Hormonal Manipulations in CRPC. NW Clarke Professor of Urological Oncology Manchester UK

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1 Hormonal Manipulations in CRPC NW Clarke Professor of Urological Oncology Manchester UK

2 Standard Treatment of CRPC Pre 2004 (and in 2013?) PSA progression 99m Tc BS negative CT scan large lymph node component C Bicalutamide stopped

3 Standard Treatment of CRPC Pre 2004 (and in 2013?) PSA progression 99m Tc BS negative CT scan large lymph node component C Bicalutamide stopped

4 Traditional Hormonal Therapies for CRPC Addition of Anti-androgens Addition of anti-androgen n PSA response 50% decline (%) Median duration (months) Bicalutamide 150 mg/day NA Bicalutamide 150 mg/day NA Bicalutamide 200 mg/day Nilutamide 200 or 300 mg/day Nilutamide 150 or 300 mg/day Bicalutamide 80 mg/day or flutamide 375 mg/day Median OS (months) 15* NA NA NA NA NM None have been shown to significantly improve overall survival 1. Kucuk et al. Urology 2001;58: Joyce et al. J Urol 1998;159: Scher et al. J Clin Oncol 1997;15: Kassouf et al. J Urol 2003;169: Desai et al. Urology 2001;58: Suzuki et al. J Urol 2008;180:921 7.

5 Traditional Hormonal Therapies for CRPC Corticosteroids / oestrogens Corticosteroids n PSA response 50% decline (%) Median duration (months) Hydrocortisone 40 mg/day Hydrocortisone 40 mg/day Prednisone 10 mg/day Prednisone 20 mg/day Dexamethasone (0.5 mg/day) Oestrogens DES 1 mg/day NA DES 3 mg/day Transdermal oestradiol 0.6 mg/day Median OS (months) NA 12.6* NM* 11.9* NA NM NA NA None have been shown to improve overall survival significantly Kelly et al. J Clin Oncol 1995;. Kantoff J Clin Oncol 1999; Tannock. J Clin Oncol Sternberg et al. Oncology 2005 Venkitaraman et al. BJU Int 2007 Smith. Urology Oh et al. J Clin Oncol Dawson et al. Cancer 2000.

6 N=270 CV Event Rate 20% TTP for DAiS (8.6 months) was significantly longer DA (4.5 months p<0,001)

7 Lancet Oncology Vol 14 April 2013

8 Evolving treatment in CRPC Hormone sensitive mcrpc asymptomatic disease (failed ADT) mcrpc mildly symptomatic disease mcrpc symptomatic pre-chemo C he m o mcrpc post-chemo Hormone therapy Sipuleucel-T Abiraterone Abiraterone Docetaxel Cabazitaxel Enzalutamide Approved for use by FDA/EMA Approved for use by FDA Positive Phase III data Radium 223 PLUS supportive care (e.g. denosumab/bisphosphonates/β-emitters)

9 Ongoing Phase III Trials in Metastatic CRPC Asymptomatic mcrpc (failed ADT) Mildly symptomatic mcrpc mcrpc symptomatic pre-chemo C he m o mcrpc post-chemo Ipilimumab vs. placebo Cabazitaxel vs. Docetaxel (FIRSTANA) Cabozantinib vs. prednisone (COMET-1) PROSTVAC-V/F ± GM-CSF vs. placebo (PROSPECT) Tasquinimod vs. placebo Dasatinib vs. placebo (+ docetaxel, both arms) (READY*) Enzalutamide vs. placebo (PREVAIL) Cabozantinib vs. mitoxantrone + prednisone (COMET-2) Cabazitaxel 20 mg/m² vs. 25 mg/m² (PROSELICA) Custirsen ± docetaxel + prednisone (SYNERGY) Ipilimumab vs. placebo following RT Orteronel vs. placebo Orteronel vs. placebo

