Overcoming Resistance In Renal and Prostate Cancer Cora N. Sternberg, MD, FACP Chair, Department of Medical Oncology San Camillo and Forlanini

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1 Overcoming Resistance In Renal and Prostate Cancer Cora N. Sternberg, MD, FACP Chair, Department of Medical Oncology San Camillo and Forlanini Hospitals Rome, Italy

2 Knowledge of targets Everolimus VHL = HIF mtor VEGF PDGF TGF- VEGFR PDGFR EGFR Pazopanib Axitinib Rini BI, et al. Lancet. 2009;373(9669):

3 Survival has improved (mrcc) Treated with different immunotherapy regimens Négrier S et al. Ann Oncol 2002;13:

Survival has more than doubled OS HR (95% CI ): 0.908 (0.762-1.

4 Survival has more than doubled OS HR (95% CI ): ( ) Total number of events: 5022 OS data are not yet mature Lower 95% CI Median months Upper 95% CI Pazopanib Sunitinib Pazopanib Sunitinib Motzer R, et al. ESMO 2012 oral presentation; Abstract LBA8_PR and Motzer R, NEJM ( in press).

Mainly because of new treatment options Bevacizumab + IFN-α5 Sorafenib2

Everolimus6 Sunitinib3 2005 2006 2007 2008 2009 2010 2011 2012 IFN-α 1.

N Engl J Med 2007;356:125-134. 3. Motzer RJ, et al.

N Engl J Med 2007;356:2271-2281. 5. Escudier B, et al.

5 Mainly because of new treatment options Bevacizumab + IFN-α5 Sorafenib2 Temsirolimus4 High-dose interleukin Pazopanib7 Axitinib8 Everolimus6 Sunitinib IFN-α 1. Fyfe G, et al. J Clin Oncol 1995;13: Escudier B, et al. N Engl J Med 2007;356: Motzer RJ, et al. N Engl J Med 2007;356: Hudes G, et al. N Engl J Med 2007;356: Escudier B, et al. Lancet 2007;370: Motzer RJ, et al. Lancet 2008;372: Sternberg CN, et al. J Clin Oncol 2010;28: Rini BI, et al. Lancet 2011;378:

primary-target potency = selectivity1 Larger red circles indicate

6 Kinase selectivity of various VEGFR TKIs VEGFR, PDGFR, c-kit Pazopanib Sunitinib VEGFR, PDGFR, ckit FLT3 Sorafenib Ratio of off-target vs. primary-target potency = selectivity1 Larger red circles indicate higher-affinity binding to a specific kinase2 Adapted from Karaman et al. Nat Biotech. 2008;26:127

7 Relative Potency of Targeted Agents in mrcc Less 1,000 potent 100 Potency: IC50 (nm) VEGFR-1 VEGFR-2 VEGFR More potent 0.01 Tivozanib Axitinib Cediranib Motesanib Sunitinib AMG-706 (AV-951) (AG13736) ABT-869 Pazopanib Sorafenib Vatalanib Vandetanib PTK787 Based on the results from several different studies, AV-951 is the most potent VEGFR TKI with an IC50 of ~200 pm against all 3 VEGFRs Chow LQM, et al. J Clin Oncol. 2007; Eskens FALM, et al. AACR 2008; Sonpavde G, et al. Drugs Today 2009; Polverino A, et al. Cancer Res 2006; Albert DH, et al. Mol Cancer Ther 2006; Morabito A, et al. The Oncologist 2006; Morabito A, et al. The Oncologist 2009

8 How to Further improve survival? Avoid resistance to VEGF inhibition Understand tumor heterogeneity Targeted Immunotherapy New Targets

9 How to Further improve survival? Avoid resistance to VEGF inhibition Understand tumor heterogeneity Targeted Immunotherapy New Targets

10 Resistance to VEGF-targeted therapy is a key clinical issue Adaptive Resistance: VEGF targeted agents fail to produce enduring clinical responses Intrinsic Resistance: No predictive biomarkers avaialable to date Bergers G, Hanahan D, Nat Rev Cancer 2008; 8,

11 Adaptive Resistance to VEGF Inhibition FGF mediates escape from anti-angiogenesis therapy VEGF inhibitors VEGF inhibitors Casanovas O, et al. Cancer Cell. 2005;8:

