This document discusses multimodality treatments for locally advanced prostate cancer, including combining radiotherapy with androgen deprivation therapy or chemotherapy. It reviews randomized trials showing radiotherapy plus androgen deprivation is standard treatment. It also discusses investigating neoadjuvant, concurrent, or adjuvant chemotherapy or targeted therapies with radiotherapy to better treat micrometastatic disease and modify tumor radiosensitivity or microenvironment. Several agents targeting DNA repair, angiogenesis, hypoxia, and PI3K/AKT/mTOR pathways are discussed. Improving results may involve targeting the tumor and microenvironment with surgery and radiotherapy also discussed.

1. Locallyadvanced prostate cancer: Multimodalitytreatment and new drugscombinedwithradiotherapyStéphane Supiot, MD, PhDDepartment of Radiation OncologyIntegrated Center of Oncology (ICO) René GauducheauINSERM U892, Nantes

2. Combined modality treatmentsExternal beam radiotherapy + ADTRadical prostatectomy ± RTInvestigationalNeo-adj, concurrent or adjuvant chemotherapyTargeted therapiespre-operative strategiesJones et al J Am Coll Surg,1995;180:545-554Outline

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

4. Improving results in locally advanced cancer : Treating Local and Distant DiseaseEndothelialcellsImmune cellsStromalcellsResistanttumorcellsSensitive tumorcells

5. New drugs + RTNEOADJUVANTCONCURRENTADJUVANTThoms & Bristow. Seminars in Radiation Oncology 2010

6. New drugs + RTNEOADJUVANTCONCURRENTADJUVANTAdditive : Treatingmicrometastatic cancer Thoms & Bristow. Seminars in radiation oncology 2010

7. New drugs + RTNEOADJUVANTCONCURRENTADJUVANTAdditive : Treatingmicrometastatic cancer Synergistic : modifyingtumorradiosensitivityThoms & Bristow. Seminars in radiation oncology 2010

8. New drugs + RTNEOADJUVANTCONCURRENTADJUVANTAdditive : Treatingmicrometastatic cancer Synergistic : modifyingtumorradiosensitivitySynergistic : modifyingtumormicroenvironmentThoms & Bristow. Seminars in radiation oncology 2010

9. TargetingradioresistancemechanismswithconventionalchemotherapyResistanttumorcells

10. Phase I/II RT + LHRH + chemotherapy

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

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

13. DNA repairtargeting agents and RTPreclinicalresults in prostate cancer modelsABT 888 ImitanibKU55953Liu et al., Rad & Oncol 2008Choudhury et al, Mol Cancer Ther 2009RT + DNA repairinhibitors : No clinicalstudiesyetPrima-1Nutlin-3CP-31398UCN-01, CYC-202FlavopiridolBMS-387032CEP-3891-Supiot et al., Rad & Oncol 2008-Supiot et al, Mol Cancer Ther 2008

14. Targeting the micro-environmentEndothelialcellsImmune cellsStromalcells

15. Improving immune responsefollowingradiotherapyno chemo-inducedimmunosuppresion in early-stage prostate cancerRadiotherapystimulates expression of tumorantigensAbscopaleffect ?Sipuleucel-TKantoff et al., NEJM 2010

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

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

18. Hypoxia & prostate cancerThe whole prostate ishypoxicHypoxia = resistance to prostate radiotherapyWeak hypoxia1008060Freedom from biochemical failure (%)40HIF-1α20Severe hypoxia00134265101112879Time from randomisation(years)Score 3Score 4Score 0-2Parker et al., IJROBP 2004Vergis et al., Lancet Oncol, 2008

19. ADT reduceshypoxiaADT = p02One of the explanations of the radiosensitizingproperties of ADT ?22 ptsBicalutamide 150 mg 3 mMilosevic 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):162-4Attard G et al. Clin Cancer Res 2011

21. Targeting the tumorand the micro-environmentEndothelialcellsImmune cellsStromalcellsResistanttumorcellsSensitive tumorcells

22. Targeting the PI3K/AKT/mTOR pathwayp110α mutations : 30% of patientsPTEN mutation/loss : up to 60 % of patientsPTEN KO mice : develop PIN Sarker D et al.ClinCancer Res 2009

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

24. EGFR targetingGefitinib : 250 mg/d 7 daysneo adjuvant

25. + concurwith radiation for 7.5 weeks MTD not reachedGrade 3 liver Transaminase tox : 6 ptsJoensuu 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 2010Pickles 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. *postpostprepreProliferation(MIB1)Apoptosis(ISEL)Translational relevance of preop RTApplicable for testing new drugs +preop RT ?post RTpre RTp21p16Permanent cell cycle arrestNo apoptosisSupiot 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 prostateADT

32. Conclusion : Dose of prostate RT ?RT prostate70 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 prostateADT Implications in terms of GI toxicity

34. Conclusion : Whichcombination ?RT pelvis ?RT prostateADT concurrentNeo adjvadjuvant+ : lesstoxic- : no synergy+ : synergism- : toxicity+ : effect on microenvironment ?+: lesstoxicity ?- : no synergy ?

35. Conclusion : Whichtarget ? Which surrogate marker ? Problems :Heterogeneity of prostate cancer not reflected by biopsies

36. Cancer stem cells