1. Firstline Hormone Therapy for Prostate Cancer Alan Horwich Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, UK

3. Locally advanced disease-neoadjuvant/adjuvant

4. Locally advanced disease-sole treatment

5. Firstline for metastases

6. 2,3,4-line for metastases CRPC concept= failure of firstline hormone therapy

8. LHRH antagonists……….egDegarelix

9. Antiandrogens……………egCasodex, Flutamide, MDV 3100

10. Steroids…………………..egpredisone, dexamethasone

11. Oestrogens………………egStilboestrol

13. Androgen Suppression in Prostate Cancer

14. Diabetes and cardiovascular disease during androgen deprivation for prostate cancerKeating JNCI 2010VA Study

15. Efsathiou JCO 2009 2792-99 No. = 945 FU 8.1 yrs CVD = 117 At 9 yrs CVD 8% vs 11% With LOWER risk in LHRHagroup

16. Osteoporosis and duration of LHRHa therapy Stage I-II Ca Prostate with PSA control Morote Eur Urol 2003 44 661 Prostatectomy controls (57) Men treated with LHRHa (53) Loss of bone mineral density particularly in first 6–12m (Daniell 2000, Mittan 2002) Osteoporotic fracture rate increased. 4% 5yr, 20% 10yr (Oefelein 2001)

17. What should we advise patients on androgen deprivation therapy? Address risk factors Diabetes , Cholesterol, Hypertension Aspirin Exercise In the adjuvant setting duration of hormone therapy should be tailored to need

19. Combined androgen blockade?

20. Intermittent or continuous

21. Adjuvant bisphosphonate?

23. Samson et al 2002 “Modest benefit at 5 years probable outweighed by increased side-effects”

24. Phase 3 RCT IAS vs Continuous AD –PSA progression after local Rx; NCIC PR07 Klotz abs 2011

25. MRC Trial PR05 AD vs AD +Clodronate in Metastatic Prostate Cancer Dearnaley D P et al. JNCI J Natl Cancer Inst 2003;95:1300-1311 overall survival time from randomization symptomatic bone progression-free survival time Also STAMPEDE trial recruiting—looking at AD withzoledronate, celecoxib, docetaxel and will have an abiraterone arm

26. What is the evidence that adding hormone therapy to radiotherapy improves outcome? For how long should hormone therapy be continued? Hormone deprivation or anti-androgen? Should we add RT in patients on long term hormone therapy?

27. Roach JCO 2008 26 585-591 N = 456 1987-91 T2 (bulky) -T4 N+/- MAB 4m pre and with RT vs RT alone

28. Disease specific mortality Roach JCO 2008 26 585-591 Overall survival 10yr OS 43% vs 34% p=0.12 10yr DSM 23% vs 36% p=0.01 Fatal cardiac events Distant metastases 10 yr Dist Met 35% vs 47% p=0.006 10 yr Cardiac deaths 14% vs 10%

29. Long term androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial Bolla Lancet 2002 360 103

31. All trials show improvement in cause related and overall survival

32. RTOG 85-31 shows overall survival advantage for Gleason 8-10 only and Swedish trial for node positiveBolla Lancet 2002 360 103; Pilepich IJROBP 2005 61 1285; Granfors J Urol 2006 176 544

33. Hormones + RT versus RT alone Short course hormones markedly improve local control and disease free survival For short course hormones most trials have not shown an improvement in overall survival Long term hormones have markedly improved survival in patients with locally advanced high risk cancers. Conclusions

34. What is the evidence that adding hormone therapy to radiotherapy improves outcome? For how long should hormone therapy be continued? Hormone deprivation or anti-androgen? Should we add RT in patients on long term hormone therapy?

35. RTOG 92-02:Radiotherapy and duration of androgen suppression (4 vs 28 months)No. 1554 Follow up 56m . 3% OS benefit only in Gl 8-10 Horwitz E M et al. JCO 2008;26:2497-2504 ©2008 by American Society of Clinical Oncology

36. 6months vs 3yrs concomitant and adjuvant hormonal treatment for locally advanced Ca Prostate EORTC 22961 Bolla et al 2009 N=970 Overall survival STAD 81% vs LTAD 84.8% P Ca deaths STAD n=46 vs LTAD 28 CVD deaths STAD n= 31 vs LTAD 25 Overall STAD Overall LTAD P Ca STAD P Ca LTAD

37. Hormone duration? Long term hormone therapy compared to short term improves progression free survival Improved overall survival probably just in high risk patients As yet unclear that intermediate risk patients gain from more than 3-6 months Conclusions

38. What is the evidence that adding hormone therapy to radiotherapy improves outcome? For how long should hormone therapy be continued? Hormone deprivation or anti-androgen? Should we add RT in patients on long term hormone therapy?

39. Bicalutamide 150mg plus standard care vs standard care alone for early prostate cancer.McleodBJU Int 2006 9 247 Dearnaley ECCO September 07

40. What is the evidence that adding hormone therapy to radiotherapy improves outcome? For how long should hormone therapy be continued? Hormone deprivation or anti-androgen? Should we add RT in patients on long term hormone therapy?

41. NCRI PR3 / MRC PR07 TrialP.Warde ASCO 2010 Randomisation: Hormone Treatment alone vs HT and RT to prostate +/- pelvis No.1205 Deaths 310 CaP deaths 140 7yr OS 66% vs 74% HR 0.77 p=0.03 NNT 12.5 7 yr CSS 79% vs 90 % HR 0.57 p=0.001 NNT 9 Same result as Widmark et al 2009

42. CONCLUSIONS: Combined Modality Treatment Neo/Adjuvant hormonal therapy should be used in all men with high risk or locally advanced prostate cancer treated with external beam radiotherapy Short course (3-6m) NAD improves local control in intermediate/high risk localised and advanced localised prostate cancer Long course androgen suppression reduces development of metastases and improves survival for men with advanced localisedand high grade prostate cancer Optimal duration of ‘long term’ hormone therapy is at least 2 years for Gl ≥8 cancer, but may be shorter for more favourable disease Comparisons of LHRHa with monotherapybicalutamide are needed Men with locally advanced disease and good health should have RT as well as hormone therapy