee SA, Coel MN, Lim J, Ko JP. Prostate cancer localization with 18fluorine fluorocholine positron emission tomography. J Urol. 2005;173:252-255. 4. Langsteger W, Heinisch M, Fogelman I. The role of fluorodeoxyglucose, 18F-dihydroxyphenylalanine, 18F-choline, and 18F-fluoride in bone imaging with emphasis on prostate and breast. Semin Nucl Med. 2006;36:73-92.

23. Choline is a More Suitable Metabolic Marker Than FDG. (1,2) C-Choline-PET/CT (3) 1. 83% Sensitivity in Localizing Nodules < 5 mm. 2. Equal Sensitivity to TRUS/Biopsy but < Specific (84 vs 97%). 3. Lower Sensitivity than MRI (22 vs 63%). The Use of Mega-Voltage Cone beam CT. Endo-rectal MRI & Spectroscopy. Imaging Modalities: Limitations & New Arrivals: 1.Price DT, Coleman RE, Liao RP, Robertson CN, Polascik TJ, DeGrado TR. Comparison of [18 F]fluorocholine and [18 F]fluorodeoxyglucose for positron emission tomography of androgen dependent and androgen independent prostate cancer. J Urol. 2002;168:273-280. 2. Kwee SA, Coel MN, Lim J, Ko JP. Prostate cancer localization with 18fluorine fluorocholine positron emission tomography. J Urol. 2005;173:252- 255. 3. Martorana G, Schiavina R, Corti B, et al. 11C-choline positron emission tomography/computerized tomography for tumor localization of primary prostate cancer in comparison with 12-core biopsy. J Urol. 2006;176:954-960.

24. Localized Disease: The Ideal Trifecta: Cancer Free (No Pathology, No detectable PSA). Continence Free. Erectile Dysfunction Free. Kupelian PA, Katcher J, Levin HS, Klein EA. Stage T1-2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys. 1997;37:1043-1052.

25. Localized Prostate Cancer: Radical Prostatectomy vs Watchful Waiting: OAS Benefit 5% 10 Years. PSA Detected Disease Screen-Detected Disease Patients < 65 Years of Age

26. Localized Disease: Advances in Radiation Treatment Delivery: Conformal, IMRT, Proton Beam Rth: Pollack et al (1) : Higher Local Failures with < 70 Gy. Zeitman et al (2) : Higher DFS with 79 Gy vs. 70 Gy. Dutch Trial (3) : Higher Benefit with 78 Gy vs. 68 Gy. IMRT is now the Standard of Care Than Conformal & Non Conformal Methods of Treatment Delivery. IGRT: is the most significant achievement in High Precision Treatment Delivery Tracking The Daily Motions of Prostate Through Treatment Plans. Major Concern About 2 nd Malignancy Particularly Rectal Cancer in Patients Living > 10 Years. Proton Beam IMRT ??? (1) Pollack A, Zagars GK, Smith LG, et al. Preliminary results of a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer. J Clin Oncol. 2000;18:3904-3911. (2) Zietman A, DeSilvio M, Slater J, et al. A randomized trial comparing conventional dose (70.2GyE) and high- dose (79.2GyE) conformal radiation in early stage adenocarcinoma of the prostate: results of an interim analysis of PROG 9509. Int J Radiat Oncol Biol Phys. 2004;60:S131-S132. Copyright 2007 Clinical Care Options, LLC. All rights reserved. 22 (3) Peeters ST, Heemsbergen WD, Koper PC, et al. Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol. 2006;24:1990-1996.

27. Localized Disease: Focal Therapy: Treatment of only Diseased Portion. Limitations: 1. Underestimation of the volume of cancer. 2. The disease is multi-focal. 3. The largest identified neoplastic lesion may not be the most biologically significant. Questions to be Answered: 1. Ideal Imaging Modality. 2. Patient Selection. 3. The Ideal Method of Application. Barqawi A, Crawford ED. Focal therapy in prostate cancer: future trends. BJU Int 2005;95:273-274.

