1. Locallyadvanced prostate cancer: Multimodalitytreatment and new drugscombinedwithradiotherapy Stéphane Supiot, MD, PhD Department of Radiation Oncology Integrated Center of Oncology (ICO) René Gauducheau INSERM U892, Nantes

2. Combined modality treatments External beam radiotherapy + ADT Radical prostatectomy ± RT Investigational Neo-adj, concurrent or adjuvant chemotherapy Targeted therapies pre-operative strategies Jones et al J Am Coll Surg,1995;180:545-554 Outline

3. Randomized trials comparing RT vs RT + ADT RT + ADT = standard treatment in LAPC Martin JM, Supiot S & Berthold D, Drugs in press

4. Improving results in locally advanced cancer : Treating Local and Distant Disease Endothelialcells Immune cells Stromalcells Resistanttumorcells Sensitive tumorcells

5. New drugs + RT NEOADJUVANT CONCURRENT ADJUVANT Thoms & Bristow. Seminars in Radiation Oncology 2010

6. New drugs + RT NEOADJUVANT CONCURRENT ADJUVANT Additive : Treatingmicrometastatic cancer Thoms & Bristow. Seminars in radiation oncology 2010

7. New drugs + RT NEOADJUVANT CONCURRENT ADJUVANT Additive : Treatingmicrometastatic cancer Synergistic : modifyingtumorradiosensitivity Thoms & Bristow. Seminars in radiation oncology 2010

8. New drugs + RT NEOADJUVANT CONCURRENT ADJUVANT Additive : Treatingmicrometastatic cancer Synergistic : modifyingtumorradiosensitivity Synergistic : modifyingtumormicroenvironment Thoms & Bristow. Seminars in radiation oncology 2010

9. Targetingradioresistancemechanismswithconventionalchemotherapy Resistanttumorcells

10. Phase I/II RT + LHRH + chemotherapy

11. De Bono, Lancet 2010 Nextsteps : Cabazitaxel Adjuvant Docetaxel phase III studies(CALGB and GETUG 12) : results in 2011-2012

12. Targetingradioresistantcells : DNA repairtargeting agents and RT Choudhury et al, Seminars in radiation oncology 2006

13. DNA repairtargeting agents and RTPreclinicalresults in prostate cancer models ABT 888 Imitanib KU55953 Liu et al., Rad & Oncol 2008 Choudhury et al, Mol Cancer Ther 2009 RT + DNA repairinhibitors : No clinicalstudiesyet Prima-1 Nutlin-3 CP-31398 UCN-01, CYC-202 Flavopiridol BMS-387032 CEP-3891 -Supiot et al., Rad & Oncol 2008 -Supiot et al, Mol Cancer Ther 2008

14. Targeting the micro-environment Endothelialcells Immune cells Stromalcells

15. Improving immune responsefollowingradiotherapy no chemo-inducedimmunosuppresion in early-stage prostate cancer Radiotherapystimulates expression of tumorantigens Abscopaleffect ? Sipuleucel-T Kantoff et al., NEJM 2010

16. Asmase - / - Asmase + / + Antiangiogenicdrugs and radiotherapy Garcia-Barros et al., Science 2003 Winkleret al., Cancer Cell, 2004

17. Antiangiogenictherapiesmaylead to hypoxia ? Hypoxia ? Mazeronet al., Cancer TreatRev 2011

18. Hypoxia & prostate cancer The whole prostate ishypoxic Hypoxia = resistance to prostate radiotherapy Weak hypoxia 100 80 60 Freedom from biochemical failure (%) 40 HIF-1α 20 Severe hypoxia 0 0 1 3 4 2 6 5 10 11 12 8 7 9 Time from randomisation(years) Score 3 Score 4 Score 0-2 Parker et al., IJROBP 2004 Vergis et al., Lancet Oncol, 2008

