1. Treatment strategies for metastatic prostate cancer Oliver Hakenberg Department of Urology, Rostock University

2. prostate cancer is hormone-dependent LHRH = luteinising hormone releasing hormone LH = luteinising hormone ACTH = adrenocorticotropal hormone testosterone pineal gland cortisole adrenal androgens Prostata testes prolactine adrenal glands hypothalamus LH ACTH LHRH estrogens orchidectomy antiandrogens LHRH analogues antiandrogens

3. 0123456789 0 10 20 30 40 50 Pathologic fractures after orchidektomy n=235 Daniell et al, J Urol 1997 orchidectomy no orchidectomy years % cumulative incidence of osteoporotic fractures

4. Immediate androgen ablation permanent –advanced metastatic disease M+ –locally advanced, if androgen ablation is the only treatment option adjuvant/temporary –radical prostatectomy with positive nodes (pN+) –adjuvant with radiotherapy in intermediate and high risk disease

5. Early or delayed androgen ablation? Messing et al, Lancet Oncology 2006 RPE pN+ early vs observation/delayed randomized n= 98 Overall survival Cancer-specific survival

6. androgen ablation ↓ gonadal testosterone 10-30% serum androgens from other sources Adrenal cortex: DHEA + androstendione → transformed to testosterone in periphery (including prostate) progression after xx months → hormone resistant

7. hormone resistance? de novo intratumoral androgen synthesis in progressive CRPC → maintenance of intracellular andogen levels → androgen receptor (AR) stimulation despite low serume testosterone „castration-resistant prostate cancer“ = CRPC Locke et al, Cancer Res 2008

8. 3 new developments autologous vaccine sipuleucel-T (IMPACT) –mCRPC docetaxel-naive (85%) –improved OS vs placebo cabazitaxel (TROPIC) –mCRPC doxetaxel-refractory –improved OS vs mitoxantrone arbiraterone –hormonal principle in CPRC Kantoff et al, N Engl J Med 2010 De Bono et al, Lancet 2010

9. Arbiraterone inhibition of testosterone biosynthesis arbiraterone acetate inhibits –C 17,20 lyase –17  hydroxylase –Inhibition selective & irreversible adrenals, testes, prostate cancer cells arbiraterone acetate: prodrug good oral bioavailability Development of resistance

10. Sonpavde et al, Eur Urol 2011

11. Attard et al, Cancer Res 2009

12. Study data: arbiraterone in CRPC phase I –chemotherapy-naive CRPC patients phase-II NCT 00474383 –progression after docetaxel phase-III NCT 00638690 –progression after docetaxel phase III NCT 00887198 –asymptomatic, low metastatic load in chemotherapy-naive patients

13. phase I n=21 chemo-naive, CRPC –12/21 with PSA↓>50% and > 3 months –of which in 6/12 PSA↓ > 90% –PR (RESIST) in 5/8 patients and ↓analgesic medication –no grade grade 3/4 toxicity Attard et al, J Clin Oncol 2008

14. phase II a chemotherapy-naive CRPC patients PSA↓> 50% in 70-80% of patients RESIST response 37.5% median time to PSA-rise 225 days dexamethasone at progression with arbiraterone: further PSA↓>50% in 33% Attard et al, J Clin Oncol 2009

15. phase II b n= 47 docetaxele-pretreated CRPC PSA↓> 50% in 51% of patients 35 with RESIST –PR 17% –SD 66% 23% ECOG improvement Reid et al, J Clin Oncol 2009

18. Phase II c docetaxele-pretreated CRPC better efficacy without ketoconazole pretreatment –53% vs 33% PSA-response without/with –31% vs 4% PSA↓>90% without/with ketoconazole –median time to progression 198 vs 99 days with/without ketoconazole Danila et al, J Clin Oncol 2009

19. phase III (COU-AA-301) n=1195 docetaxel-refractory CRPC arbiraterone vs placebo 2:1 randomisation stratification –ECOG 0-1 vs 2 –prior chemotherapy schedules 1 vs 2 –pain score –type of progression: PSA vs XR