28. Localized Disease: Androgen Deprivation Therapy (ADT):

29. Localized Disease: Androgen Deprivation Therapy (ADT):

31. Neoadjuvant Androgen Depravation + Radiation Therapy: RT01: phase III study of 2 doses of conformal RT + neoadjuvant androgen deprivation (NAAD) in localized PCa Dearnaley DP, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 295. Localized prostate cancer (N = 843) Escalated-dose conformal RT 74 Gy/32f + NAAD 3-6 months* before, during RT (n = 422) Standard-dose conformal RT 74 Gy/37f + NAAD 3-6 months* before, during RT (n = 421)

32. 5-year biochemical progression-free survival (PFS) significantly longer with high-dose vs standard-dose RT 72% vs 60% (HR: 0.66; 95% CI: 0.52-0.84; P < .001) 5-year PFS significantly longer with high-dose vs standard-dose RT 92% vs 86% (HR: 0.57; 95% CI: 0.38-0.87; P = .010) Increased incidence of long-term adverse events with high-dose RT Significantly more late bowel, bladder toxicity Neoadjuvant Androgen Depravation + Radiation Therapy: Dearnaley DP, et al. 2007 ASCO Prostate Cancer Symposium. Abstract 295.

33. Neoadjuvant Androgen Depravation + Radiation Therapy: Rth Rth + ADT 6 months Rth + ADT 2.5 Years Rth Rth + ADT 6 months Rth + ADT 2.5 Years Rth Rth + ADT 6 months

34. Neoadjuvant Androgen Depravation + Radiation Therapy:

35. Neoadjuvant Androgen Depravation + Radiation Therapy:

36. Neoadjuvant Androgen Depravation + Radiation Therapy:

37. ADT + Radiation Therapy Summary of RCTs:

38. Androgen Deprivation Therapy + Surgery: Prostate Cancer T2b (282) ADT (3 months) No ADT RP # 5-Year Biochemical Failure +ve S.M. Soloway MS, Pareek K, Sharifi R, et al. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol. 2002;167:112-116. Not The Standard of Care Outside Clinical trials.

39. Androgen Deprivation Therapy + Surgery: Prostate Cancer L.Ns. +ve (98 Patients) ADT Observation RP Updated 10-Year Result 72.4% vs 49% Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared withobservation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999;341:1781-1788.

40. ADT & Chemotherapy: CTh in Metastatic Hormone Refractory Prostate Cancer Survival Benefit (1) . CTh + Rth or Prior to Prostatectomy in Early Disease Starting Progression (2) . 1. Goodin S, Medina P, Capanna T, et al. Effect of docetaxel in patients with hormonedependent prostate-specific antigen progression after local therapy for prostate cancer. J Clin Oncol. 2005;23:3352-3357. 2. Oh WK. High-risk localized prostate cancer: integrating chemotherapy. Oncologist. 2005;10 Suppl 2:18-22.

41. ADT & Chemotherapy:

42. Timing of ADT in Metastatic Disease: 17% Mortality Risk Reduction 15% Non- Prostate Cancer Specific Mortality No Overall Survival Advantage for Early vs Late ADT Symptomatic & Rapidly Progressive Disease Immediate ADT 17% Mortality Risk Reduction Loblaw DA, Virgo KS, Nam R et al. Initial hormonal management of androgen sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2007; 25: 15961605

43. Intermittent ADT: Non Inferiority in Time of Disease Progression & Survival. Better Quality of Life. Lower Treatment Cost.

44. Adding an Anti-Androgen; Bicalutamide. Withdrawal of Anti-Androgen. The Use of Ketoconazole. Treatment with Estrogen. Adding an Alternative Anti-Androgen. Targeting The Androgen Receptors; Abirterone. Strategies to Overcome Initial Hormone Unresponsiveness:

45. Androgen Deprivation Therapy: Co-Morbid Events CVS Therapy Induced Events. Decreased Bone Mineral Density. Decreased Muscular Bulk.

46. Bisphosphonate Indications Focus on PC Indication Prevention of SREs HCM Multiple myeloma Breast cancer Prostate cancer a Other solid tumors Clodronate (oral) Pamidronate (IV) Zoledronic acid (IV) Ibandronate (oral and IV) = European Registration = Worldwide Registration PC, prostate cancer; SREs, skeletal-related events; HCM, hypercalcemia of malignancy; IV, intravenous. a In the United States, prostate cancer must have progressed despite hormone therapy. Prescribing information for pamidronate and zoledronic acid is available at: www.pamidronate.com and www.zometa.com. Further information for clodronate and ibandronate is available at www.bayer.nl/ebbsc/cms/nl/healthcare/bayer_schering_pharma and www.roche.com.

