1. 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 (Clinical Science Symposium)

2. 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.

3. 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.

4. 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): Copyright © 2009 Massachusetts Medical Society. All rights reserved

5. 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.

6. 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.

7. 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.

8. 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.