12 Rationale for targeting FGFRs in cancer FGF family describes 23 members 18 FGF receptor ligands (FGF1 FGF10 and FGF16 FGF23) Genetic alterations for FGFs/FGFRs that occur in various types of cancer: P P P P Activating mutations Gene amplifications Chromosomal translocations Beenken A et al. Nature Rev. Drug Discov. 2009; 8:

Vascular endothelial cell Dovitinib (TKI258 multi-kinase inhibitor) (FGFR) inhibitor of receptor Tyrosine Kinases DECREASED ANGIOGENESIS TKI258 FGFR PDGFR VEGFR BGJ398 Tumor cell FGFR PDGFR TKI258

13 Vascular endothelial cell Dovitinib (TKI258 multi-kinase inhibitor) (FGFR) inhibitor of receptor Tyrosine Kinases DECREASED ANGIOGENESIS TKI258 FGFR PDGFR VEGFR BGJ398 Tumor cell FGFR PDGFR TKI258 APOPOSIS CELL CYCLE ARREST TKI258 is potent inhibitor of FGFR-1, -2, -3, VEGFR & PDGFR Inhibits proliferation of a variety of human tumor-derived cancer cell lines; Breast, bladder, MM, AML, prostate, colon, lung, ovarian Increases apoptosis in primary MM cells bearing t(4,14) translocation and FGFR-3 overexpression FGFR, fibroblast growth factor receptor; AML, acute myeloid leukemia; MM, multiple myeloma; PDGFR, platelet-derived growth factor; VEGFR, vascular endothelial growth factor receptor. 1. Choi DY, et al. J Biol Chem. 2001;276: ; 2. Novartis, data on file; 3. Lam JS, et al. ASCO Abstract # 4538; 4. Carvalho I, et al. Breast Cancer Res. 2005;7:R788-R795

14 Dovitinib (TKI258) in 3rd-line advanced or mrcc (anti-vegf/mtor refractory pts) (n=550) R A N D O M I Z E Stratification: MSKCC risk group Dovitinib (TKI258) Sorafenib n=550 Primary endpoint: PFS (central), 411 events Futility analysis after 123 PFS (central) events Secondary endpoints: OS PFS (local) (NCT )

15 Tumour volume The future: Turning mrcc into a chronic disease Time Larkin J & Gore M. Lancet 2010;376:

16 How to Further improve survival? Avoid resistance to VEGF inhibition Understand tumor heterogeneity Targeted Immunotherapy New Targets

18 Intratumoral heterogeneity

19 Intratumoral heterogeneity

21 Intratumor heterogeneity

22 Intratumor heterogeneity

23 Clonal evolution

24 Resistance and escape from antiangiogenesis therapy is multifactorial Bottsford-Miller J N et al. JCO 2012;30:

25 How to Further improve survival? Avoid resistance to VEGF inhibition Understand tumor heterogeneity Targeted Immunotherapy New Targets

26 Novel Immunotherapy Several Ongoing trials Anti-PD-1 (Phase III) AGS-003 (Phase III mrcc) BMS (Phase I/II) TROVAX (negative) 177Lu-DOTA-cG250 ( Phase II/III) MVA-T54 (Phase III mrcc) HSPPC-96 (Phase III adjuvant) IMA901 (Phase III) MGN 1601 Inman BA, Harrison MR, George DJ, EU Urol 63 (2013)

27 PD-1 blockade as a strategy

Partial regression of mrcc with 1 mg/kg BMS-936558 Durable benefit of therapy 48-year-old patient with

and thoracic surgery Therapy held after 3 cycles due to near CR Response has continued for 3 years,

28 Partial regression of mrcc with 1 mg/kg BMS Durable benefit of therapy 48-year-old patient with low volume but poorly differentiated mrcc Developed progressive disease after sunitinib, sorafenib, and thoracic surgery Therapy held after 3 cycles due to near CR Response has continued for 3 years, while off therapy Brahmer JR, et al. N Eng J Med 2012;366: Courtesy of M. Sznol, Yale Cancer Center

