1. Initial Androgen Treatment for Progressive, Metastatic or Recurrent Prostate Cancer Andrew Loblaw BSc, MD, MSc, FRCPC, CIP Department of Radiation Oncology Sunnybrook Health Sciences Centre January 28, 2011

2. Objectives 1.To review the standard initial hormonal interventions for prostate cancer 2.To discuss the evidence behind the use of AA monotherapy 3.To review the published literature on the benefit of combined androgen blockade 4.To review emerging evidence on the benefit of bicalutamide CAB for prostate cancer 5.To review the evidence behind the timing of ADT 6.To review the pros/cons of intermittent androgen blockade

3. Standard ADT

4. Standard ADT* Seidenfeld J Ann Int Med 2002; 132(7):566-77 (aberelix) * * * *

5. Combined Androgen Blockade

6. PCTCG Indiv Pt Data Meta-Analysis 8275 men, 27 trials 88% D2 Overall Death Rate 70.4 vs 72.4% ARR 2% NSAA Death Rate 72.4 vs 75.3% ARR 2.9% (p<0.005) PCTCG. Lancet 2000;355:1491-8

7. Schmitt et al Meta-Analysis 20 RCTs, 6320 men with prostate cancer Efficacy 2 y OS: OR 1.16 (95% CI 1.00 – 1.33) 5 y OS: OR 1.29 (95% CI 1.11 – 1.50) Toxicity diarrhea (10% v 2%) gastrointestinal pain (7% v 2%) non-specific ophthalmologic events (29% v 5%) Schmitt et al Urology 57:727-32, 2001

9. Anti-androgen Use Today Steroidal Antiandrogens Ketoconazole Cyproterone acetate Non-steroidal Antiandrogens Flutamide Nilutamide Bicalutamide

10. CCO MAB Guideline

12. Side Effects

13. Patient Decision Making n = 10 men with prostate cancer on RT “ What potential survival advantage (at 5 years) would you expect to justify these additional side effects and the inconvenience of taking a daily pill” 1 (10%) < 1 % survival benefit at 5 y 5 (50%) 1-5% survival benefit at 5 y 3 (30%)5-10% survival benefit at 5 y 1 (10%)10-15% survival benefit at 5 y

14. New Data Klotz et al. Combined data from PCTCG and Schellhammer’s RCT of bicalutamide + LHRH vs flutamide + LHRH –Same methods used to get FDA approval of capecitabine in colon CA RHR = HR (PCTCG) * HR (Schell) = HR(flut vs castration) * HR (bical vs flut) = HR (bical vs castration) =.80 (95% CI 0.66 - 0.98) Klotz L, Schellhammer P. Clin Prostate Cancer. 2005 Mar;3(4):215-9.

15. Docetaxel for HR Prostate Cancer Tannock NEJM 2004Petrylak NEJM 2004 HR 0.76 HR 0.80 16.5 mo 18.9 mo

16. Relative Benefit vs Accepted Treatments Potential benefit of bicalutamide CAB Pound Series 5 year median survival from diagnosis of metastatic disease Bicalutamide CAB would increase median OS 1.25y over castrate therapies alone (with HR 0.80) Potential Costs CAB pack $(3900) per 6 months Docetaxel $20 000 per 6 months

17. ASCO 2006 Update An interim analysis of an RCT 2 and a study that combined data from an individual patient data metaanalysis and a randomized active control study, 3 were published since the last guideline. Overall survival is greater with the addition of an NSAA to medical or surgical castration, but increased adverse effects may occur as a result. Loblaw DA et al., JCO April 2007

18. Akaza update Double-blind RCT, N=205, 40% D2 CAB vs LHRHa (or CAB at progression) Median F/U 5.2y HR 0.78 (0.60 – 0.99) p=0.0498 or 0.042 5y OS 75 vs 63% CSS HR 0.79 (.55 – 1.11) Akaza H et al Cancer 115: 3437-45; 2009

19. Summary CAB Several meta-analyses have shown small to moderate improvements in overall survival with CAB Two recent clinical practice guidelines recognize these improvements but are concerned about additive toxicity All studies in MA used older AA which are rarely used today Bicalutamide CAB has very tolerable side effects and has a large OS benefit

20. Clinical Practice “I think there is a compelling survival advantage with bicalutamide CAB and I will speak to my patients about that option” or “I am not convinced that there is a compelling survival advantage with bicalutamide CAB and a clinical trial should be designed to address the issue”

21. Timing of ADT i) Watchful Waiting Patients

22. 1960-1975, n=954 locally advanced or metastatic disease Randomized to one of four arms: placebo, orch+placebo, DES (5mg), or orch+DES Patients with metastatic disease in the placebo arm were allowed active treatment upon progression Jordan WP. South Med J 1977;70(12):1411-1413 VACURG I Study 12 year survivalPOrch+PDESOrch+DES Cause specific (%) Overall (%) 65 10 70 12 77 13 76 13