Cytotoxic Chemotherapy: Docetaxel and Cabazitaxel in CRPC Phase 3,

mitoxantrone + prednisone in mcrpc previously treated with

PSA progression, tumour response (RECIST), pain response 25 mg/m 2

mcrpc progression after Docetaxel 1:1 12 mg/m 2 mitoxantrone IV

10 Cytotoxic Chemotherapy: Docetaxel and Cabazitaxel in CRPC Phase 3, randomized, open-label trial of cabazitaxel + prednisone versus mitoxantrone + prednisone in mcrpc previously treated with docetaxel Primary endpoint: OS Secondary endpoints: PSA response, PSA progression, tumour response (RECIST), pain response 25 mg/m 2 cabazitaxel IV every 3 weeks + prednisone 10 mg QD (n=378) n=755 mcrpc progression after Docetaxel 1:1 12 mg/m 2 mitoxantrone IV every 3 weeks + prednisone 10 mg QD (n=377) de Bono JS, et al. Lancet 2010;376:

11 Standard Treatment of CRPC Post 2005 (? in 2013) Docetaxel is initiated: 8 cycles 75 mg/m 2 + prednisone 5 mg bid Response after 6 cycles: PSA 256 to 162 ng/ml, small decrease on LN 8 cycles of docetaxel 75 mg/m 2

12 Standard Treatment of CRPC Post 2005 Treatment with docetaxel is stopped after 9 cycles due to PSA progression, Grade 3 fatigue and multiple lymph node metastases This was followed by a more rapid PSA progression Multiple lymph nodes metastases 99m TC BS Docetaxel

13 Standard Treatment of CRPC Post 2005 Treatment with docetaxel is stopped after 9 cycles due to PSA progression, Grade 3 fatigue and multiple lymph node metastases This was followed by a more rapid PSA progression Multiple lymph nodes metastases 99m TC BS Docetaxel

14 Novel Androgenic Approaches in CRPC LHRH agonists LH ACTH Androstenedione Ligand-dependent Receptor tyrosine kinase Ligand-independent 4 Ligand-independent activation of AR 1 2 Alternate ligands 6 Coactivators Corepressors Nuclear localisation Transcription 5 7 AR splice variants Nucleus Cytoplasm

15 Standard Treatment of CRPC in 2013 / 2014 Abiraterone Docetaxel AFFIRM: A Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Patients With Progressive Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy (NCT )

16 Standard Treatment of CRPC in 2013 / 2014 PSA progression Patient asymptomatic Hb 10.5 mg/dl from 12.5 mg/dl Abiraterone Docetaxel

17 Standard Treatment of CRPC in 2013 / 2014 PSA progression Patient is now moderately symptomatic in cervical spine (treated by paracetamol and piroxicam) Hb 10.5 mg/dl from 12.5 mg/dl Abiraterone Docetaxel

18 Standard Treatment of CRPC in 2013 / 2014 Increase cervical pain with neurological symptoms in both arms, urinary retention Abiraterone Docetaxel Enzalutamide

19 Standard Treatment of CRPC in 2013 / 2014 Increase cervical pain with neurological symptoms in both arms, urinary retention Abiraterone Enzalutamide Docetaxel Enzalutamide Abiraterone

20 Problems and Uncertainties in CRPC Who gets the drugs Who gives the drugs? What is the optimal sequencing and combination What about poor performance status patients Who pays the bill.?

21 Problems and Uncertainties in CRPC Who gets the drugs Who gives the drugs? What is the optimal sequencing and combination What about poor performance status patients Who pays the bill.?

22 prevention Survival Palliation What Are the Aims and Expectations Chemotherapy Hormones Radiotherapy Radionuclide Non-metastatic PSA increasing Metastatic Asymptomatic Metastatic Symptomatic (bone pain)

23 prevention Survival Palliation What Are the Aims and Expectations Chemotherapy Hormones Radiotherapy Radionuclide Chemotherapy Hormones Radiotherapy Radionuclide Non-metastatic PSA increasing Metastatic Asymptomatic Metastatic Symptomatic (bone pain)

24 prevention Survival Palliation What Are the Aims and Expectations Chemotherapy Hormones Radiotherapy Radionuclide Chemotherapy Hormones Radiotherapy Radionuclide Chemotherapy Hormones Radiotherapy Radionuclide Non-metastatic PSA increasing Metastatic Asymptomatic Metastatic Symptomatic (bone pain)