20. OS 14.8 vs 10.4 months TTP 10.2 vs 6.6 months rPFS 5.6 vs 3.6 months PSA RR 29.1% vs 5.5% toxicity –hyperhydration 2.3% vs 1.0% –hypokalaemia 3.8% vs 0.8% –hypertension 1.3% vs 0.3% –cardiopulmonary 4.1% vs 2.3% phase III (COU-AA-301) 1.interim analysis 2010 De Bono et al, ESMO 2010

21. arbiraterone n=1195 docetaxel resistant 2:1 randomisation –arbiraterone 1000 mg + 5 mg prednisone vs –placebo + 5 mg prednisone overall survival –arbiraterone 14.8 months –placebo 10.9 months de Bono et al, N Engl J Med 2011

22. treatment options for metastatic prostate cancer hormonal –androgen ablation orchidectomy LHRH-antagonists or –agonists androgen blockers –androgen conversion blocker arbiraterone chemotherapy –docetaxel –cabazitaxel bisphosphonates pain treatment nuclear medical tretament: samarium, strontium best supportive care

23. Prognosis of metastatic prostate cancer initial response to androgen ablation > 80% progression in 50-60% of patients within 2 years after that median survival 23-37 months 5 year survival rate with M+ oss 20%

24. androgen antagonists steroidal –cyproterone acetate non-steroidal –bicalutamide –flutamide –nilutamide

25. proportion without event 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 061218243036424860 time (months) bicalutamide 150 mg + standard care Placebo + standard care 54 reduction of the risk of PSA progression by 59 % Kaplan-Meier curve of time to PSA progression HR 0.41; 95% CI 0.38, 0.45; p<<0.0001 Early Prostate Cancer Program

26. natural course of prostate cancer after radical prostatectomy and PSA recurrence (n= 311) 150510 years PSA recurrence distant metastases death of prostate cancer Pound et al., JAMA 1999

27. Hormone-independent prostate cancer hormone independent hormone sensitive hormone dependent hormone withdrawal hormone naive hormone independent

28. definition of castration-resistant prostate hormone- refractory prostate cancer (HRPC) serume testosteron at castration level secondary hormonal treatment without effect ketoconazole estrogens rising PSA at 3 consecutive measurements at intervals of 1 week at leastt with continued LHRH – blockade and after witrhdrawal of androgen blocker lowest PSA limit: 0.4 ng/ml

29. Chemotherapy for prostate cancer? Reviews response rates 1985: (17 Studien)6,5 % M. Eisenberger, J Clin Oncol 1985 1992: (26 Studien)8,7 % Yagoda & Petrylak, Cancer 1993 P.Walsh 1995: „This is going to be an extremely short discussion. Not only does it fail to cure the cancer, it doesn’t even prolong survival to any significant degree, and its side effects only add to the unpleasantness of having prostate cancer.“

30. phase III: mitoxantrone (12mg/m²) + prednisone (10mg/d) vs. prednisone (10mg/d) –161 patients. (80 M+P; 81 P) phase III: mitoxantrone (14mg/m²) + hydrocortisone (40mg/d) vs. hydrocortisone (40mg/d) –242 patients results –improvement in pain –improvement in quality of life –duration of response 5-7 months –no influence on survival chemotherapy for prostate cancer – mitoxantrone for HRPC? Tannock et al. 1996 Kantoff et al. 1999 mitoxantrone approved by FDA as standard chemotherapy in HRPC

31. docetaxel TAX 327 SWOG 9916 both studies showed overall survival advantage for docetaxel Petrylak, N Engl J Med 2004 Tannock, N Engl J Med 2004

32. 20% 40% 60% 80% 100% 0 12243648 months D + E M + P no. at Risk 338 336 217 235 median survival (months) 18 16 HR: 0.80 (95% CI 0.67, 0.97), p = 0.01 med. F/U: 1 J docetaxel chemotherapy overall survival SWOG 9916 no (n) died Petrylak et al, N Engl J Med 2004

33. SWOG 99-16 Petrylak J NCI 2006

34. Survival in subgroups docetaxel 3 weekly vs mitoxantrone 0.20.40.60.811.2 1.4 Intent to Treat age < 65 age ≥ 65 age ≥ 75 pain no pain yes KPS ≥ 80 KPS ≤ 70 hazard ratio in favour of docetaxel mitoxantrone Tannock et al, N Engl J Med 2004

35. Cochrane Review chemotherapy of HRPC n=6929 patients; 47 studies investigated substances: –EMP –docetaxel –5-FU –cyclophosphamide –doxorubicine –mitoxantrone –vinorelbine Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006

