Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer

1
Phase II trial of the oral PARP inhibitor
olaparib (AZD2281) in BRCA-deficient advanced
ovarian cancer

• MW Audeh,1 RT Penson,2 M Friedlander,3 B Powell,4
  KM Bell-McGuinn,5 C Scott,6 JN Weitzel,7 J
  Carmichael8 and A Tutt9

1Cedars-Sinai Cancer Center, Los Angeles,
CA 22DF/HCC and Massachusetts General Hospital,
Boston, MA, USA 3Prince of Wales Cancer Center,
Randwick, Sydney, New South Wales,
Australia 4University of California, San
Francisco, CA, USA 5Memorial Sloan-Kettering
Cancer Center, New York, NY, USA 6The Royal
Melbourne Hospital, Victoria, Australia 7City of
Hope Comprehensive Cancer Center, Duarte,
California, USA 8AstraZeneca, Macclesfield, UK
9Kings College London School of Medicine, Guy's
Hospital, London, UK
Study ID KU36-58 D0810C00009
2
Poly(ADP-Ribose) Polymerase (PARP)
A key regulator of DNA damage repair processes
3
PARP inhibition and tumor-selective synthetic
lethality
DNA damage (SSBs)
PARP inhibition
PARP
DNA replication(accumulation of DNA DSBs)
HR-mediated DNA repair
Impaired HR- mediated DNA repair
Cell survival
Cell death
Tumor-selective cytotoxicity
Farmer H et al. Nature 2005434917921 Bryant
HE et al. Nature 2005434913917 McCabe N et
al. Cancer Res 20066681098115
DSB, double-strand break HR, homologous
recombinationSSB, single-strand break
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BRCA tumor-selective killing
BRCA1 or BRCA2 Carrier Normal tissue
BRCA1 or BRCA2 Carrier Tumor tissue
DNA DAMAGE
DNA DAMAGE
HR NHEJ SSA BER NER etc
HR NHEJ SSA BER NER etc
x
Tutt A et al. Cold Spring Harb Symp Quant Biol
200570139148 McCabe N et al. Cancer Res
20066681098115
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Olaparib A novel, orally active PARP inhibitor

• A Phase I trial identified olaparib (AZD2281
  KU-0059436) 400 mg bid as the maximum tolerated
  dose1 with a 28 (13/46 pts) response rate
  (RECIST) in BRCA-mutated ovarian cancer2

• Most common toxicities CTCAE grade 1 and 2
  nausea and fatigue
• Significant PARP inhibition and tumor response at
  olaparib doses 100400 mg bid

1. Yap T et al. J Clin Oncol 200725(18S)abst
3529 2. Fong P et al. J Clin Oncol
200826(15S)abst 5510
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Study design

• An open-label, single-arm, multicenter Phase II
  study

Recurrent (stage IIIB/IIIC/IV) ovarian cancer
after failure of 1 prior platinum based
chemotherapy
Sequential cohorts

• Patients
• Confirmed germline BRCA1 or BRCA2 mutation
• Measurable disease
• ECOG performance status 02

MTD, maximum tolerated dose (determined during
Phase I evaluation)
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Study endpoints

• Primary
• Objective response rate (ORR)
• Complete response (CR) partial response (PR)
  by RECIST
• Secondary endpoints included
• Progression-free survival (PFS)
• Response by either RECIST or GCIG (CA-125)
  criteria ( gt50 reduction in CA125)
• Safety and tolerability

GCIG, Gynecologic Cancer Intergroup RECIST,
Response Evaluation Criteria in Solid Tumors
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Patient characteristics
Olaparib400 mg bid(n33) Olaparib100 mg bid(n24)
AgeMedian (years)Range 54 3574 56 3969
Race, n ()CaucasianAshkenazi Jewish 31 (94)9 (27.3) 22 (92)2 (8.3)
BRCA mutation status, n ()BRCA1BRCA2 21 (64)12 (36) 19 (79) 5 (21)
ECOG status0/1/2 21/12/0 15/6/3
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Patient characteristics
Olaparib400 mg bid(n33) Olaparib100 mg bid(n24)
Time since diagnosisMedian (months)Range 40.3 15193 45.6 14134
No. of prior systemic therapiesMedian Range 3 110 4 116
Platinum status, n ()Sensitive (PD gt6 months after last platinum)Resistant (PD 6 months after last platinum) 7 (21)26 (79) 8 (33)16 (67)
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Efficacy
Olaparib400 mg bid(n33)