47. Test drug N Results Reference Etidronate 57 Transient pain reduction Smith 1989, J Urol Clodronate 75 Only transient Elomaa 1992, symptomatic benefit Int Urol Nephrol Placebo-Controlled Studies Clodronate 311 No significant benefit Dearnaley 2003, JNCI Pamidronate 378 No significant benefit Small 2003, JCO Clodronate 209 No significant benefit Ernst 2003, JCO Zoledronic acid 643 Significant objective and Saad 2002-4, JNCI durable benefits Bisphosphonates in the Treatment of Bone Metastases From Prostate Cancer

48. Methods of Androgen Deprivation: Castration. GnRH Agonists. Anti-Androgen. Monotherapy Maximum Androgen Blockade MAB

49. Methods of Androgen Deprivation: LHRH LHRH Hypothalamus Pituitary gland LH ACTH Adrenal gland Testis Circulating t estosterone Androgens Other target tissues DHT Casodex (bicalutamide) Prostate cell Androgen receptor -ve feedback control DHT X Zoladex (goserelin)

50. Casodex (bicalutamide) 150 mg monotherapy in M0 disease

51. Overall survival in M0 patients: median 6.3 years follow-up % patients surviving 0 20 40 60 80 100 Time (days) 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 HR 1.05; 95% CI 0.81, 1.31; p=0.70 Iversen et al 2000 Casodex (bicalutamide) 150 mg Castration 2800

52. Pharmacological adverse events in M0 patients Adapted from Iversen et al 2000 Adverse event Hot flushes Gynaecomastia Breast pain Casodex (bicalutamide) 150 mg (n=314) 41 (13.1%) 155 (49.4%) 126 (40.1%) Castration (n=160) 80 (50.0%) 7 (4.4%) 3 (1.9%) Only 4 (1.3%) patients withdrew due to breast pain and/or gynaecomastia

53. Quality of life: M0 patients -2 -1 1 2 3 4 5 0 Physical capacity Emotional wellbeing Sexual interest Vitality Social functioning Pain Activity limitation Bed disability Overall health Favours castration Favours Casodex (bicalutamide) 150 mg Treatment effect and 95% 2-sided CI * ** Iversen et al 2000 *p=0.046; **p=0.029

54. Casodex (bicalutamide) 50 mg in advanced disease

55. Casodex (bicalutamide) 50 mg (Schellhammer): study design Schellhammer et al 1995 Randomised n=813 Casodex (bicalutamide) + Zoladex (goserelin) n=268 Casodex (bicalutamide) + leuprolide n=136 Flutamide + Zoladex (goserelin) n=272 Flutamide + leuprolide n=137 Casodex (bicalutamide) + LHRH agonist n=404 Flutamide + LHRH agonist n=409

56. Sarosdy et al 1998 Casodex (bicalutamide) 50 mg and flutamide in MAB: an exploratory analysis 100 0 365 730 1095 1460 1825 Casodex + Zoladex Casodex + leuprolide Time (days) % patients surviving 80 60 40 20 0 Flutamide + Zoladex Flutamide + leuprolide p=0.26 p=0.008 p=0.99 p=0.047

57. Sarosdy et al 2000 Overall survival for prolonged versus short-term MAB therapy: an exploratory analysis A. All patients (n=810)* B. Patients who lived longer than 2 years (n=544)** *HR 0.28; 95% CI 0.21, 0.36; p=0.0001 **HR 0.42; 95% CI 0.25, 0.70; p=0.0001 0 365 730 1095 1480 1825 2190 > 120 days <120 days % patients surviving Time (days) Time (days) 0 365 730 1095 1480 1825 2190 0 20 40 60 80 100

58. Adverse events Most frequently occurring adverse events regardless of causality Schellhammer et al 1997 Abnormal LFT Dizziness Anaemia Abdominal pain Haematuria Nocturia Diarrhoea Peripheral oedema Infection Asthenia Back pain Pain Hot flushes Casodex (bicalutamide) 50 mg + LHRH agonist Flutamide + LHRH agonist Dyspnoea Nausea Pelvic pain Bone pain Constipation *26% vs 12%, p<0.0001; **12% vs 6%, p=0.007 % patients 0 30 10 20 40 50 LFT, liver function test ** *

