Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 Co-Chair Gynecology, NCIC CTG Types of DNA damage and repair Type of damage: Singlestrand breaks (SSBs) Doublestrand breaks (DSBs) Bulky adducts O6alkylguanine Insertions & deletions Mismatch repair Repair pathway: Base excision repair Poly Repair ADP enzymes: Ribose Polymer ase Recombinational repair HR NHEJ ATM DNA-PK BRCA Nucleotideexcision repair XP, MSH2, poly- MLH1 merases Direct reversal AGT PARP-1 is a key enzyme involved in the repair of singlestrand DNA breaks DNA damage PAR chains are degraded via PARG PARP Binds directly to SSBs Repaired DNA NAD+ Nicotinamide +pADPr Repair enzymes PAR Once bound to damaged DNA, PARP modifies itself producing large branched chains of PAR Inhibiting PARP-1 increases double-strand DNA damage DNA SSB PNK 1 XRCC1 pol β LigIII PARP Inhibition of PARP-1 prevents recruitment of repair factors to repair SSB Replication (S-phase) DNA DSB Selective effect of PARP-1 inhibition on cancer cells with BRCA1 or BRCA2 mutation DSB in DNA Normal cell DSB repaired effectively via HR pathway Cell survival BRCA-deficient cancer cell Deficient HR pathway – DSB not repaired Cancer cell death Tumour Selective Synthetic Lethality HR deficient e.g. BRCA1/2-/- Normal or heterozygote for HR defect DNA DAMAGE HR NHEJ SSA BER NER etc x PARPi DNA DAMAGE HR NHEJ SSA BER NER etc x x PARPi Lethality Error prone repair Genomic instability Cell death RESPONSE TO AZD 2281, Parp inhibitor OLAPARIB BY PLATINUM-FREE INTERVAL Total Platinum sensitive Platinum resistant Platinum refractory 46 10 25 11 Responders by RECIST 13 (28%) 5 (50%) 8 (32%) 0 (0%) Responders by GCIG CA125 18 (39%) 8 (80%) 8 (32%) 2 (18%) Responders by either RECIST or GCIG criteria 21 (46%) 8 (80%) 11 (44%) 2 (18%) SD (> 4 cycles) 9 (15%) 1 (10%) 4 (16%) 1 (9%) 31 (10-96) 31 (16-96) 29 (10-84) 39 (27-51) No. of evaluable patients Median duration of response in weeks (range) Strong family history Ovarian BRCA123 mm/- Ovarian BRCA1-/- 12 mm 6.8 mm Breast BRCA? 21.05.07 03.04.07 6.5 mm 3 mm Platinum-free interval (months) CORRELATION OF PLATINUM SENSITIVITY WITH RESPONSE TO OLAPARIB 24 Resistant Sensitive Refractory 18 12 6 0 CR/PR SD >4 months PD 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 POTENTIAL OF PARP INHIBITOR (SINGLE AGENT) IN SPORADIC OVARIAN CANCER Question: Answer: Therefore: 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? • 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 potentially half the cases of serous ovarian ca could benefit from targeted single agent treatment - how can these be identified? Phase I-II studies Phase I: Phase II: Combination with - platinum, topotecan Single agent BRCA +/- Randomized Phase II/III Post chemo consolidation/maintenance Combination/maintenance Carbo/taxol +/- Parp inhibitor 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 PARP Inhibitors in Clinical Trials Agent Company Strategy AG014699 Pfizer Combination* KU59436 AstraZenecaKudos Single Oral ABT-888 Abbott Single Oral BSI-201 BiPar Single Combinations IV INO-1001 InotekGenentech Combination* IV MK Merck Single agent and combination Oral GPI 21016 MGI Pharma Combination* Oral Adapted Ratnam K, Low JA Clin Cancer Res 2007;13: 1383-1388 Administration IV FURTHER DEVELOPMENT OF OLAPARIB - 1 Patients with advanced ovarian cancer with BRCA-1 or 2 mutations, relapsed within 12 months of platinum-based chemotherapy R A N D O M I S E olaparib 400 mg bd cont 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) FURTHER DEVELOPMENT OF OLAPARIB - 2 Patients with serous ovarian cancer, responding to 2nd or 3rd line platinum-based chemo, with CR/PR (penultimate treatment-free interval >6 m) R A N D O M I S E olaparib 400 mg bd until PD placebo until PD n = 250 - BRCA mutation not necessary Primary end point: progression-free survival Recruitment now underway 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