11 (33) 20 (61) 290 126513
RECIST response rate, n () Responders by
RECIST and/or GCIG criteria, n () Duration of
response Median (days) Range
ITT analysis
Confirmed responses there were an additional 3
unconfirmed responders in the 400 mg cohort
(unconfirmed ORR 42) Duration of response is
underestimated as some patients are still
responding
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Summary of best RECIST response
n () Olaparib400 mg bid(n33)
Complete response
Partial response
Stable disease
Progressive disease
Not evaluable
2 (6) 9 (27) 11 (33) 9 (27) 2 (6)
ITT analysis Confirmed responses there were
an additional 3 unconfirmed responders in the 400
mg cohort
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Best change from baseline in target lesions
100
Olaparib 400 mg bid cohort
80
BRCA1
BRCA2
60
40
Increasing tumor shrinkage
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Best change from baseline
0
-20
-40
-60
-80
-100
Figure includes 3 unconfirmed responses. Data
are not included for 2 patients as they had no
RECIST data and subsequently died
13
Changes in serum CA-125
Olaparib 400 mg bid cohort

BRCA1
BRCA2
Best change from baseline
Truncated values ( change gt100) Data are not
included for 4 patients 2 patients had no RECIST
data and subsequently died, and there were no
baseline CA-125 data for 2 patients
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Response by platinum sensitivity
Olaparib 400 mg bid
Platinumresistant
Platinumsensitive
Total
Evaluable patients Responders by RECIST
33 11 (33)
7 1 (14)
26 10 (38)
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Progression-free survival
Median PFS (95 CI)
Olaparib 400 mg 5.8 (2.412) months
No. of patients at risk
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Most frequently reported AEs
n () Olaparib400 mg bid(n33) Olaparib400 mg bid(n33) Olaparib100 mg bid(n24) Olaparib100 mg bid(n24)
n () Any grade Grade 3/4 Any grade Grade 3/4
Nausea 21 (64) 2 (6) 15 (63) 3 (13)
Fatigue 17 (52) 1 (3) 13 (54) 0
Diarrhea 12 (37) 0 7 (29) 0
Vomiting 11 (33) 2 (6) 6 (25) 2 (8)
Abdominal pain 9 (27) 1 (3) 4 (17) 1 (4)
25 reported in either cohortCTCAE, Common
Terminology Criteria for Adverse Events
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Dose adjustments and discontinuations
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Overall summary

• Olaparib 400 mg bid po has confirmed single-agent
  activity in advanced, heavily pre-treated BRCA1
  or BRCA2 carriers with ovarian cancer
• Objective response rate (RECIST) 33 and/or GCIG
  61
• Median PFS 5.8 months
• Median duration of response 9.6 months
• Both doses were well tolerated in this patient
  population
• Side effects predominantly CTCAE grade 2
• Tolerability in BRCA1/BRCA2 carriers was similar
  to that reported previously in non-carriers

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Conclusions

• This study provides positive proof-of-concept of
  the activity and tolerability of
  genetically-defined targeted therapy with
  olaparib in BRCA1 or BRCA2 carriers with ovarian
  cancer
• Olaparib is also active and well tolerated in
  advanced chemotherapy-refractory BRCA1 or BRCA2
  carriers with breast cancer1
• Further studies are currently ongoing in this
  patient population

1. ASCO 2009 oral presentation Tutt A et al
(abst CRA501)
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Acknowledgements

• The patients and their families
• ICEBERG Trial Investigators
• Judy Garber, Niklas Loman, Karen Lu, Anna
  Oaknin, Rita Schmutzler
• with particular thanks to
• Ursula Matulonis, MD (Dana-Farber Cancer
  Institute)
• Beth Y Karlan, MD (Cedars-Sinai Cancer Center)
• BRCA carrier advocacy community
• FORCE

• Alan Ashworths Group, Breakthrough Breast Cancer
• Chris Lord, Hannah Farmer, Nuala McCabe
• KuDOS Pharmaceuticals/ AstraZeneca