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On behalf of the TROPIC Investigators

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).

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On behalf of the TROPIC Investigators

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  1. 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. Sartor Royal 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 On behalf of the TROPIC Investigators TROPIC was sponsored by Sanofi-Aventis

  2. 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. 2

  3. Disclosures

  4. The Unmet Medical Need in mCRPC • Standard of care in first-line mCRPC is docetaxel¹ • 19.2 months median overall survival (OS) with docetaxel vs16.3 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.

  5. 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.

  6. R A N D O M I Z E mCRPC patients progressing during and after treatment with a docetaxel-based regimen (N=755) • Stratification factors • ECOG PS (0, 1 vs 2) • Measurable vs non-measurable disease • 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 TROPIC:Study Design—146 Centers in 26 Countries cabazitaxel 25 mg/m² q 3 wk+ prednisone* for 10 courses (CBZP) (n=378) mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 courses (MP) (n=377) *Oral prednisone/prednisolone: 10 mg daily.

  7. 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 7

  8. Main Eligibility Criteria • mCRPC patients with documented disease progression* • If measureable: (RECIST) progression • If non-measurable : Documented rising PSA levels (at least2 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.

  9. Summary of Patient Characteristics *PSA: Prostate-specific antigen.

  10. Pre-Protocol Treatments

  11. Pre-Protocol Treatments

  12. Treatment Exposure on Study

  13. 100 80 60 28% reduction in risk of death 40 Censored MP 20 CBZP Combined medianfollow-up: 13.7 months 0 0 6 12 18 24 30 Numberat Risk MP CBZP Primary Endpoint:Overall Survival—Updated ITT Analysis* Proportion of OS (%) Time (months) 377 378 299 321 195 241 94 137 31 60 9 19 * Data cut-off 3/10/2010

  14. 0 0.5 1 1.5 2 Overall Survival—Updated Subgroup Analysis *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.

  15. 100 80 60 40 Censored MP 20 CBZP Combined medianfollow-up: 13.7 months 0 0 3 6 9 12 15 18 21 Time (months) Numberat Risk MP CBZP Progression-Free Survival 25% reduction in risk of progression Proportion of PFS (%) 377 378 117 168 55 92 30 55 12 18 9 6 6 1 4 1

  16. Secondary Endpoints:Response Rate and Time to Progression (TTP) *Determined only for subjects with at baseline measurable disease, PSA ≥20 ng/ml, or pain, respectively.NR=Not reached.

  17. Most Frequent Treatment-EmergentAdverse Events* *Sorted by ≥2% incidence rate for grade ≥3 events in the cabazitaxel arm.

  18. Hematological Results *Prophylactic use of G-CSF was permitted except for cycle 1 of treatment at the discretion of the investigator. • 58% grade ≥3 neutropenia in MP arm of the TROPIC study compares to 22% reported for the TAX 327 (first-line) study

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

  20. 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

  21. TROPIC Study: Countries and Investigators • 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 • 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 • 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 Thank you to all the patients and their families

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