19. ADT reduceshypoxia ADT = p02 One of the explanations of the radiosensitizingproperties of ADT ? 22 pts Bicalutamide 150 mg 3 m Milosevic et al., Cancer Res, 2007

20. New drugs targeting the AR : Effects combined with prostate cancer irradiation ? Effect on the tumormicroenvironment ? No expectedtoxicity ? Vanek N, et al., Radiotherapyenhances the toxicity of aminoglutethimide, Med PediatrOncol. 1990;18(2):162-4 Attard G et al. Clin Cancer Res 2011

21. Targeting the tumorand the micro-environment Endothelialcells Immune cells Stromalcells Resistanttumorcells Sensitive tumorcells

22. Targeting the PI3K/AKT/mTOR pathway p110α mutations : 30% of patients PTEN mutation/loss : up to 60 % of patients PTEN KO mice : develop PIN Sarker D et al.ClinCancer Res 2009

23. PI3K/AKT/mTOR inhibition + RT : effects on tumorcells and vasculature Normalization of vasculaturethroughinhibition of oncogenicsignaling Evolimusradiosensitizes PTEN null prostate cancer cells Cao et al.. Cancer Res 2006 Qayum N, et al.. Cancer Res, 2009. NCT00943956: Everolimus, Bicalutamide, and Leuprolide Acetate in Treating Patients Undergoing Radiation Therapy For High-Risk LAPC

25. + concurwith radiation for 7.5 weeks MTD not reached Grade 3 liver Transaminase tox : 6 pts Joensuu et al. A phase I/II trial of gefitinibgivenconcurrentlywithradiotherapy in patients withnonmetastatic prostate cancer. Int J RadiatOncolBiolPhys (2010)

26. Novelstrategies in LAPC ?

27. Role of surgery in LAPC “Our results also suggest a need for a surgical arm in future trials of therapy for high-risk cancers. Zelefsky M J et al. JCO 2010

28. Adjuvant Radiotherapy after Surgery “It isrecommendedthat patients shouldbeoffered adjuvant externalbeamradiotherapy“ Thoms et al., Nature Reviews ClinOnc 2010 Pickles T et al;, Guroc consensus, Can Urol Assoc J 2008

29. Patients athighrisk of post-opertaivemargins :Preoperativeradiotherapy ? Thoms et al, Nature Reviews ClinOnc 2011

30. * post post pre pre Proliferation (MIB1) Apoptosis (ISEL) Translational relevance of preop RTApplicable for testing new drugs +preop RT ? post RT pre RT p21 p16 Permanent cell cycle arrest No apoptosis Supiot et al. A phase I trial of pre-operativeradiotherapy for prostate cancer: clinical and translationalstudies. RADIOTHERAPY AND ONCOLOGY 2008

31. Conclusion : How to design phase I studiescombining new targeted agents + RT in LAPC ? RT prostate ADT

32. Conclusion : Dose of prostate RT ? RT prostate 70 or 80 Gy ? Fixed dose of RT ? Or escalating dose of RT and fixed dose of drug ? ADT Implications in terms of GI and GU toxicity

33. Conclusion : Targeting the pelvis ? RT pelvis ? Or Extendedlymphadenectomy ? RT prostate ADT Implications in terms of GI toxicity

34. Conclusion : Whichcombination ? RT pelvis ? RT prostate ADT concurrent Neo adjv adjuvant + : lesstoxic - : no synergy + : synergism - : toxicity + : effect on microenvironment ? +: lesstoxicity ? - : no synergy ?

36. Cancer stem cells

37. Poorimaging techniquesRT pelvis ? RT prostate HT concurrent Neo adjv adjuvant Dose escalationbased on acute toxicity ? Latetoxicity ? Deutsch E, et al., New concepts for phase I trials: evaluating new drugscombinedwith radiation therapy, Nat Clin PractOncol. 2005

39. New effective treatments for metastatic patients = new doors for patients with locally advanced PC