23. T3/4 or M1 Prostate Cancer RANDOMIZERANDOMIZE n=934 MRC Prostate Cancer Working Party Investigators Group Br J Urol 1997;79:235-246 Immediate ADT Deferred ADT (at symptom onset) n=469 n=465 Distant Progression Overall survival Cause specific survival Pain-free survival TURP Ureteric obstruction Metastatic complication Outcomes MRC Study Schema

24. Minimum follow-up of 2.7 years 38 47 26 7 42 58 59 86 45 12 37 46 Deferred (%) 2p Immediate (%) <0.001 <0.025 0.02 0.001 n =934, T3/4 or M1 Distant progression Painful metastases TURP Urinary obstruction 5 yr OS 5 yr CSS MRC Study Outcomes MRC Prostate Cancer Working Party Investigators Group Br J Urol 1997;79:235-246

25. Minimum follow-up of 9.5 years 7 42 58 12 37 46 Deferred (%) 2p Immediate (%) 0.09 0.25 0.26 n =934, T3/4 or M1 Overall survival Extraskeletal metastases Urinary obstruction MRC Study Outcomes Kirk, 2004

26. No standardized follow-up schedule - 29 patients (6.2%) randomized to deferred arm died of prostate cancer before receiving treatment Minority of patients had PSA measured on follow-up Generalizability? - Results from locally advanced or M1 tumors may not reflect biology of biochemical failures post-RT MRC Criticisms

27. Localized Prostate Cancer Too unwell for radical therapy RANDOMIZERANDOMIZE Immediate Orchiectomy Deferred Orchiectomy (at symptom onset) n=197 Studer et al. J Clin Oncol 2004;22:4109-4118 n=96 n=92 SAKK 08/88 Study Schema Cause specific survival Overall survival First pain Symptom-free survival Ureteric obstruction New metastases Outcomes

28. Overall Survival Cause Specific Survival Time to Hormone Resistant Disease SAKK 08/88 Results

29. T0-4 N0-2 M0 Prostate Cancer n=985 Studer UE et al. J Clin Oncol 2006;24:1868-76 n=493 n=492 Too unwell for radical therapy Excluded Age > 80 yr Other CA (non-BCC) Symptomatic Pr CA “juxtaregional LN” Immediate ADT Deferred ADT (at symptom onset) RANDOMIZERANDOMIZE EORTC 30891 Study Schema Overall survival Cause specific survival Non-PC survival Symptom-free survival Time to Dist Mets Symptomatic AIPC Castrate Metastases TURP Outcomes

30. Overall Hazard Ratio 1.25 (1.05-1.48) Non-inferiority p = 0.47 36% 25% 68% 61% SURVIVAL p = 0.44p = 0.062 9 25 13 26 Deferred (%) Immediate (%) 5 yr 10 yr Cause specific Mortality 23 39 26 46 Deferred (%) Immediate (%) 5 yr 10 yr All cause Mortality

31. Cause-Specific Mortality Studer UE et al. Eur Urol 2008;53:914-9 Immediate Arm Deferred Arm By PSAdt in deferred arm

32. Timing of ADT iii) N+ Post-Radical Prostatectomy Patients

33. ECOG 3886 N+ post rP Messing E et al. N Engl J Med 1999;341:1781-8

34. EORTC 30846 N+, no rP OS HR 1.23 [0.88-1.71] medOS 7.8 vs 6.2 y CSS no difference Difference w/ ECOG 3886 More T3 (66%) No local treatment

35. Timing of ADT iii) Recurrent Cancer Post-RT

36. Sathya JCO 2005 Peeters JCO 2006 n=305 Dose Escalated Radiation Therapy Pollack IJROBP 2002 Zeitman JAMA 2005

37. Skarsgard D, Tonita J. Ca Cause Control 2000; Cdn Cancer Stats 2006 Burden of Problem Extent of diseaseIncidence Localized17,225(85%) Metastatic3,151(15%)

38. Skarsgard D, Tonita J. Ca Cause Control 2000; Cdn Cancer Stats 2006 970 1941 1745 485 970 873 5 yr Biochemical Failure Localized disease At risk (n) Post-RT (n) Burden of Problem Low risk Intermediate High risk Incidence 5391 4852 6982 (31%) (28%) (41%) 30% overall (2570 post-RT)

39. Post-Radiotherapy Failure Local therapies –Radical prostatectomy –Cryotherapy –HiFU –Seed brachytherapy* ANDROGEN DEPRIVATION THERAPY –ASCO Androgen Sensitive Guideline 2006 Update available Jan 29 th, 2007