Partial regression of mrcc with 1 mg/kg BMS-936558 Pretreatment 6 months

sunitinib, temsirolimus, sorafenib, and pazopanib In cycle 6 with ongoing PR

29 Partial regression of mrcc with 1 mg/kg BMS Pretreatment 6 months 57-year-old patient who developed progressive disease after receiving sunitinib, temsirolimus, sorafenib, and pazopanib In cycle 6 with ongoing PR Brahmer JR, et al. N Eng J Med 2012;366: Courtesy of C. Drake, John Hopkins University

30 PD-L1 expression in biopsies and outcome

31 Increased PD-L1 expression and survival

32 Nivolumab vs. Everolimus in mrcc Study Design Efficacy endpoints (ITT) 822 patients with mrcc who failed 1 or 2 prior anti-angiogenic therapy PS > 70% R A N D O M I Z E D Nivolumab 3 mg/kg IV Q2 wks 1 endpoint: OS (32% improvement; HR 0.76) 2nd endpoints: Everolimus 10 mg PO QD PFS ORR SNP, biomarker Phase 3 multicenter, randomized, open label, controlled study (150 sites in 25 countries; USA, South America, Europe, Asia) Stratification by: MSKCC prognostic risk group (favorable- vs intermediate- vs poor-risk) Number of prior anti-angiogenic therapy regimens in the advanced or metastatic setting (1 vs. 2) Region (US/Canada vs. W. Europe vs. Rest of World)

33 Adapt Trial

34 I AGS-003: Fully Personalized u otherapy Platfor Key Ele e ts Captures all antigens, including mutated Non-mutated antigens are ignored Expands only memory T-cells Known to correlate with good clinical outcome RCC patients are systemically immune suppressed Targeted immune response correlated with survival Overcomes tumor-induced immunosuppression Demonstrated mechanism of action 34

35 How is AGS-003 Produced for Each Patient? Overnight Shipment Overnight Shipment 1-2 Day Shipment RNA that encodes autologous RCC antigens is isolated and amplified from a small, fresh tumor sample (~200mg) isolated during nephrectomy Monocytes isolated from a single leukapheresis are differentiated into DCs The mature DCs are co-electroporated with RCC and CD40L RNA, vialed and frozen for shipment One production run yields up to five years of treatment per patient (~24 doses)

36 Pivotal Phase ADAPT Trial I itiati g H Pre-treatment Pre-treatment Diagnosis, Nephrectomy, Screening Registration; Leukapheresis (Arm A only) InductionInduction Arm A: AGS-003 (8 doses) plus Standard treatment* for 48 weeks (N = 300) Booster Booster SD AGS-003 quarterly + Standard treatment* until PD SD Standard treatment* until PD Stratification based upon number of baseline Heng risk factors (1, 2, 3, or 4) Arm B: Standard treatment* for 48 weeks (N = 150) * Standard treatment initiates with 6-week sunitinib cycles (50mg daily, 4 weeks on, 2 weeks rest.) Other compatible agents may be substituted for intolerance and/or early PD prior to week 48. Open-label design, no placebo-control or requirement for leukapheresis for Arm B subjects Primary endpoint: Overall Survival (80% power to detect HR=0.708) Additional endpoints: ORR, PFS, Immune response, Safety Initiating under SPA with FDA Global Study PIs: Robert Figlin, MD (Cedars-Sinai); Christopher Wood, MD (MDACC) Collaboration with SUO-CTC in North America to support multidisciplinary efforts

37 How to Further improve survival? Avoid resistance to VEGF inhibition Understand tumor heterogeneity Targeted Immunotherapy New Targets

38 Rationale for combining MET and VEGFR inhibition

39 Cabozantinib (cmet and VEGFR-2 inhibitor)

40 Cabozantinib

41 Cabozantinib Bone scan changes in RCC

42 Cabozantinib Resolving RCC lytic bone lesions

43 METEOR study

44 Prostate Cancer

45 Unprecedented progress: approved drugs post docetaxel Trial/ Agent/ Mechanism Date Approved Comparator Hazard Median OS Ratio (Months) p-value TROPIC1 Cabazitaxel 2010 Cytotoxic Mitoxantrone Prednisone vs 12.7 < COU-AA-3012 Abiraterone 2011 CYP17 inhibitor Placebo Prednisone vs 10.9 < AFFIRM3 Enzalutamide 2012 Androgen receptor signalling inhibitor Placebo vs 13.6 < de Bono JS, et al. Lancet 2010;376(9747): de Bono JS, et al NEJM 2011;364(21): Scher HI, et al. NEJM 2012;367(13):

Genomic Complexity in CRPC 50 patients: Rapid Autopsy Program Prostate carcinogensis involves the hijacking/alteration of multiple processes/pathways.

46 Genomic Complexity in CRPC 50 patients: Rapid Autopsy Program Prostate carcinogensis involves the hijacking/alteration of multiple processes/pathways. Advanced prostate cancer: Next Generation Sequencing - DNA repair - AR signaling - ETS gene rearrangements - PTEN loss & PI3K/AKT - P53 mutation 9 genes significantly mutated + 3 others without described roles in prostate cancer Grasso AS et al, Nature 2012 July (7406)

47 Genomic Complexity This genomic complexity makes targeting multiple proteins/pathways/networks necessary to maximally impact CRPC Examples: Targeting AR signaling and PI3K/AKT/TOR signaling in CRPC Targeting MEK and AKT in RAS driven cancers de Bono J, ESMO education 2012

48 Abiraterone inhibits CYP17: α-hydroxylase/17,20-lyase ACTH (with prednisone) Pregnenolone CYP17: 17α-hydroxylase 17OH-pregnenolone CYP17: C17,20-lyase DHEA Deoxycorticosterone Corticosterone Aldosterone Abiraterone 11-deoxycortisol Cortisol Abiraterone Testosterone Androstenedione Oestradiol ACTH=adrenocorticotropic hormone; CYP=cytochrome P450; DHEA=dehydroepiandrostenedione.. Attard G, et al. J Clin Oncol ; :

Abiraterone Phase 3 study: Post-docetaxel Phase

abiraterone + prednisone versus placebo +

endpoint: OS Secondary endpoints: Time to PSA

Abiraterone 1000 mg QD + prednisone 5 mg BID

chemotherapy regimens, 1 with docetaxel 2:1

49 Abiraterone Phase 3 study: Post-docetaxel Phase 3, double-blind placebo-controlled trial of abiraterone + prednisone versus placebo + prednisone in mcrpc post-chemotherapy Primary endpoint: OS Secondary endpoints: Time to PSA progression, radiographic PFS, PSA response Abiraterone 1000 mg QD + prednisone 5 mg BID (n=797) n=1195 progressive mcrpc Failed 1 or 2 chemotherapy regimens, 1 with docetaxel 2:1 Placebo BID + prednisone 5 mg BID (n=398) de Bono J, et al. N Engl J Med 2011;364:

Overall survival: Second pre-planned analysis Median benefit 4.6 months 100 HR=0.74 (95% CI,0.638 0.859) p<0.0001 26% reduction in risk of death Survival (%) 80 Abiraterone + prednisone: 15.

50 Overall survival: Second pre-planned analysis Median benefit 4.6 months 100 HR=0.74 (95% CI, ) p< % reduction in risk of death Survival (%) 80 Abiraterone + prednisone: 15.8 months Placebo: 11.2 months 20 Median follow-up 20.2 months 0 0 Abiraterone (n) 797 Placebo (n) Time to death (Months) Fizazi K, et al. Lancet Oncol ; :.

AR=androgen receptor; DHT=dihydrotestosterone; ERK=extracellular signal-regulated kinase; mtor=mammalian target of rapamycin;

51 CRPC remains driven by androgen receptor signalling AR splice variants2 AR overexpression2 AR mutants2 PI3K/AKT/ERK/mTOR Androgen production by adrenal glands and prostate tumor2 AR T/DHT PI3K/AKT/ERK/mTOR NUCLEUS Upregulation of AR Signaling cross-talk1,2 cofactors1,2 AR=androgen receptor; DHT=dihydrotestosterone; ERK=extracellular signal-regulated kinase; mtor=mammalian target of rapamycin; PI3K=phosphatidylinositol-3 kinase; T=testosterone. 1. Heinlein CA, Chang C. Endocr Rev 2004;25: ; 2. Hu R et al. Expert Rev Endocrinol Metab 2010;5:

52 Enzalutamide Enzalutamide is an AR signalling inhibitor (ARSI) 2. Impairs nuclear translocation 1. Blocks AR binding CYTOPLASM DHT ENZALUTAMIDE AR 3. Blocks DNA binding and activation NUCLEUS ENZALUTAMIDE ENZALUTAMIDE Tran C, et al. Science 2009;324:

Enzalutamide Phase 3 study: AFFIRM Post-docetaxel Phase 3, double-blind

chemotherapy Primary endpoint: OS Secondary endpoints: Radiographic PFS, time

chemotherapy regimens, 1 with docetaxel Enzalutamide 160 mg QD (n=800) 2:1

53 Enzalutamide Phase 3 study: AFFIRM Post-docetaxel Phase 3, double-blind placebo-controlled trial of enzalutamide versus placebo in mcrpc post chemotherapy Primary endpoint: OS Secondary endpoints: Radiographic PFS, time to first SRE, time to PSA progression n=1195 progressive mcrpc Failed 1 or 2 chemotherapy regimens, 1 with docetaxel Enzalutamide 160 mg QD (n=800) 2:1 Placebo QD (n=399) No corticosteroids required Scher HI, et al. N Engl J Med 2012;367:

54 AFFIRM overall survival: Median benefit 4.8 months HR=0.631 (95% CI: 0.529, 0.752) p< % reduction in risk of death 100 OS (%) 80 Enzalutamide: 18.4 months (95% CI: 17.3 NYR) Placebo: 13.6 months (95% CI: ) No. at risk: Enzalutamide (n) Placebo (n) Duration of OS (months) Scher HI, et al. N Engl J Med 2012;367:

55 CROSS RESISTANCE

56 Both abiraterone and enzalutamide work after two lines of chemotherapy COU-AA-3011 (Abiraterone vs Placebo) AFFIRM2 (Enzalutamide vs Placebo) Median OS after 1 prior line chemotherapy (months) 17.1 vs 11.7 NR vs 14.2 Median OS after 2 prior lines chemotherapy (months) 14.2 vs vs Fizazi, et al. Lancet Oncol Lancet Oncol Oct;13(10): Scher, et al. N Engl J Med 2012;367:

Short response to 1st line ADT predicts poor response abiraterone & enzalutamide 108 mcrpc patients after failure of primary ADT Treated with secondary hormonal manipulations: Abiraterone, DES,

57 Short response to 1st line ADT predicts poor response abiraterone & enzalutamide 108 mcrpc patients after failure of primary ADT Treated with secondary hormonal manipulations: Abiraterone, DES, ketoconazole, enzalutamide Median duration of response to primary ADT: 16 months [0 118] Duration of response to ADT PSA response PFS rate (median) o ths < 16 months p-value 58% 18% <0.043 ADT: Androgen deprivation therapy. DES: Diethylstilbestrol. mcrpc: Metastatic castration-resistant prostate cancer. PFS: Progression-free survival. PSA: Prostate-specific antigen Loriot Y & Fizazi K, J Clin Oncol 2012;30 (suppl. 5),abstract 213

58 Cross Resistance in mcrpc Phase I/II data of abiraterone then docetaxel: diminished benefit from subsequent docetaxel treatment OS: 12.5 months vs months for docetaxel in the TAX327 study 1,2 No responses to docetaxel were seen in abiraterone-refractory patients In a study evaluating 35 patients treated with abiraterone followed by docetaxel, activity of docetaxel post-abiraterone was lower than anticipated with no treatment responses.1 In contrast, similar patients recruited at the same institution receiving first-line docetaxel, prior to enrollment in the COU-AA-301, showed responses to docetaxel similar to TAX327 data Antitumor activity of docetaxel following abiraterone1 26% Expected first-line activity of docetaxel2 45% Median time to PSA progression 4.6 months months OS 12.5 months 18.9 months % PSA decli e 1. Mezynski J, et al. Ann Oncol 2012;23: ; 2. Tannock IF, et al. J Clin Oncol 2004;351:

$Cross Resistance A study of 44 patients found that those who were refractory to first-line docetaxel were also refractory to second-line abiraterone PSA$

59 Cross Resistance A study of 44 patients found that those who were refractory to first-line docetaxel were also refractory to second-line abiraterone PSA Change at Week 12 on Abiraterone Acetate Docetaxel stopped due to toxicity Docetaxel refractory All other patients Mukherji D, et al. J Clin Oncol. 2012;30(5):17.

60 PSA Response with Abiraterone after Progression with Enzalutamide Potential for cross resistance among newer hormonal agents Multicenter review of 30 patients with mcrpc treated with abiraterone acetate and prednisone after progressing on enzalutamide 50% decline in PSA: 60% of patients on enzalutamide; 3% of patients receiving subsequent abiraterone Best PSA of Patients on MDV3100 Best PSA on AA in Pts Progressing on MDV3100 In patients progressing after enzalutamide, treatment with abiraterone is associated with a modest response rate and brief duration of effect Noonan KL, et al. Ann Oncol 2013; April 12 epub

$fall in abiraterone in 3/38 patients (8%; 95% CI: 2-21%) Modest antitumour activity of abiraterone in both enzalutamide refractory and sensitive subgroups Suggests blockade of increased hormone$

61 Antitumor Activity of Abiraterone Against mcrpc Progressing Post Docetaxel and Enzalutamide Retrospective analysis of 38 mcrpc patients given abiraterone post-docetaxel and enzalutamide > 50% PSA fall in abiraterone in 3/38 patients (8%; 95% CI: 2-21%) Modest antitumour activity of abiraterone in both enzalutamide refractory and sensitive subgroups Suggests blockade of increased hormone synthesis alone post-enzalutamide imparts limited clinical benefit Enzalutamide Non-Sensitive Sensitive (n=17) (n=21) Maximum PSA change on abiraterone Enzalutamide Treatment Median duration; mos (range) 6 (2-12) 12 (2-24) Median % PSA drop (range) 10 (0-16) 80 (50-100) 4 (1-13) 3 (1-7) 1 (6) 2 (10) Abiraterone Treatment Median duration; mos (range) >50% PSA drop; n(%) Loriot Y, Ann of Onc 2013; April 10 epub

62 Antitumour Activity of Abiraterone Against mcrpc Progressing Post Docetaxel and Enzalutamide Median PFS: 2.7 months (95% CI ) PFS of patients treated with abiraterone post enzalutamide Median OS: 7.2 months (95% CI 5.0 NR) OS of patients treated with abiraterone post enzalutamide Results are lower than those expected from the COU-AA-301 study of post-docetaxel abiraterone, suggesting the possibility of cross-resistance between abiraterone and enzalutamide Loriot Ann of Onc 2013; April 10 epub

63 Available choices in Italy in mcrpc in 2013 Both cabazitaxel and abiraterone available, but what is the optimal sequence? Docetaxel followed by: Cabazitaxel or abiraterone initially? Abiraterone or cabazitaxel in third line? Cabazitaxel pre- or post-abiraterone? Does androgen signalling blockade affect the effectiveness of taxanes?

64 In prostate cancer cells, taxanes inhibit AR nuclear transport and signalling Inhibition of the androgen receptor as a novel mechanism of taxol chemotherapy in prostate cancer1 Gan L, et al. Masonic Cancer Center, University of Minnesota, Minneapolis, USA Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer2 Zhu ML, et al. University of Kentucky College of Medicine, Lexington, USA Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer3 Darshan MS, et al. Weill Cornell Medical College of Cornell University, New York, USA Does androgen signalling blockade impede the effectiveness of taxanes? If so, how strong is the effect? 1. Gan, et al. Cancer Res 2009;69: Zhu, et al. Cancer Res 2010;70: Darshan, et al. Cancer Res 2011;71:

Decreased efficacy of docetaxel in chemonaïve mcrpc post-abiraterone? TAX3271 (Docetaxel q3w) Phase I II2 (Abiraterone Docetaxel) PSA Decrease 50% 45% 26% Median Time to PSA Progression (months) 7.

65 Decreased efficacy of docetaxel in chemonaïve mcrpc post-abiraterone? TAX3271 (Docetaxel q3w) Phase I II2 (Abiraterone Docetaxel) PSA Decrease 50% 45% 26% Median Time to PSA Progression (months) Median Overall Survival (months) chemo-naïve mcrpc patients treated with docetaxel following disease progression with abiraterone 1. Tannock IF, et al. N Engl J Med 2004;351: Mezynski J, et al. Ann Oncol Nov;23(11):2943-7

Predictive factors of response to abiraterone Factor OR (95% CI) Number of prior CT lines : 1 vs >1 0.55 (0.35 0.85) Gleason 6/7 vs 8 10 0.60 (0.39 0.

66 Predictive factors of response to abiraterone Factor OR (95% CI) Number of prior CT lines : 1 vs > ( ) Gleason 6/7 vs ( ) Gleason score 8 10 and >1 CT line predictive of non-response to abiraterone ABI: Abiraterone. CT: Chemotherapy. CI: Confidence interval. OR: Odds ratio Azria D, et al. J Clin Oncol 2012;30(suppl 5, abstr 149)

67 Pre-chemotherapy Phase III trial of abiraterone in asymptomatic or mildly symptomatic mcrpc 1,000 patients with asymptomatic or mildly symptomatic metastatic CRPC Chemo-naïve Stratified by ECOG performance status (0 vs 1) R A N D O M I Z E Abiraterone 1,000 mg daily Prednisone 5 mg twice daily TREAT UNTIL PROGRESSION Placebo daily Prednisone 5 mg twice daily 2:1 Primary endpoint: 50% improvement in radiologic progression-free survival 25% improvement in overall survival

Interim analysis results of rpfs AA + P (median, mos): NR PL + P (median, mos): 8.3 HR (95% CI): 0.43 (0.35 0.52) p-value: < 0.

68 Interim analysis results of rpfs AA + P (median, mos): NR PL + P (median, mos): 8.3 HR (95% CI): 0.43 ( ) p-value: < Data cutoff 12/20/2010 AA: Abiraterone acetate. CI: Confidence interval. HR: Hazard ratio. NR: Not reached. P: Prednisone. PL: Placebo. rpfs: Radiological progression-free survival Ryan, et al. N Engl J Med 2013;368:138 48

Interim analysis results of OS AA + P (median, mos): NR PL + P (median, mos): 27.2 HR (95% CI): 0.75 (0.61 0.93) p-value: 0.

69 Interim analysis results of OS AA + P (median, mos): NR PL + P (median, mos): 27.2 HR (95% CI): 0.75 ( ) p-value: Data cutoff 12/20/2011 Pre-specified significance level by O Brien-Fleming Boundary = AA: Abiraterone acetate. CI: Confidence interval. HR: Hazard ratio. NR: Not reached. P: Prednisone. PL: Placebo. OS: Overall survival Ryan, et al. N Engl J Med 2013;368:138 48

Updated analysis results of OS Subjects Without

95) p=0.0151 Pre-specified p for significance: 0.

1 months Months From Randomisation Second interim

Third interim analysis: 56% death2 Ryan, et al.

70 Updated analysis results of OS Subjects Without Death (%) Overall Survival HR=0.79 (95% CI: ) p= Pre-specified p for significance: AA + P 35.3 months PL + P 30.1 months Months From Randomisation Second interim analysis: 43% death1. Third interim analysis: 56% death2 Ryan, et al. NEJM 2013;368: Rathkopf DE, et al. J Clin Oncol 2013;31(Suppl 6:abstr 5) presented at ASCO GU

71 Interim Analysis COU-AA-302: Subsequent therapy Abiraterone + Prednisone Placebo + Prednisone (N=546) (N=542) n (%) n (%) No. with selected subsequent therapy for mcrpc 242 (44.3) 327 (60.3) Docetaxel 207 (37.9) 287 (53.0) Cabazitaxel 45 (8.2) 52 (9.6) Ketoconazole 39 (7.1) 63 (11.6) Sipuleucel-T 27 (4.9) 24 (4.4) Abiraterone 26 (4.8) 54 (10.0) mcrpc: Metastatic castrate-resistant prostate cancer Ryan, et al. N Engl J Med 2013;368:138 48

72 Conclusions Improve survival in mrcc - understanding mechanisms of action, resistance and sequence and eventual combinations Improve survival in mcrpc - understanding mechanisms of action, resistance, sequence and combinations

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