Transcript Phase II trial of the oral PARP inhibitor olaparib

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
9King’s College London School of Medicine, Guy's Hospital, London, UK
Study ID: KU36-58; D0810C00009
Poly(ADP-Ribose) Polymerase (PARP)
A key regulator of DNA damage repair processes
PARP inhibition and tumor-selective
synthetic lethality
DNA damage (SSBs)
PARP
PARP inhibition
DNA replication
(accumulation of DNA DSBs)
Normal cell
with functional HR
pathway
HR-deficient tumor
cell (e.g. BRCA 1/2-/-)
HR-mediated
DNA repair
Cell survival
Cell death
Impaired HRmediated
DNA repair
Tumor-selective cytotoxicity
DSB, double-strand break; HR, homologous recombination
SSB, single-strand break
Farmer H et al. Nature 2005;434:917–921
Bryant HE et al. Nature 2005;434:913–917
McCabe N et al. Cancer Res 2006;66:8109–8115
BRCA tumor-selective killing
BRCA1 or BRCA2 Carrier
BRCA1 or BRCA2 Carrier
Normal tissue
Tumor tissue
DNA DAMAGE
HR NHEJ SSA BER NER etc
x
DNA DAMAGE
HR NHEJ SSA BER NER etc
x
x
Lethality
Tutt A et al. Cold Spring Harb Symp Quant Biol 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115
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 100–400 mg bid
1. Yap T et al. J Clin Oncol 2007;25(18S):abst 3529; 2. Fong P et al. J Clin Oncol 2008;26(15S):abst 5510
Study design
An open-label, single-arm, multicenter Phase II study
Cohort 1
Olaparib 400 mg po bid (MTD)
Recurrent (stage IIIB/IIIC/IV)
ovarian cancer after failure
of ≥1 prior platinum based
chemotherapy
Sequential
cohorts
(28-day cycles)
(n=33)
Cohort 2
Olaparib 100 mg po bid
(28-day cycles)
(n=24)
Patients
• Confirmed germline BRCA1 or BRCA2 mutation
• Measurable disease
• ECOG performance status 0–2
MTD, maximum tolerated dose (determined during Phase I evaluation)
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 ( >50% reduction in CA125)
• Safety and tolerability
GCIG, Gynecologic Cancer Intergroup; RECIST, Response Evaluation Criteria in Solid Tumors
Patient characteristics
Olaparib
400 mg bid
(n=33)
Olaparib
100 mg bid
(n=24)
54
35–74
56
39–69
Race, n (%)
Caucasian
Ashkenazi Jewish
31 (94)
9 (27.3)
22 (92)
2 (8.3)
BRCA mutation status, n (%)
BRCA1
BRCA2
21 (64)
12 (36)
19 (79)
5 (21)
ECOG status
0/1/2
21/12/0
15/6/3
Age
Median (years)
Range
Patient characteristics
Time since diagnosis
Median (months)
Range
No. of prior systemic therapies
Median
Range
Platinum status, n (%)
Sensitive (PD >6 months after last platinum)
Resistant (PD ≤6 months after last platinum)
Olaparib
400 mg bid
(n=33)
Olaparib
100 mg bid
(n=24)
40.3
15–193
45.6
14–134
3
1–10
4
1–16
7 (21)
26 (79)
8 (33)
16 (67)
Efficacy
Olaparib
400 mg bid
(n=33)
Olaparib
100 mg bid
(n=24)
RECIST response rate, n (%)*
11 (33)
3 (13)
Responders by RECIST
and/or GCIG criteria, n (%)
20 (61)
4 (17)
290
126–513
269
169–288
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
Summary of best RECIST response
Olaparib
400 mg bid
(n=33)
Olaparib
100 mg bid
(n=24)
Complete response*
2 (6)
0
Partial response*
9 (27)
3 (13)
Stable disease
11 (33)
7 (29)
Progressive disease
9 (27)
12 (50)
Not evaluable
2 (6)
2 (8)
n (%)
ITT analysis
* Confirmed responses; there were an additional 3 unconfirmed responders in the 400 mg cohort
Best % change from baseline
in target lesions
100
Olaparib 400 mg bid cohort
80
BRCA1
BRCA2
60
40
Best %
change from
baseline
Increasing tumor shrinkage
20
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
Changes in serum CA-125
Olaparib 400 mg bid cohort
100
80
60
* *
BRCA1
BRCA2
40
20
Best %
change from
baseline
0
-20
-40
-60
-80
-100
*Truncated values (% change >100%)
Data are not included for 4 patients; 2 patients had no RECIST data and subsequently died, and there were no baseline CA125 data for 2 patients
Response by platinum sensitivity
Olaparib
400 mg bid
Evaluable patients
Responders by RECIST
Olaparib
100 mg bid
Evaluable patients
Responders by RECIST
Total
Platinum
sensitive
Platinum
resistant
33
7
26
11 (33%)
1 (14%)
10 (38%)
Total
Platinum
sensitive
Platinum
resistant
24
8
16
3 (13%)
2 (25%)
1 (6%)
Progression-free survival
Freedom from progression (%)
100
Median PFS (95% CI)
Olaparib 400 mg: 5.8 (2.4–12) months
Olaparib 100 mg: 1.9 (1.8–3.7) months
90
80
70
NB: Non-randomized sequential cohorts
60
50
40
30
20
10
0
0
50
100
150
200
250
300
350
400
450
500
550
600
PFS (days)
No. of patients at risk
400 mg: 33
31
20
17
15
13
11
8
6
4
4
3
0
100 mg: 24
19
8
5
4
3
2
1
1
0
0
0
0
Most frequently reported AEs*
Olaparib
400 mg bid
(n=33)
Olaparib
100 mg bid
(n=24)
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)
n (%)
*≥25% reported in either cohort
CTCAE, Common Terminology Criteria for Adverse Events
Dose adjustments and
discontinuations
Olaparib
400 mg bid
(n=33)
Olaparib
100 mg bid
(n=24)
Discontinuations due to AEs, n (%)
4 (12)
1 (4)
Dose interruption due to AEs, n (%)
12 (36)
4 (17)
Dose reduction due to AEs, n (%)
9 (27)
0
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
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)
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 Ashworth’s Group,
Breakthrough Breast Cancer
– Chris Lord, Hannah Farmer,
Nuala McCabe
• KuDOS Pharmaceuticals/
AstraZeneca