25 prevention Survival Palliation What Are the Aims and Expectations? Chemotherapy Non-metastatic PSA increasing Metastatic Asymptomatic Metastatic Symptomatic (bone pain)

26 prevention Survival Palliation What Are the Aims and Expectations? Chemotherapy Non-metastatic PSA increasing Metastatic Asymptomatic Metastatic Symptomatic (bone pain)

27 prevention Survival Palliation What Are the Aims and Expectations? Non-metastatic PSA increasing Metastatic Asymptomatic Metastatic Symptomatic (bone pain)

28 prevention Survival Palliation What Are the Aims and Expectations? Non-metastatic PSA increasing Metastatic Asymptomatic Metastatic Symptomatic (bone pain)

29 prevention Survival Palliation What Are the Aims and Expectations Palliate symptoms Improve survival? Prevent onset and complications of bone metastases? Non-metastatic PSA increasing Metastatic Asymptomatic Metastatic Symptomatic (bone pain)

30 Cumulative incidence Older Men Have a Higher Risk of Dying Due to PCa Cumulative incidence of PCa-related death <75 Years from prostate cancer diagnosis Skosyrev E et al. Cancer 2012;118:

Treatment Should be Adapted to Health Status Fit Vulnerable Frail No serious co-morbidity (CIRS-G rating: 0 2) Functionally independent No malnutrition 70 75 years (50% ) and 80 85 years (25%)

31 Treatment Should be Adapted to Health Status Fit Vulnerable Frail No serious co-morbidity (CIRS-G rating: 0 2) Functionally independent No malnutrition years (50% ) and years (25%) Uncontrolled co-morbidity Dependent in at least one IADL Risk of malnutrition Reversible through geriatric intervention Two or more uncontrolled co- morbidities Dependent in one or more IADL Severe malnutrition Too sick Terminal illness Bedridden Major co-morbidities Cognitive impairments Same treatment as younger patients Geriatric intervention => Standard treatment Geriatric intervention => Adapted treatment (or palliation) Only palliative treatment Standard Treatment Geriatric Intervention Droz JP et al. Crit Rev Oncol Hematol 2010;73:61 91 Droz JP et al. BJU Int 2010;106:462 9

32 What Do We Combine in CRPC? Advances in the understanding of mcrpc have led to the development of new agents with diverse mechanisms of action: Second-generation taxanes Androgen-lowering agents AR signalling inhibitors Radiopharmaceuticals Bone Protective Agents Tyrosine kinase inhibitors Others Hou X, Flaig TW. Adv Urol 2012;2012;978531; Fizazi K, et al. Ann Oncol 2012;23(Suppl. 10):x264 7.

33 Figure 2 Overall survival HR=hazard ratio. AA=abiraterone acetate. P=prednisone. Karim Fizazi, Howard I Scher, Arturo Molina, Christopher J Logothetis, Kim N Chi, Robert J Jones, John N St... Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study The Lancet Oncology null 2012 null

34 The Lancet Oncology null 2012 null

35 The Affirm Study MDV3100 Placebo Median OS (months) Hazard ratio 0.63 P value < NEJM Sept 2012

36 Orteronel (TAK-700): Clinical Studies Phase 1/2 study in metastatic CRPC: Phase 2 results Percent change from baseline in PSA at 24 weeks by patient Bars with darker shading marked X indicate patients who received prior ketoconazole At 24 weeks, 36 patients (64% of evaluable, 38% of intent-to-treat population) had PSA decreases of 50% (PSA50) Agus DB, et al. ASCO 2011, Chicago, IL, USA; Abstract 4531

37 Orteronel (TAK-700) Registration Study C21005: mcrpc Following Docetaxel Failure Patients 1,083 patients, progressive, mcrpc Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel Orteronel po BID Prednisone po BID Placebo po BID Prednisone po BID Efficacy Endpoints Primary: OS Secondary: PSA response Pain response rpfs rpfs = radiographic progression-free survival accessed June 2011

38 Phase III PREVAIL Trial: Study Design CRPC R 1:1 MDV mg daily Placebo Co-primary endpoints: overall survival and progression-free survival Secondary endpoints: time to first SRE; time to start of chemotherapy Key inclusion criteria: No prior treatment with cytotoxic chemotherapy Asymptomatic or mildly symptomatic Estimated primary completion date September 2014 Clinicaltrials.gov identifier # NCT