40. TROG Timing of Androgen Deprivation (TOAD) ongoing RCTs Timing of ADT Post Radical RT

41. Skarsgard D, Tonita J. Ca Cause Control 2000; Cdn Cancer Stats 2006 <10 10-20 20-50 >50 20 18 32 24 28 50 20 2 2000 USA 53 36 11 0 1994 Canada 2004 Canada Trigger PSA (ng/mL) for starting ADT Patterns of Care Survey Oncologists Survey (%)

42. Hormone-Sensitive Prostate Cancer (2004) Timing of ADT Systematic review of literature –1 meta-analysis –1 Markov model Loblaw DA et al. J Clin Oncol 2004;14:2927-41 ASCO Guidelines

43. “...antiandrogen in addition to castrate therapy. Until data from studies using modern medical diagnostic/biochemical tests and standardized follow-up schedules become available, no specific recommendations can be issued regarding the question of early versus deferred ADT. A discussion about the pros and cons of early versus deferred ADT should occur.” Loblaw DA et al J Clin Oncol 2004;14:2927- 41 ASCO Guidelines

44. Meta-Analysis of Literature Inclusion criteria – RCTs on patients with metastatic or untreated localized prostate cancer – ADT Intervention Literature search – Medline 1966 – Mar 2006 – Cochrane Database of Systemic Reviews Exclusion Criteria – Patients previously treated with ADT – Patients undergoing primary RT with ADT

45. Meta-Analysis of Literature Methods of analysis – Outcomes: all cause death, prostate cancer mortality – RevMan 4.2.8 – Visual and statistical evaluation of heterogeneity – Combined Relative Ratio, 95% confidence intervals – Sensitivity analyses performed for methodological weakness, heterogeneity

46. Prostate Cancer Mortality

47. Overall Mortality

48. “Until data from studies using modern medical diagnostic/ biochemical tests and standardized follow-up schedules become available, no specific recommendations can be issued regarding the question of early versus deferred ADT. A discussion about the pros and cons of early versus deferred ADT should occur.” Loblaw DA et al J Clin Oncol 2004;14:2927- 41 ASCO Guidelines Loblaw DA et al J Clin Oncol April 2006 “In metastatic or progressive PCa, immediate versus symptom- onset institution of ADT results in a moderate decrease (17%) in relative risk (RR) for PCa-specific mortality, a moderate increase (15%) in RR for non–PCa-specific mortality, and no overall survival advantage. Therefore, the Panel cannot make a strong recommendation for early ADT initiation.… For patients electing to wait until symptoms for ADT, regular monitoring visits are indicated.”

49. 1.What are the benefits of immediate ADT following radiation therapy Unanswered Questions −Can we extrapolate from Watchful Waiting / Metastatic patient data? 2. What is the magnitude of detriment on QOL?

50. Vasomotor symptoms Decreased libido  erectile dysfunction Decreased muscle mass Decreased energy Metabolic syndrome Osteopenic effects ADT Side Effects

51. 50,613 men with Prostate Cancer in SEER database 1992-1997 19% vs 12% had (any) fracture (living >5 yr) ─ bone metastases not excluded

52. 73,197 men > 66 yr in SEER, Medicare 1/3 had LHRH agonist Excluded prevalent M1, DM, CAD In 10 years9% 11% 3%4%

53. Prognostic Factors Overall Mortality Distant Metastases Predictors Cause specific Mortality D’Amico 2006 PSAdt (< 6months) Gleason Score (8-10) PSA response to ADT Age < 75yr Kim-Sing 2004 Pound 1999 Pound 1999 D’Amico 2006 D’Amico 2006 3. Does the effect of timing of ADT differ by PSAdt, Gleason?

54. Timing of ADT for Recurrent Prostate Cancer

55. 96 Canadian Specialists –42 GU Radiation Oncologists –50 Urologists –4 Medical Oncologists ELAAT Survey Current Practice –Trigger: PSAdt (28%), PSA (3%), both (69%) –Start treatment if PSAdt < 12months (95%) –Start treatment if PSA (ng/mL) <10 (53%), 10-20 (36%) –Orchiectomy (0%)

56. Trial comfort zones to start ADT –Lowest PSA to start ADT: 4 ng/mL (58%) 5 ng/mL (86%) –Highest PSA to withhold ADT: 25 ng/mL (61%) –PSAdt trigger: < 12 months (71%) ELAAT Survey Need for Trial –Moderate to very important (86%) –Very important (51%) –Number of patients per year: 1500+

