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Amit M. Oza Professor of Medicine, Princess Margaret Hospital, University of Toronto Co-Chair Gynecology, NCIC CTG

NEW AGENTS ON THE HORIZON: IMPLICATIONS FOR PHASE I, II & III TRIALS DNA Repair and PARP inhibitors Carol Aghajanian, Nicoletta Colombo & Amit Oza Acknowledgements: Stan Kaye and AZ for slides. Amit M. Oza Professor of Medicine, Princess Margaret Hospital, University of Toronto

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Amit M. Oza Professor of Medicine, Princess Margaret Hospital, University of Toronto Co-Chair Gynecology, NCIC CTG

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  1. NEW AGENTS ON THE HORIZON: IMPLICATIONS FOR PHASE I, II & III TRIALSDNA Repair and PARP inhibitorsCarol Aghajanian, Nicoletta Colombo & Amit OzaAcknowledgements: Stan Kaye and AZ for slides Amit M. Oza Professor of Medicine, Princess Margaret Hospital, University of Toronto Co-Chair Gynecology, NCIC CTG

  2. Types of DNA damage and repair Type of damage: Single- strand breaks(SSBs) Double- strand breaks(DSBs) Bulky adducts O6- alkylguanine Insertions & deletions Mismatch repair Base excision repair Recombinational repair Repair pathway: Nucleotide- excision repair Directreversal HR NHEJ Poly ADP Ribose Polymerase Repair enzymes: ATM DNA-PK XP, poly-merases AGT MSH2,MLH1 BRCA

  3. PARP-1 is a key enzyme involved in the repair of single-strand DNA breaks DNA damage PARP PAR chains are degraded via PARG Binds directly to SSBs RepairedDNA NAD+ Nicotinamide+pADPr Repair enzymes PAR Once bound to damaged DNA, PARP modifies itself producing large branched chains of PAR

  4. DNA SSB PNK 1 XRCC1 pol β LigIII Inhibition of PARP-1 prevents recruitment of repair factors to repair SSB PARP Replication (S-phase) DNA DSB Inhibiting PARP-1 increases double-strand DNA damage

  5. Cancer cell death Cellsurvival Selective effect of PARP-1 inhibition on cancer cells with BRCA1 or BRCA2 mutation DSB in DNA Normal cell BRCA-deficient cancer cell DSB repaired effectively via HR pathway Deficient HR pathway – DSB not repaired

  6. x x Tumour Selective Synthetic Lethality HR deficient e.g. BRCA1/2-/- Normal or heterozygote for HR defect DNA DAMAGE DNA DAMAGE HRNHEJ SSABERNER etc HRNHEJ SSABERNER etc x PARPi PARPi Error prone repair Genomic instability Cell death Lethality

  7. RESPONSE TO AZD 2281, Parp inhibitor - OLAPARIB BY PLATINUM-FREE INTERVAL

  8. Strong family history Ovarian BRCA1-/- 23 mm

  9. Ovarian BRCA1-/- 12 mm 6.8 mm Breast BRCA? 21.05.07 03.04.07 3 mm 6.5 mm

  10. CORRELATION OF PLATINUM SENSITIVITY WITH RESPONSE TO OLAPARIB Resistant Sensitive Refractory Platinum-free interval (months) CR/PR SD >4 months PD

  11. SINGLE AGENT TREATMENT WITH OLAPARIB • Well tolerated oral therapy not associated with the typical toxicities of chemotherapy • Clear evidence of beneficial tumour response in BRCA mutated ovarian cancer patients • 46% (21/46 pts) response rate (RECIST or GCIG CA125) • 15% meaningful disease stabilisation • Total clinical benefit rate of 61% • Median response duration: 8 m • Randomized trials now underway

  12. POTENTIAL OF PARP INHIBITOR (SINGLE AGENT) IN SPORADIC OVARIAN CANCER Question: What proportion of ovarian cancer patients will have BRCA1/2 dysfunction, either due to mutation of either gene or for other reasons, e.g. methylation of this or related genes? Answer:•approx 15% of sporadic ovarian cancers have mutation of either gene; in serous histological subtypes, proportion is 18% • approx 15-20% more cases have BRCA dysfunction, through methylation, etc. • approx 10% have FANCF methylation Therefore: potentially half the cases of serous ovarian ca could benefit from targeted single agent treatment - how can these be identified?

  13. Phase I-II studies • Phase I: • Combination with - platinum, topotecan • Phase II: • Single agent BRCA +/- • Randomized Phase II/III • Post chemo consolidation/maintenance • Combination/maintenance • Carbo/taxol +/- Parp inhibitor

  14. Parp Inhibition • Compelling efficacy data in hereditary ovarian cancer patients • Studies in hereditary ovarian cancer. • High grade serous histology –“BRCAness” • Without BRCA mutations • Combination studies • Chemotherapy • Targeted agents

  15. PARP Inhibitors in Clinical Trials Adapted Ratnam K, Low JA Clin Cancer Res 2007;13: 1383-1388

  16. FURTHER DEVELOPMENT OF OLAPARIB - 1 R A N D O M I S E olaparib 400 mg bd cont Patients with advanced ovarian cancer with BRCA-1 or 2 mutations, relapsed within 12 months of platinum-based chemotherapy olaparib 200 mg bd cont caelyx/doxil 50 mg/m2 q4 weekly n = 90, recruitment complete primary end point = PFS statistical analysis: combined olaparib arms vs caelyx/doxil, aimed at detecting incr. in PFS from 4 m to 7.3 m (HR 0.55, 80% power)

  17. FURTHER DEVELOPMENT OF OLAPARIB - 2 R A N D O M I S E Patients with serous ovarian cancer, responding to 2nd or 3rd line platinum-based chemo, with CR/PR (penultimate treatment-free interval >6 m) olaparib 400 mg bd until PD placebo until PD n = 250 - BRCA mutation not necessary Primary end point: progression-free survival Recruitment now underway

  18. PATIENT SELECTION FOR SINGLE AGENT Predictive biomarker: • immunohistochemistry, with BRCA 1/2 antibodies • functional (ex vivo) test for loss of HR (RAD 51 foci-formation) • molecular signature (gene array) and/or: background of • repeated response to platinum-based chemo • prolonged survival (>5 yrs) • serous histology

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