39 Updated Interim Analysis (55% OS) of COU-AA-302, a Randomized Phase 3 Study of Abiraterone Acetate in Metastatic Castration-Resistant Prostate Cancer Patients Without Prior Chemotherapy Dana Rathkopf,1 Matthew R Smith,2 Johann S. de Bono,3 Christopher Logothetis,4 Neal D. Shore,5 Paul de Souza,6 Karim Fizazi,7 Peter F.A. Mulders,8 Paul Mainwaring,9 John D. Hainsworth,10 Tomasz M. Beer,11 Scott North,12 Yves Fradet,13 Tom Griffin,14 Youn C. Park,15 Thian Kheoh,14 Eric J. Small,16 Howard I. Scher,1,17 Arturo Molina,14 Charles J. Ryan18 on behalf of the COU-AA-302 Investigators Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

40 Subjects Without Progression or Death (%) Abiraterone and Time to rpfs Abiraterone (median, mos): 16.5 Prednisone (median, mos): 8.3 HR (95% CI): 0.53 ( ) p Value: < Abiraterone Prednisone Months From Randomization Abiraterone Prednisone Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

41 Subjects Without Death (%) Abiraterone and Overall Survival 100 Abiraterone (median, mos): 35.3 Prednisone (median, mos): 30.1 HR (95% CI): 0.79 ( ) p Value a : Abiraterone Prednisone Months From Randomization Abiraterone Prednisone Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

42 Subsequent Therapy After Abiraterone Abiraterone (n = 419) n (%) Prednisone (n = 482) n (%) No. with selected subsequent therapy for mcrpc a 274 (65) 347 (72) Docetaxel 239 (57) 304 (63) Cabazitaxel 60 (14) 70 (15) Ketoconazole 39 (9) 63 (13) Abiraterone b 38 (9) 78 (16) Sipuleucel-T 33 (8) 28 (6) Rathkopf et al. ASCO GU 2013; Abstract 5

43 Safety Profile Abiraterone (n = 542) % Prednisone (n = 540) % Adverse event All grades Grades 3/4 All grades Grades 3/4 Fatigue Fluid retention Hypokalemia Hypertension Hyperglycemia Weight gain Cardiac disorders ALT increased AST increased Rathkopf et al. ASCO GU 2013; Abstract 5

44 COU-AA-302 Updated Interim Analysis: Summary 8.2 months rpfs improvement (16.5 vs 8.3 months) 5.2 months OS improvement (35.3 vs 30.1 months) 9.7 months delay chemotherapy (26.5 vs 16.8 months) Delayed time to opiate use (NR vs 23.7 months) Improved QoL Tolerated treatment with longer exposure Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

45 Problems and Uncertainties in CRPC Who gets the drugs Who gives the drugs? What is the optimal sequencing and combination What about poor performance status patients Who pays the bill.?

46 Chemotherapy or Hormonal Treatment First?

47 When Should Chemotherapy be Started? Not all men are suitable for chemotherapy Both QoL and pain can be improved by chemotherapy Men with minimal symptoms had prolonged survival Berthold, D. R. et al. J Clin Oncol; 26:

48 Should Docetaxel Responders be Re-Treated Re-Treatments of Initial Responders 59% Response to 1 st Line 90% Response to 2 nd Line 71% Response to 3 rd Line Duration of Response Weeks N Sepsis st Line /4.2 2 nd Line /5.2 % 3 rd Line Ansari et al GU ASCO 2009 # 185

49 Survival (%) TROPIC results: Efficacy Median follow-up: 12.8 months Median OS: Cabazitaxel 15.1 months Mitoxantrone 12.7 months HR=0.70 (95% CI: ); p< % reduction in risk of death Mitoxantrone Cabazitaxel Months Mitoxantrone (n) Cabazitaxel (n) CI=confidence interval; HR=hazard ratio. de Bono JS, et al. Lancet 2010;376:

50 Novel Androgen Receptor Signalling Should all patients receive this routinely as the first 2 nd line agent How do we decide whether to give chemotherapy 1 st or 2 nd How will regulation affect sequencing?