57. Andrew Loblaw, Sergio Faria, Himu Lukka, Tom Pickles, Patrick Cheung, Lawrence Klotz, Kathy Pritchard, Martin Gleave, Tulay Koru-Singul, Mark Levine A Randomized Comparison of Immediate versus Deferred Androgen Deprivation Therapy using Goserelin for Recurrent Prostate Cancer after Radical Radiotherapy ELAAT STUDY

58. Localized Prostate Cancer Asymptomatic biochemical failure post RT RANDOMIZERANDOMIZE Immediate LHRH Deferred LHRH (at symptom onset) (or PSA>25ng/mL) Time to Androgen Independent Disease Cause specific survival Overall survival Quality of Life Complications of Advanced Malignancy Bone Fractures Outcomes ELAAT Study Schema

59. ELAAT Enrolment PSAdt Gleason Score Immediate LHRH Deferred LHRH Randomization n= 1100 Clinical Trial Centre ≤12months>12months 2-78-102-78-10 Centre

60. 1.Adults (> 18 years old) with histopathologically confirmed adenocarcinoma of the prostate 2.Patients who have failed biochemically after radical radiation therapy (total prostate dose ≥52 Gy) 3.PSA <6 ng/mL within 30 days of randomization ELAAT Inclusion Criteria

61. 1.Patients who have had a primary or salvage radical prostatectomy, salvage cryotherapy, thermal ablation, photodynamic therapy or high intensity focus ultrasound 2.Patients who are within 4 years of their brachytherapy implantation date 3.Patients with medical conditions in which goserelin or bicalutamide is contraindicated in the opinion of the supervising oncologist or urologist 4.Patients with another active malignancy or malignancy treatment within 5 years (except for basal or squamous cell skin cancers) 5.Patients who are geographically inaccessible for follow-up 6.Patients who fail to provide written informed consent ELAAT Exclusion Criteria

62. 1.Bicalutamide 50 mg po OD days 1-30 (may be given continuously at the discretion of supervising oncologist) 2.Goserelin 10.8 mg SC day 10-17 + q3months until patient discontinuation ELAAT Treatment

63. ELAAT Outcomes Time to androgen independent disease (AID) Cause specific survival Overall survival Quality of Life Complications of advanced malignancy (CAM) Bone Fractures

64. ELAAT Follow-Up Physical exam + digital rectal examination CBC, Testosterone, PSA ( within 30days of randomization) Quality of Life Goserelin compliance √√√√√√ During the last 6 months: Fractures Need for palliative radiotherapy, palliative surgery, TURP, spinal cord compression or ureteric obstruction Chemotherapy, antiandrogens, bisphosphonates, calcium, vitamin D or erythropoietin Dual x-ray absorption (DEXA) scan√* Baselineq 6months √√√√√√√√ √√√√√√ √** * within 1 month of 1 st injection, ** every 2 years after 1 st injection of goserelin

65. ELAAT Statistical Considerations Sample size determination – A non-inferiority time to event analysis based on two exponential survival curves Assumptions on sample size calculation – Androgen independent disease at 10 years = 30% for immediate LHRH group – True difference 7.5% (i.e. Hazard Ratio = 1.318) – (Deferred LHRH - Immediate LHRH) < 7.5% – Alpha 2.5% – Power 80% Total 1064 patients (n=532/per arm) – Total recruitment will be 1100 patients (n=550/per arm) to account for 3.2% lost to follow-up

66. Canadian survey: 1500 eligible patients per year Accrual estimate:225 patients for 1 st year 450 patients for subsequent years Complete accrual:3-4 years First analysis:at 7 years median follow-up ELAAT Study Timelines Contract SignedJun 2006 Health Canada CTA NOL Aug 2006 Ontario Cancer REB ApprovalNov 2006 Study ActivationAug 2007

67. Clinical Practice “After RT failure, I don’t think there is a compelling survival advantage with early ADT and I recommend not starting ADT until symptoms arise” or “I don’t know when ADT should be started after RT failure and I would support a clinical trial designed to address the issue”

68. Summary Recurrent prostate cancer after radical treatment a common problem Well characterized toxicity profile but… –Conflicting evidence for WW and CSS benefit –No evidence for N0 post rP or RT –Benefit in OS, CSS for N+ after rP? Further study in development

69. Intermittent Androgen Blockade N = 766 (626 enrolled), locally advanced / M1 3 mo IAB (CPA + LH) vs CAB Trigger: PSA < 4 ng/ml (or 80% reduction) mFU 51 mo Progression: HR 0.81 (0.63 – 1.05, p=0.11) OS: 0.99 (0.80 – 1.23) Improved QOL 52 wk median off-treatment IAB Calais da Silva FEC Eur Urol 55:1269-77;2009

71. IAB Cont’d NCIC PR7 press release May 2010 – failed to reach primary endpoint IAB practiced commonly ? Sufficient evidence to change guidelines