Audeh MW et al. ASCO 2009; Abstract 5500. (Clinical Science Symposium) Phase II Trial of the Oral PARP Inhibitor Olaparib (AZD2281) in BRCA-Deficient Advanced Ovarian Cancer Audeh MW et al. ASCO 2009; Abstract 5500. (Clinical Science Symposium)

Introduction Poly(ADP-ribose) polymerase (PARP) is a key regulator of the DNA damage repair process BRCA1/2-deficient cells are highly sensitive to PARP inhibition Olaparib is a novel, orally active PARP inhibitor 400 mg BID identified as the maximum tolerated dose (Yap et al. ASCO 2007) Phase I ORR (RECIST) = 28% in BRCA-mutated ovarian cancer (Fong et al. ASCO 2008) Current study objectives: Evaluate the objective response rate (ORR), progression-free survival (PFS) and safety of single-agent olaparib 400 mg BID and 100 mg BID in patients with BRCA1 or 2 mutations who have recurrent ovarian cancer whose disease has progressed on at least one prior platinum-based chemotherapy Source: Audeh MW et al. ASCO 2009; Abstract 5500.

Poly (ADP-Ribose) Polymerase (PARP): A Key Regulator of DNA Damage Repair Processes PARP: a key signaling enzyme involved in triggering the repair of single-strand DNA damage. PARP-1 acts to detect and signal the presence of DNA single-stranded breaks. Following the binding to sites of DNA damage, PARP-1 catalyses the cleavage of NAD+ into nicotinamide and ADP-ribose to produce highly charged branched chains of poly-ADP ribose that serve to recruit other repair enzymes and initiate repair. PARP inhibition has been demonstrated to selectively kill tumor cells lacking components of the homologous recombination (HR) DNA repair pathway while sparing normal cells. Known defects in HR repair include hereditary BRCA1 and BRCA2 mutations as well as nonhereditary BRCA mutations. Source: With permission from AstraZeneca Oncology. www.astrazenecaoncology.com/oncology-research/dna-repair-parp-inhibition.aspx

Mechanism of Cell Death from Synthetic Lethality Induced by PARP Inhibition In normal cells, both base-excision repair (BER) and homologous recombination (HR) are available for the repair of damaged DNA (A). In cells that have lost either BRCA1 or BRCA2, HR is nonfunctional, and BER and other DNA-repair processes can compensate for the loss of HR (B). In cells that have lost BER function because of PARP1 inhibition but retain at least one functioning copy of BRCA1 and BRCA2, HR is intact and can repair DNA damage, including damage left unrepaired because of the loss of BER (C). In the cancer cells of mutation carriers, all BRCA1 or BRCA2 function is absent, and when PARP1 is inhibited, cancer cells are unable to repair DNA damage by HR or BER, and cell death results. Source: With permission from Iglehart JD, Silver DP. NEJM 2009;361(2):189-91. Copyright © 2009 Massachusetts Medical Society. All rights reserved

Phase II Open-Label Single-Arm, Multi-Cohort Study Olaparib 400 mg BID (MTD) 28 day cycles (n = 33) Eligibility Recurrent (Stage IIIB/C or IV) ovarian cancer after failure of ≥ 1 platinum-based chemotherapy Confirmed BRCA1 or 2 mutation Sequential cohorts Cohort 2 Olaparib 100 mg BID 28 day cycles (n = 24) MTD = maximum tolerated dose (determined during Phase I evaluation) Source: Audeh MW et al. ASCO 2009; Abstract 5500.

Efficacy: Intent-to-Treat Analysis Endpoint Olaparib 400 mg BID (n = 33) 100 mg BID (n = 24) Overall response rate (ORR) by RECIST Complete response Partial response Stable disease 33% 6% 27% 13% 0% 29% ORR by RECIST and/or GCIG criteria (≥50% reduction in CA-125) 61% 17% ORR by platinum-sensitivity Platinum-sensitive (400mg n=7; 100mg n=8) Platinum-resistant (400mg n=26; 100mg n=16) 14% 38% 25% Duration of response (DOR)* 290 days 269 days Progression-free survival (median) 5.8 mos 1.9 mos * DOR is underestimated, since some patients are still responding Source: Audeh MW et al. ASCO 2009; Abstract 5500.

Safety: Most Frequently Reported Adverse Events (AEs)* Olaparib 400 mg BID (n = 33) Olaparib 100 mg BID (n = 24) Adverse event Any Grade Grade 3/4 Nausea 64% 6% 63% 13% Fatigue 52% 3% 54% 0% Diarrhea 37% 29% Vomiting 33% 25% 8% Abdominal pain 27% 17% 4% Dose adjustments and discontinuations due to AEs Discontinuation 12% Dose interruption 36% Dose reduction * ≥ 25% reported in either cohort Source: Audeh MW et al. ASCO 2009; Abstract 5500.

Summary and Conclusions Olaparib 400 mg BID has demonstrated single-agent activity in advanced, heavily pretreated BRCA1 or BRCA2 carriers with ovarian cancer ORR: 33% by RECIST; 61% by RECIST and/or GCIG criteria Median PFS: 5.8 mos Median duration of response: 9.6 mos Olaparib 400 mg BID and 100 mg BID were well tolerated Side effects predominantly Grade ≤ 2 Most frequent side effects: nausea, fatigue, diarrhea, vomiting and abdominal pain Positive proof-of-concept of the activity and tolerability of genetically-defined targeted therapy with olaparib in BRCA1 or BRCA2 carriers with ovarian cancer Further studies are ongoing in this patient population Source: Audeh MW et al. ASCO 2009; Abstract 5500.