36. Cochrane Review PSA response (>50%): –EMP48% –docetaxel52% –5-FU20% –cyclophosphamiden.d. –doxorubicine50% (CAVE: only 1 study!) –mitoxantrone 33% –vinorelbinen.d. Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006

37. only DOC => overall survival ↑ (<2.5 months) pain ↓DOC > Mit + Pred quality of life ↑ DOC > Mit + Pred results authors‘ conclusion: „At the present time this* probably represents the best chemotherapeutic regime available for men with HRPC“ *- docetaxel q3w Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006

38. secondary hormone manipulation or chemotherapy? secondary hormone manipulation chemotherapy CALGB9583SWOG 9916TAX-327 AAW + Ketokonazol EMP docetaxel vs MP DP q3w vs DP q1w vs MP n2607701006 overall survival in better arm 16.7 months17.5 months18.9 months overall survival in worse arm 15.3 months15.6 months16.5 months Bellmunt, Eur Urol Suppl 2009

39. open questions when to start with chemotherapy? should asymptomatic M+ patients be treated? how long to continue treatment? secondary treatment? intermittent chemotherapy? re-exposition?

40. Early vs late chemotherapy? for –benefit established for other entities (breast cancer, colorectal cancer) –lower tumour mass –treatment prolongs survival against –toxicity vs unreliable response –early induction of chemotherapy-refractory state –outcome is not influenced since no difference in survival between symptomatic vs asymptomatic patients (TAX327)

41. forms of HRPC indications for starting with chemotherapy only rising PSA asymptomatic, low metastatic load asymptomatic, large metastatic load symptomatic metastases  no indication PSA doubling time?  individual decision inclusion in study?  yes

42. Estimating the prognosis in CPRC PSA doubling time günstig –TAX 327:PSA-DT > 55 Tage –Oudard et al:PSA-DT > 45 Tage Armstrong et al, Clin Cancer Res 2007 Oudard et al, Ann Oncol 2007

43. Armstrong, A. J. et al. Clin Cancer Res 2007;13:6396-6403 nomographic estimation

44. rising PSA under chemotherapy… often initiial PSA flare-up no negative influence on survival, unless there are signs of clinical progression => minimum of 8 weeks treatment before deciding to discontinue ! Olbert Anticancer Drugs 2006

45. Copyright restrictions may apply. Thuret et al, Ann Oncol 2008 PSA-Flare with chemotherapy in patients with subsequent PSA response or stable disease PSA values normalized to a starting point of 100 ng/ml

46. Chemotherapy until… best number of cycles unknown TAX 327: mean of 8 cycles but: chronic toxicity increases with no of cycles intermittend chemotherapy?

47. When to discontinue chemotherapy…? definite worsening of physical state PSA doubling time < 3 Monate slow PSA increase: - discontinue if clinically progressive Miller et al. Akt Urol 2006

48. First line chemotherapy docetaxel Mono (75mg/m² KO d1, q21d) Second line chemotherapy options: –docetaxel (M  D)PR: 44-85% –docetaxel weekly PR: 72% –mitoxantrone (D  M)PR: 6-15% –satraplatin (SPARC) –cabazitaxel

49. Cabazitaxel second line overall survival de Bono et al, Lancet 2010 open label, randomized, n= 755 CPRC patients with progression on docetaxel cabazitaxel 25 mg/m 2 q3w + prednisone 10 mg p.o. daily vs mitoxantrone 12 mg/m 2 q3w i.v.+ prednisone 10 mg p.o. daily mean survival overall CABA15.1 months MITO12.7 months

50. Cabazitaxel second line progression-free survival de Bono et al, Lancet 2010

51. ketoconazole 200 or 400 mg tid p.o. ketoconazole + hydrocortisone replacement doses 30-0-10 mg p.o. n= 114 response depends on disease burden Keizman et al, Prostate 2010

52. Beltran et al, Eur Urol 2011

53. Hypothetical calculation Future prognosis of metastatic prostate cancer? initial response to androgen ablation > 80% progression in 50-60% of patients within 2 years after that median survival 23-37 months + 4 months with docetaxel + 4 months with cabazitaxel + 4 months with arbiraterone

54. „This will buy you three months“

55. Rostock