51 Novel Androgen Receptor Signalling Should all patients receive this routinely as the first 2 nd line agent How do we decide whether to give chemotherapy 1 st or 2 nd How will regulation affect sequencing?

52 Docetaxel in Chemotherapy-naive Patients after Abiraterone Failure N = 35 TAX (Docetaxel q3w) Phase I-II 2 (Abiraterone Docetaxel) PSA decrease 50% 45% 26% Time to PSA progression (median) Overall survival (median) 7.7 mo 4.6 mo 18.9 mo 12.5 mo Docetaxel after AA failure maybe not as effective as docetaxel 1 st line 1. Tannock IF et al. N Engl J Med 2004;351: Mezynski J et al. Ann Oncol 2012;epub ahead of print.

53 Androgen Receptor Inhibition After Chemotherapy COU-AA (Abiraterone vs Placebo) AFFIRM 2 (Enzalutamide vs Placebo) OS after 1 prior line chemotherapy OS after 2 prior lines chemotherapy 17.1 vs 11.7 mo NR vs 14.2 mo 14.2 vs 10.4 mo 15.9 vs 12.3 mo Abiraterone and enzalutamide both effective after 2 lines of chemotherapy 1. Fizazi K et al. Lancet Oncol Scher H et al. N Engl J Med 2012;367:

Cumulative survival Sequence after Docetaxel Failure 1. 0 0. 8 0. 6 0. 4 0.

54 Cumulative survival Sequence after Docetaxel Failure Abiraterone Median OS 8 months Cabazitaxel Median OS 18 months Docetaxel Cabazitaxel Docetaxel Abiraterone Months (Treatment start) Malik Z et al. J Clin Oncol 2012;30 (Suppl):abstract e15135

55 Problems and Uncertainties in CRPC Who gets the drugs Who gives the drugs? What is the optimal sequencing and combination What about poor performance status patients Who pays the bill.?

56 The Lancet Oncology null 2012 null

57 Survival (%) ECOG Status 100 OS: ECOG status (0-1 vs 2) AA ECOG months AA ECOG months 40 Placebo ECOG 2 7 months Placebo ECOG months Time to Death (Months) Scher et al. J Clin Oncol 2011; 25 (suppl 7); Abstract 4 (oral presentation)

58 Survival (%) Survival (%) Prior Chemotherapy OS: 1 prior line of chemotherapy OS: 2 prior lines of chemotherapy AA 15.4 months 80 AA 14.0 months Placebo 11.5 months 20 Placebo 10.3 months Time to Death (Months) Time to Death (Months) de Bono et al. Ann Oncol 2010; 21 (10 suppl 8): Abstract LBA5 (oral presentation) Scher et al. J Clin Oncol 2011; 25 (suppl 7): Abstract 4 (oral presentation)

59 Survival (%) Survival (%) Pain Status OS: Pain (0-3 [absent]) OS: Pain (4-10 [present]) AA 16.2 months 80 AA 12.6 months Placebo 13 months 20 Placebo 8.9 months Time to Death (Months) Time to Death (Months) *Brief Pain Inventory scale Scher et al. J Clin Oncol 2011; 25 (suppl 7); Abstract 4 (oral presentation)

60 Problems and Uncertainties in CRPC Who gets the drugs Who gives the drugs? What is the optimal sequencing and combination What about poor performance status patients Who pays the bill.?

61 Costs 2930 / Month ($4640) 46,800-50,000 / QALY Initially rejected by NICE: Too Costly Accepted June 2012 after Renegotiation of the price

62 Costs 2930 / Month ($4640) 46,800-50,000 / QALY Initially rejected by NICE: Too Costly Accepted June 2012 after Renegotiation of the price

63 Costs

64 Hormonal Manipulations in CRPC NW Clarke Professor of Urological Oncology Manchester UK

Novel treatment for castration-resistant prostate cancer

Novel treatment for castration-resistant prostate cancer Cora N. Sternberg, MD, FACP Chair, Department of Medical Oncology San Camillo and Forlanini Hospitals Rome, Italy Treatment options for patients