59. Casodex (bicalutamide) 150 mg monotherapy in early prostate cancer (EPC)

60. 1:1 randomisation 8113 patients recruited Placebo + standard care (RP, RT, WW) [n=4061] Casodex (bicalutamide) 150 mg/day + standard care (RP, RT, WW) [n=4052] First analysis at 2 years minimum follow-up Median 3 years (minimum 2 years) follow-up Average 2 years duration of therapy EPC programme: design

61. Casodex (bicalutamide) 150 mg reduces the risk of disease progression HR 0.58; 95% CI 0.51, 0.66; p<<0.0001 Casodex (bicalutamide) 150 mg + standard care Placebo + standard care 0 100 200 300 400 500 600 Number of patients n=363/4052 n=559/4061 See et al 2002 Incidence of objective clinical progression

62. Casodex (bicalutamide) 150 mg reduces the risk of disease progression by 42% Time (months) 0 6 12 24 30 36 42 48 54 0.0 0.2 0.4 0.6 0.8 1.0 Casodex (bicalutamide) 150 mg + standard care Placebo + standard care 60 See et al 2002 Proportion without event (progression-free survival) HR 0.58; 95% CI 0.51, 0.66; p<<0.0001

63. Casodex (bicalutamide) 150 mg reduces the incidence of bone metastases by 33% 0 50 100 150 200 250 300 350 Number of patients Placebo + standard care n=321/4061 n=214/4052 See et al 2002 Casodex (bicalutamide) 150 mg + standard care RR 0.67; 95% CI 0.56, 0.79; p<<0.0001

64. Casodex (bicalutamide) 150 mg reduces the risk of PSA progression 200 400 600 800 1000 1200 1400 n=689/4052 n=1340/4061 See et al 2002 Number of patients Casodex (bicalutamide) 150 mg + standard care Placebo + standard care 0 HR 0.41; 95% CI 0.38, 0.45; p<<0.0001

65. EPC programme: tolerability Gynaecomastia alone Breast pain alone Gynaecomastia plus breast pain Hot flushes Impotence Asthenia Diarrhoea Weight gain Loss of libido Abnormal liver function test Casodex (bicalutamide) 150 mg + standard care (n=4022) 13.1 19.7 53.1 9.0 9.0 10.2 6.3 5.7 3.6 3.4 Placebo + standard care (n=4031) 4.8 4.3 2.9 5.2 6.1 7.2 6.4 2.8 1.1 1.9 Patients (%) See et al 2002

66. Withdrawals due to: all adverse events breast pain alone gynaecomastia alone breast pain plus gynaecomastia Progression Death Lost to follow-up/patients choice Investigators decision Withdrawals from therapy Casodex (bicalutamide) 150 mg + standard care (n=4022) 25.8 5.8 3.5 6.4 2.6 2.1 6.2 1.4 38.1 Placebo + standard care (n=4031) 8.1 0.2 0.2 0.1 9.3 1.7 6.5 6.2 31.8 EPC programme: withdrawals See et al 2002 Patients (%)

67. E, no. events EPC Program: overall subgroup analyses 0.125 0.25 0.5 1.0 2.0 4.0 Overall analysis Localised disease Locally advanced disease Pre-therapy PSA >10 ng/mL Gleason score 24 Gleason score 56 Gleason score 710 Pre-therapy PSA < 4 ng/mL Pre-therapy PSA 410 ng/mL N- N+ Nx RP RT WW (n=4454, E=285) (n=1370, E=178) (n=2285, E=458) (n=5429, E=480) (n=2682, E=442) (n=3719, E=592) (n=1792, E=208) (n=3598, E=376) (n=2648, E=327) (n=3157, E=501) (n=4806, E=378) (n=8113, E=922) (n=150, E=43) (n=3230, E=226) (n=918, E= 72) HR plus 95% CI AstraZeneca, data on file

68. Keep in Mind: ADT is being used increasingly in Localized Prostate Cancer in Conjunction with Standard Care Options. The Gold Standard in Advanced and Metastatic Disease. Immediate Use is Superior to Deferred Therapy in Non- Metastatic Disease. Long Term is Superior to Short Term Use. Chemotherapy is Being Integrated in Different Manners (Not State of ART). The Use of Bisphosphonate is Crucial in Preventing Skeletal Related Events & Preservation of BMD. Targeting the AR is The Upcoming Event.

69. Give an Attention to PSA Velocity. Give an Attention to Therapy Related Events especially in The Indolent Course of Disease. Home Message: