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On behalf of the TROPIC InvestigatorsTROPIC was sponsored by Sanofi-Aventis

Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Final results of a multinational Phase III trial (TROPIC)

J. S. de Bono, S. Oudard, M. Ozguroglu, S. Hansen, J. P. H. Machiels,L. Shen, P. Matthews, A. O. SartorRoyal Marsden National Health Service Foundation Trust and Institute of Cancer Research, Sutton, Surrey; Oncologie Médicale, Hôpital Européen Georges Pompidou and Inserm U674 Génômique Fonctionnelle des Tumeurs Solides, Paris, France; Istanbul University, Istanbul, Turkey; Odense Universitets Hospital, Odense, Denmark; Université Catholique de Louvain Cliniques Universitaires Saint-Luc, Brussels, Belgium; sanofi-aventis Research, Malvern, PA; United Kingdom Tulane University, New Orleans, LA

Conflict of interest

• I have served as a paid consultant for Sanofi Aventis as well as multiple other pharmaceutical and biotechnology companies including Johnson & Johnson, Astellas, Medivation, Merck, AstraZeneca, Genentech, Roche, Pfizer, Novartis, Bristol Myers Squibb, Takeda.

• I am an employee of The Institute Of Cancer Research, London, which has a commercial interest in the development of abiraterone acetate which is also being evaluated in this setting.

• I am the co-Chief Investigator of the abiraterone acetate and MDV3100 Phase III clinical trials.

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Disclosures

Employment/Leadership position: The ICR

Consultant/Advisory role: Sanofi Aventis

Stock ownership: None

Honorarium: Sanofi Aventis

Research support: None

Expert testimony: None

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The Unmet Medical Need in mCRPC

• Standard of care in first-line mCRPC is docetaxel¹ – 19.2 months median overall survival (OS) with docetaxel vs

16.3 months with mitoxantrone– 21% reduction in risk of death (HR=0.79 [95% CI: 0.67–0.93],

P =.004)

• When progression on or after treatment withdocetaxel occurs²:– No currently approved standard second-line therapy– Treatment options include supportive care or investigational drugs– Palliation only, no OS benefit demonstrated

1. Berthold DR, Pond GR, Soban F, et al. J Clin Oncol. 2008;26(2):242-245.2. Garmey EG, Sartor O, Halabi S, et al. Clin Adv Hematol Oncol. 2008;6(2):118-1132.

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Cabazitaxel:A New Tubulin-Targeting Agent

• New semi-synthetic taxane– Selected to overcome the emergence of taxane resistance¹,²

• Preclinical data¹,²– As potent as docetaxel against sensitive cell lines and tumor models– Active against tumor cells/models resistant to currently available

taxanes

• Clinical data– In Phase I trials dose-limiting toxicity was neutropenia3

– Antitumor activity in mCRPC including docetaxel-resistant disease³

1. Attard G, Greystoke A, Kaye S, De Bono J. Pathol Biol (Paris). 2006;54(2):72-84.2. Pivot X, Koralewski P, Hidalgo JL, et al. Ann Oncol. 2008;19(9):1547-1552.3. Mita AC, Denis LJ, Rowinsky EK, de bono JS et al. Clin Can Res. 2009; Jan 15;15(2):723-30.

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TROPIC:Study Design—146 Centers in 26 Countries

*Oral prednisone/prednisolone: 10 mg daily.

mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 courses (MP)

(n=377)

cabazitaxel 25 mg/m² q 3 wk+ prednisone* for 10 courses (CBZP)

(n=378)mCRPC patients progressing during and after treatment with a

docetaxel-based regimen

(N=755)

RANDOMIZE

Premedication• Premedication in the cabazitaxel group:

antihistamine, steroid, and H₂ antagonist administered by IV infusion at least 30 minutes prior to each dose of cabazitaxel

• Antiemetic prophylaxis was administered when necessary

Stratification factors• ECOG PS (0, 1 vs 2)

• Measurable vs non-measurable disease

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Statistical Considerations• Objectives

– Primary objective: Overall survival (OS)– Secondary objective: PFS (objective tumor progression, pain progression, PSA

progression, or death from any cause), Response Rate, Safety

• Statistical plan– 90% power to detect a HR of 0.75; ITT analysis with a 2-side type I error of 0.05

required 511 deaths for a target significance level of 0.0452 accounting for interim analyses

• Final analysis at data cut-off September 25, 2009– 755 patients randomized– 513 deaths, 10 patients (3 CBZ/7 MP) were lost to follow-up

•Updated OS analysis at data cut-off March 10, 2010– 585 deaths, 15 patients (6 CBZ, 9MP) were lost to follow-up

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Main Eligibility Criteria

• mCRPC patients with documented disease progression*– If measureable: (RECIST) progression– If non-measurable : Documented rising PSA levels (at least

2 consecutive rises in PSA over a reference value taken at least1 week apart ) or appearance of new lesion

• Previous treatment with a docetaxel-containing regimen

• No previous treatment with mitoxantrone

• ECOG-PS: 0–2

• Normal organ function (CBC and serum chemistries)

*The protocol was amended after the first 59 patients were enrolled in order tomandate that eligible patients had to have received >225 mg/m² of docetaxel.

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MP (n=377) CBZP (n=378)

Age (years)

Median [range] 67 [47–89] 68 [46–92]≥65 (%) 57.0 64.9

ECOG PS (%)

0, 1 91.2 92.62 8.8 7.4

PSA* (ng/mL)

Median [range] 127.5 [2–11220] 143.9 [2–7842]Measurability of disease (%)

Measurable 54.1 53.2Non-measurable 45.9 46.8

Disease site (%)

Bone 87.0 80.2Lymph node 44.8 45.0Visceral 24.9 24.9

Summary of Patient Characteristics

*PSA: Prostate-specific antigen.

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Pre-Protocol Treatments

MP (n=377) CBZP (n=378)

Chemotherapy (%)

1 regimen 71.1 68.82 regimens 21.0 24.9≥3 regimens 8.0 6.3

Docetaxel-containing regimens administered (% patients)

1 regimen 86.7 83.62 regimens 11.4 14.0≥3 regimens 1.9 2.4

Total prior docetaxel dose (mg/m²)

Median 529.2 576.6Months from last docetaxel dose to progression

Median 0.70 0.80

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Pre-Protocol Treatments

MP (n=377) CBZP (n=378)

Total prior docetaxel dose

Median (mg/m²) 529.2 576.6 Median cycles 7 7% of patients per docetaxel dose

<225 mg/m² 8.0 7.7≥225 to 450 mg/m² 29.7 24.9≥450 to 675 mg/m² 27.9 29.6≥675 to 900 mg/m² 15.1 19.6≥900 mg/m² 18.0 17.5Unknown 1.3 0.8

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Treatment Exposure on Study

MP (n=371) CBZP (n=371)

Number of cycles

Median 4 6Range [1–10] [1–10]

Total cumulative dose (mg/m²)

Median 46.4 148.5Range [10.9–123.3] [22.5–258.4]

Relative dose intensity (%)

Median 97.3 96.1Cycles delayed (%)

Delay 7–9 days 4.7 5.1Dose reduction (%)

Cycles 5.1 9.8

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Primary Endpoint:Overall Survival—Updated ITT Analysis*

28% reduction in risk of death

Time (months)

Pro

po

rtio

n o

f O

S (

%)

377378

299321

195241

94137

3160

919

100

80

60

40

20

00 6 12 18 24 30

MP CBZP

Median OS (months) 12.7 15.1

Hazard ratio 0.72

95% CI 0.61–0.84

P-value <.0001

Numberat Risk

MP CBZP

CensoredMPCBZP

Combined medianfollow-up: 13.7 months

* Data cut-off 3/10/2010

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Overall Survival—Updated Subgroup Analysis

Factor SubgroupPatientNumber

Hazard ratio (95%CI)

favors CBZP favors MP

ITT population All patients 755 0.72 (0.61–0.84)

ECOG status 0,1 694 0.71 (0.60–0.84)

ECOG status 2 61 0.78 (0.46–1.33)

Measurable disease No 350 0.72 (0.56–0.92)

Measurable disease Yes 405 0.71 (0.57–0.88)

No. of prior chemo 1 528 0.71 (0.58–0.86)

No. of prior chemo ≥2 227 0.73 (0.54–0.99)

Age <65 295 0.81 (0.62–1.05)

Age ≥65 460 0.66 (0.53–0.81)

Rising PSA at baseline No 159 0.85 (0.60–1.20)

Rising PSA at baseline Yes 583 0.68 (0.56–0.82)

Total docetaxel dose* <225 mg/m² 59 1.02 (0.55–1,87)

Total docetaxel dose ≥225 to 450 mg/m² 206 0.61 (0.44–0.84)

Total docetaxel dose ≥450 to 675 mg/m² 217 0.81 (0.59–1.10)

Total docetaxel dose ≥675 to 900 mg/m² 131 0.77 (0.52–1.12)

Total docetaxel dose ≥900 mg/m² 134 0.57 (0.39–0.84)

Progression During last docetaxel treatment 219 0.71 (0.53–0.96)

Progression <3 months since last docetaxel dose 339 0.70 (0.56–0.89)

Progression ≥3 and <6 mos since last docetaxel dose 108 0.76 (0.48–1.20)

Progression >6 months since last docetaxel dose 84 0.77 (0.43–1.38)

0 0.5 1 1.5 2

*The protocol was amended after the first 59 patients were enrolled in order tomandate that eligible patients had to have received >225 mg/m² of docetaxel.

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Progression-Free Survival

Pro

po

rtio

n o

f P

FS

(%

)

377378

5592

1218

61

41

100

80

60

40

20

0Time (months)0 6 12 18 213 9 15

117168

3055

96

25% reduction in risk of progression

MP CBZP

Median PFS (months) 1.4 2.8

Hazard ratio 0.75

95% CI 0.65–0.87

P-value 0.0002

Numberat Risk

MP CBZP

CensoredMPCBZP

Combined medianfollow-up: 13.7 months

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Secondary Endpoints:Response Rate and Time to Progression (TTP)

MP (n=377) CBZP (n=378) Hazard ratio (95% CI) P-value

Tumor assessment

Response rate* (%) 4.4 14.4 – .0005

Median TTP (months) 5.4 8.8 0.61 (0.49–0.76) <.0001

PSA assessment

Response rate* (%) 17.8 39.2 – .0002

Median TTP (months) 3.1 6.4 0.75 (0.63–0.90) .001

Pain assessment

Response rate* (%) 7.8 9.2 – .6286

Median TTP (months) NR 11.1 0.91 (0.69–1.19) .5192

*Determined only for subjects with at baseline measurable disease, PSA ≥20 ng/ml, or pain, respectively.NR=Not reached.

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MP (n=371) CBZP (n=371)

All grades (%) Grade ≥3 (%) All grades (%) Grade ≥3 (%)

Any adverse event 88.4 39.4 95.7 57.4

Febrile neutropenia 1.3 1.3 7.5 7.5

Diarrhea 10.5 0.3 46.6 6.2

Fatigue 27.5 3 36.7 4.9

Back pain 12.1 3 16.2 3.8

Nausea 22.9 0.3 34.2 1.9

Vomiting 10.2 0 22.6 1.9

Hematuria 3.8 0.5 16.7 1.9

Abdominal pain 3.5 0 11.6 1.9

Most Frequent Treatment-EmergentAdverse Events*

*Sorted by ≥2% incidence rate for grade ≥3 events in the cabazitaxel arm.

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Hematological Results

MP (n=371) CBZP (n=371)

All grades (%) Grade ≥3 (%) All grades (%) Grade ≥3 (%)

Hematology

Anemia 81.4 4.9 97.3 10.5

Leukopenia 92.5 42.3 95.7 68.2

Neutropenia* 87.6 58.0 93.5 81.7

Thrombocytopenia 43.1 1.6 47.4 4.0

• 58% grade ≥3 neutropenia in MP arm of the TROPIC study compares to 22% reported for the TAX 327 (first-line) study

*Prophylactic use of G-CSF was permitted except for cycle 1 of treatment at the discretion of the investigator.

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Fatal Events—Update (cut-off date 3/10/10)

MP (n=371) CBZP (n=371)

Total deaths during study 304 (81.9%) 270 (72.8%)

Due to progression 264 (71.2%) 218 (58.8%)

Due to AE 7 (1.9%) 18 (4.9%)

Due to AE (N America, n=235) 1 (0.8%) 1 (0.9%)

Due to AE (Europe, n=402) 6 (3.0%) 10 (4.9%)

Due to other reasons 15 (4.0%) 12 (3.2%)

Cause unknown (> 3 mo following last dose)

11 (3.0%) 20 (5.4%)

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Conclusions

• Cabazitaxel demonstrated a statistically and clinically significantOS improvement compared with mitoxantrone in study population– 15.1 months vs 12.7 months– 28% reduced risk of death (HR=0.72, P <.0001)– OS benefit was consistent across subgroups

• Secondary endpoints of PFS, RR, and TTP also significantly improved

• Safety profile was manageable– Proactive management of side effects recommended (neutropenia/diarrhea)

Cabazitaxel is the first treatment to show a survival benefit in patients with mCRPC after failure of docetaxel-based therapy

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TROPIC Study: Countries and Investigators

Thank you to all the patients and their families

DENMARK G. Daugaard L. Sengelov S. Hansen

FINLAND P. Mali T. Marttila

FRANCE S. Oudard D. Pouessel G. Gravis F. Priou

GERMANY S. Muller B. Otremba P. De Geeter P. Albers S. Wille A. Heidenreich

HUNGARY I. Bodrogi

INDIA R. Sood R. Rangaraju B. Parikh N. Mohanty

ITALY F. Boccardo S. Bracarda S. Salvagni L. Dogliotti A. Sobrero

KOREA H.Y. Lim S.H. Lee H. Kim Y.J. Min

MEXICO S. De Leon-Jaen J. Lopez-Hernandez E. Martinez-Cruz

NETHERLANDS J. Coenen Wr. Gerritsen

RUSSIAN FEDERATION O. Karyakin

SINGAPORE A.H.T. Tan Toh Chee Keong

SLOVAKIA J. Mardiak

ARGENTINA L. Fein C. Bas

BELGIUM J.P. Machiels G. Pelgrims F. Van Aelst

BRAZIL J. Fleck M. Zereu E. Moreira D. Herchenhorn

CANADA A. Nabid S. North M. Mackenzie R. Segal H. Assi

CHILE H. Harbst P. Gonzalez A. Cordova F. Orlandi

CZECH REPUBLIC I. Kocak K. Cwiertka M. Kohoutek

SOUTH AFRICA A. Jordann D. Vorobiof G. Cohen J. Raats R. De Bruyne

SPAIN R. Bastus J. Perez D. Castellano N. Batista

SWEDEN I. Turesson M. Cwikiel

TAIWAN Y-S. Pu Y-C. Ou Y-H-W. Chang

TURKEY M. Ozguroglu B. Karabulut

UNITED KINGDOM J. de Bono A. Bahl J. Graham R. Jones Z. Malik A. Lydon S. Sundar

UNITED STATES B. Poiesz R. Alter B. Baltz J. Beck M. Cassidy F. Chu S. Divers M. Eisenberger D. Scott Ernst R. Singal J. Feldman N. Gabrail G. Gross J. Gurtler R. Giudice A. Koletsky J. Leach E. Lester J. Maher P. Rode Ch. Mccanless O. Melnyk R. Brito T. Neiderman R. Orlowski R. Reiling N. Savaraj D. Perry J.S. Smith C. Srodes J. Hajdenberg

UNITED STATES P. Van Veldhuizen G. Shumaker M. Cooney T. Flaig D. Gravenor B. Kasimis S. Tejwani M.E. Taplin Paul Monk M. Rarick D. Sahasrabudhe W. Dugan F. Millard F. Belette B. Mirtsching P. Dighe A. Ucar J. Wade K.D. Liem S. Dakhil I. Anderson W. Heim W. Butler A. Baron N. Gupta M. Dees O. Sartor