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PARP Inhibition: A New Approach To Cancer Therapy? Dr. Geert Kolvenbag Date 1 Potential Conflict of Interest • Employee and Shareholder / 1988 – AstraZeneca Date 2 PARP Inhibition: A New Therapeutic Approach? Geert J.C.M. Kolvenbag MD PhD Global Product Vice President AstraZeneca Targeting DNA Repair in Oncology DNA damage occurs all the time in all cells Why is DNA repair a good target? DNA repair defects lead to increased cancer susceptibility and increased sensitivity to DNA damaging agents Normal cells have multiple DNA repair pathways but some are lost in cancer cells Inhibiting DNA repair in cancer cells that have impaired repair pathways leads to selective cell killing and an increased therapeutic ratio Inducing Synthetic Lethality in Cancer Cells Normal Cell Pre-cancerous Cell Full complement of repair pathways DNA damage leads to continuous activation of pathway A AB AB Cancer Cell Alternative DNA repair pathways available B AB Pathway B inhibitor Selective pressure loss of pathway A, genetic instability, reliance on pathway B Death Survival AB B Cancer Cells are Highly Susceptible to DNA Repair Inhibition Cancer cells Undergo deregulated proliferation less time for DNA repair than in normal cells Grow under stress, which causes ongoing DNA damage Have DNA repair defects mutator phenotype allow growth despite ongoing genome instability Are reliant on the DNA repair pathways they still retain Focus on DDR Pathways for SSBs/DSBs Type of damage: Singlestrand breaks (SSBs) Doublestrand breaks (DSBs) Bulky adducts O6alkylguanine Insertions & deletions Mismatch repair Repair pathway: Base excision repair Repair enzymes: PARP Recombinational repair HR NHEJ ATM BRCA DNA-PK Nucleotideexcision repair XP, MSH2, poly- MLH1 merases Direct reversal AGT Mechanisms of Action of Olaparib PARP olaparib SSBs increased by dacarbazine, temozolomide and topotecan Replicating cells Mechanism 2: Potentiation DSBs increased by platinums Normal cell Repair by Homologous Recombination Survival Cancer cell with HRD Mechanism 1: Tumor specific killing by olaparib No effective repair (No HR pathway) Cell death Hypothesis In situations where the DNA repair is compromised inhibition of PARP will lead to synthetic lethality of the cell DNA repair factors deficient in functioning: BRCA gene deficient in genotype or phenotype Other Homologues Recombination Repair factors deficient in functioning (HRD) , eg ATM, MDC1, MRE11 In presence of DNA damaging agents Chemotherapy Radiotherapy Olaparib: An oral inhibitor of Poly (ADP-ribose) Polymerase (PARP) IC50 on PARP-1 = 4.9 nM IC50 on PARP-2 ≈ 5nM IC50 on PARP-3 ≈ 50nM IC50 on Tankyrase >1M O N N O N F N O • olaparib (AZD2281; KU-0059436) • Favorable PK • Good bioavailability across species • Tumor PK -Significant levels at 24 hrs following single oral dose Does the PARP inhibition result in therapeutic effects In vitro In vivo Clinical response Increased Sensitivity of BRCA1-/- and BRCA2-/- Cells to PARP Inhibition BRCA2+/+ BRCA1+/+ BRCA2+/- BRCA1+/BRCA1-/- BRCA2-/- No difference in sensitivity between heterozygous and wild-type BRCA cells Targeted inhibition selective and less toxic therapy Farmer et al. Nature 2005; 434:917-21 BRCA 1 & 2 -/- ES Cells are Very Sensitive to PARP Inhibition -1 -2 Wild type BRCA2 +/BRCA2 -/- -3 -4 0 10-9 10-8 10-7 10-6 10-5 10-4 PARP inhibitor concentration (M) Mean number of chromatid aberrations per cell 0 Log surviving fraction Increased levels of chromosomal aberrations in PARP inhibitor treated BRCA2 -/- cells 4 3 Complex aberrations 2 Chromatid breaks 1 0 WT WT BRCA-/- BRCA2-/+ PARPi + PARPi Farmer et al. Nature 2005; 434:917-21 KU95 Cell Line Panel: Olaparib Sensitivity Olaparib IC50 data by tumor type RAD51 DNA damage induced foci HRD and Sensitive HR Proficient and Resistant HRD is Strongly Linked with Cancer Breast Ovarian H&N NSCLC BRCA1 ATM BRCA2 MDC1 BRCA1 ATM BRCA2 Mre11 ATM Mre11 Mre11 BRCA TN Breast FANC CHK2 ATM MDC1 Serous Ovarian BRCA MDC1 ATM /MRE11 GI, HCC Mre11 Head & Neck ATM /MRE11 Pancreas Paediatrics BRCA1 FANC BRCA2 NSCLC MDC1 CRC MRE11 CFA Analysis of Breast Cancer Lines using Olaparib 25 cell lines from the Slamon breast cancer panel Olaparib IC50 LOG [µM] 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 1 10 0.1 Non-luminal / basal (n=7) Non-luminal / post-EMT (n=11) 0.01 0.001 Luminal (n=7) Alan Lau; Richard Finn & Dennis Slamon Response to Olaparib by HR Status Triple Negative cell lines (n=14) %Sensitive (< 1µM) %Insensitive HRD (n=12) %Sensitive (< 1µM) %Insensitive 25.00 43.75 56.25 75.00 ER-, PR -, Her2+ cell lines (n=11) %Sensitive (< 1µM) %Insensitive 22.22 77.78 HR proficient (n=13) %Sensitive (< 1µM) 0.00 100.00 %Insensitive Olaparib Inhibits Growth of HRD Tumors in vivo MDA-MB-231 (HR proficient) MDA-MB-468 (HRD) 5.0 4.0 Vehicle AZD2281 4.0 Vehicle AZD2281 3.5 Mean relative tumour volume Mean relative tumour volume 4.5 3.5 3.0 2.5 2.0 1.5 1.0 3.0 2.5 2.0 1.5 1.0 0.5 0.5 0.0 0.0 0 2 4 6 8 10 12 Time (days) 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Time (days) MDA-MB-231 (HR proficient) and MDA-MB-468 (HRD) triple-negative cells were implanted s.c. on the flank of female nude mice. At tumour volumes of 100-200mm3, mice were treated with vehicle or olaparib (100mg/kg) administered IP once daily (n=8 for each group). Data are presented as mean relative tumour volume (mean RTV) and error bars represent SEM. Aaron Cranston (KuDOS) & Richard Finn (UCLA) Olaparib in Spontaneous BRCA2-Deficient Tumors Relative Tumour Volumes 30 25 Vehicle PARPi qdx28 i.p. 50mg/kg RTV 20 Mean RTV day 28 = 15.3 15 10 5 Mean RTV day 28 = 1.20 0 0 5 10 15 Days after treatment 20 25 30 BRCA2-deficient KO Mice From Targeted Therapy to the Olaparib Phase I Study Oral, small molecule PARP inhibitor IC50 for PARP1 enzyme in the low nM range Phase I trial began at RMH then NKI; later expanded to other centres Escalation phase: All tumor types Primary objectives of safety and tolerability Expansion phase: BRCA mutation carriers (HR deficient) especially ovarian cancer Further assessment of efficacy Overall Recruitment Escalation Phase (n=46)1,2 Various tumor types; BRCA carrier status not mandatory 10 dose level cohorts: 10mg daily given for 2 out of 3 weeks 600mg bid continuous dosing 11 BRCA carrier ovarian cancer Expansion phase (n=52) at 200mg bid continuous2 Confirmed BRCA mutation carriers 39 ovarian cancer 1Fong 2Yap et al. Proceedings of ASCO 2006 et al. Proceedings of ASCO 2007 Demographics BRCA-Mutated Ovarian Cancer Subpopulation Characteristics BRCA1 / BRCA2 / Family history Median age (range) ECOG PS 0-1 Median duration from diagnosis to treatment (range) Platinum status Sensitive (PD > 6 months after platinum) Resistant (PD ≤ 6 months after platinum) Refractory (PD on platinum or on completion of platinum) Median no. of prior systemic therapies (range) Number 41 / 8 / 1 52 (37-80) yrs 47 4.7 (0.5–16) yrs 10 27 13 3 (1-8) Toxicities first 60 patients, all tumor types) Most toxicities were Grade 1-2 (≥95%) Most common toxicities were: nausea 28%, vomiting 18%, dysgeusia 13%, anorexia 12% fatigue 28% Grade 3-4 toxicities were rare: myelosuppression (≤5%) nausea and vomiting (2-3%) CNS: dizziness or mood changes (2-3%) Pattern of toxicity similar in BRCA mutation carriers Dose Limiting Toxicities (DLT) Dose (mg)/ Schedule Tumour type 400 bid continuous Ovarian Ca 600 bid continuous Mesothelioma 600 bid continuous Breast Ca DLT Outcome G3 low mood and Resolved within 24 hours of drug discontinuation G3 fatigue G4 thrombocytopenia G3 somnolence Recurred with re-challenge Resolved 2 weeks after drug discontinuation Resolved within 24 hours of drug discontinuation G1 on lower dose Maximum Tolerated Dose (MTD) = 400mg bid Response to 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%) 6 (13%) 1 (10%) 4 (16%) 1 (9%) 24 (10-77) 23 (16-77) 24 (10-65) 26 (20-32) No. of evaluable patients SD (> 4 cycles) Median duration of response in weeks (range) Platinum-free interval (months) Platinum Sensitivity Correlated with Response to Olaparib 24 Resistant Sensitive Refractory 18 12 6 0 CR/PR SD >4 months PD 23 mm Ovarian BRCA1-/- 12 mm 6.8 mm Breast BRCA? 21.05.07 03.04.07 6.5 mm 3 mm Olaparib Resistance Pre-clinical Over expression of pgp (olaparib is pgp substrate) Reactivating BCRA mutation Clinical Todate no evidence of PARP inhibitor resistence Note: Platinum resistence has been shown due to reactivating BRCA mutation Olaparib Overcoming Drug Resistance Pre-clinical Overcome TMZ resistence Potentiation of chemotherapy, e.g. TMZ Clinical No data yet Summary AZD2281 is a potent inhibitor of PARP and has impressive clinical activity in BRCA patients with breast and ovarian cancer The drug has additional potential to benefit a larger group of patients with HRD tumors Patient selection is key to the success of this project and is a paradigm for personalized health care The development of biomarkers and a diagnostic are complex but pivotal to: Delivery of the right drug, at the right dose to the right patient Acknowledgements The patients and their families Royal Marsden Hospital Janet Hanwell Dimitrios Magkos Netherlands Cancer Institute Jana van der Sar Marja Voogel Edinburgh Cancer Centre UZ Brussel Oncologisch Centrum International Hereditary Cancer Centre, Poland Jan Lubinski Cancer Research UK Institute of Cancer Research/ Breakthrough Breast Cancer Research UK Andrew Tutt Pei-Jun Wu Alan Ashworth AstraZeneca John Stone Mark O’Connor Helen Swaisland Peter Mortimer Jim Carmichael Clinical teams Theradex UK FECS/AACR/ASCO Methods in Clinical Cancer Research Workshop, Flims, 2005