PAOLA-1 - Slide deck 2021.pptx

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PAOLA-1
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For reactive use. The information provided here includes details of indications that may be off-label and are for scientific medical exchange
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AT- 4720; 03/2021, expiry 03/2022
An ENGOT/GCIG Phase III trial of olaparib vs. placebo added to standard of care
bevacizumab as maintenance treatment in patients with advanced ovarian cancer
following response to first-line platinum-based chemotherapy plus bevacizumab

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Study design and patient population

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Despite curative intent, the majority of patients with advanced ovarian
cancer relapse following first-line multi-modal therapy
PFS=progression-free survival
1. Bookman MA, et al. J Clin Oncol. 2009;27:1419–1425; 2. Burger RA, et al. N Engl J Med. 2011;365:2473–2483; 3. Perren TJ, et al. N Engl J Med. 2011;365:2484–2496;
4. du Bois A, et al. Cancer. 2009;115(6):1234-1244; 5. Ledermann JA, et al. Ann Oncol. 2013;24(Suppl 6):vi24-32;
6. SEER Research Data. Available at: https://seer.cancer.gov/statfacts/html/ovary.html. Last accessed October 2019.
There is a significant need for better frontline treatment to improve outcomes
for women with ovarian cancer1-5
~70%
of women relapse within 3
years of first-line treatment4,5
29%
5-year survival rate6
10–18 months
Median PFS1–3
Platinum-based
chemotherapy
Bevacizumab
2

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Olaparib maintenance treatment has been investigated in newly
diagnosed advanced ovarian cancer in two Phase III studies
*Surgery may be upfront or interval debulking
†HRD-positive determined by tBRCAm or Myriad myChoice® CDx genomic instability score ≥42. HRD-negative determined by non-tBRCAm and Myriad myChoice® CDx genomic instability score <42
BRCAm=mutation in BRCA; CDx=companion diagnostic test; HRD=homologous recombination deficiency; tBRCAm=tumour BRCA mutation
1. Moore K, et al. N Engl J Med. 2018;379(26):2495-2505; 2. Study NCT02477644. Available at: https://clinicaltrials.gov/ct2/show/NCT02477644. Last accessed December 2019;
3. Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428; 4. Ray-Coquard I, et al. N Engl J Med. 2019;381:Supplementary appendix.
Surgery*
Any surgical outcome
Newly diagnosed
advanced ovarian cancer2-4
tBRCAm Non-tBRCAm
Any surgical outcome
Newly diagnosed
advanced ovarian cancer1
BRCAm
Chemotherapy Olaparib maintenance
Bevacizumab
Surgery*
Chemotherapy Olaparib maintenance
PAOLA-1
HRD-positive† HRD-negative†
3

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PAOLA-1: Olaparib maintenance in newly diagnosed advanced ovarian
cancer patients treated with chemotherapy and bevacizumab
N=762 patients were planned to be randomised in the study so that maturity of the PFS data is ~60%. 458 events will give >80% power, at 5% alpha, to show HR 0.75, mPFS from 15.8 months (control) to 21.1 months (olaparib)
*Also includes fallopian tube and primary peritoneal cancer.
†
Bevacizumab: 15 mg/kg, every 3 weeks for a total of 15 months, including when administered with chemotherapy.
‡By central labs
1L= first-line; BICR=blinded independent central review; BID=twice daily; BRCAm=mutation in BRCA; CDx=companion diagnostic test; CR=complete response; FIGO=Fédération Internationale de Gynécologie Obstétrique;
HRQoL=health-related quality of life; NED=no evidence of disease; OS=overall survival; PFS=progression-free survival; PFS2= time to second progression or death; PR=partial response;
PRO=patient-reported outcomes; RECIST=Response Evaluation Criteria in Solid Tumours; tBRCA=tumour BRCA; tBRCAm=mutation in tumour BRCA; TFST=time to first subsequent therapy
1. Ray-Coquard I, et al. N Engl J Med. 2019;381:Clinical Study Protocol; 2. Study NCT02477644. Available at: https://clinicaltrials.gov/ct2/show/NCT02477644. Last accessed December 2019.
Sponsored by ARCAGY research
• FIGO stage III–IV
high-grade ovarian
cancer (serous or
endometrioid)* or non
mucinous BRCAm
• Surgery
(upfront or interval)
• Platinum
taxane-based
chemotherapy
• ≥3 cycles of
bevacizumab
†
2:1 randomisation; N=806
Stratification by tBRCA status‡ and
1L treatment outcome
Primary endpoint
• Investigator-assessed PFS
(RECIST 1.1)
Sensitivity analysis by BICR
• TFST
• PFS2
• TSST
• OS
• Safety
• PRO/HRQoL
2 years’ maintenance treatment
Pre-specified exploratory endpoints
• PFS in pre-defined subgroups
including tBRCAm and Myriad
myChoice® CDx
Olaparib (300 mg BID) x 2 years
Placebo x 2 years
Secondary endpoints
NED/
CR/PR
+ bevacizumab
†
+ bevacizumab
†
4

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PAOLA-1 is an externally sponsored study, designed closely with the
academic community, to reflect clinical practice
*tBRCA status as per randomisation (tBRCAm vs. tBRCAwt/VUS/unk) and tBRCA status by Myriad myChoice® CDx (tBRCAm vs. non-tBRCAm)
†Tumour HRD status by Myriad myChoice® CDx (HRD-positive [tBRCAm and/or genomic instability score ≥42] vs. absence of HRD biomarker)
‡Tumour HRR-associated gene mutations including BRCAm by Myriad myChoice® CDx (HRRm vs non-HRRm)
1L=first-line; BRCAm=mutation in BRCA; CDx=companion diagnostic test; HRD=homologous recombination deficiency; HRRm=homologous recombination repair gene mutation;
SoC=standard of care; tBRCAm=mutation in tumour BRCA
1. Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428; 2. Ray-Coquard I, et al. N Engl J Med. 2019;381:Clinical Study Protocol; 3. Burger RA et al. N Engl J Med 2011;365:2473–83;
4. Gonzalez Martin A et al. N Engl J Med. 2019; 381:2391-2402; 5. Coleman RL, et al. N Engl J Med. 2019; 381:2403-2415; 6. Moore K, et al. N Engl J Med. 2018; 379:2495-2505
Active maintenance
bevacizumab
Representative 1L
patient population
Pre-specified biomarker
assessment
Unselected by biomarker status,
surgical outcomes and platinum
responses1
Pre-planned subgroup analyses by
tBRCAm,* HRD† and
HRRm‡ status1,2
Only Phase III study of a PARP
inhibitor with an active SoC
comparator1,3-6
5

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Additional efficacy endpoints were included to evaluate the effect of
olaparib plus bevacizumab beyond first progression
DCO=data cut-off; HRQoL=health-related quality of life; OS=overall survival; PFS=progression free survival; PFS2=time from randomisation to second progression or death;
TFST=time from randomisation to first subsequent therapy or death; TSST=time from randomisation to second subsequent therapy or death
Gonzalez-Martin A, et al. Presented at ESMO Virtual Congress 2020. 19-21 September. Abstract #LBA33
TSST
Platinum-based
chemotherapy
+ bevacizumab
First
subsequent
therapy
Other
treatments
Olaparib +
bevacizumab
Placebo +
bevacizumab
Death
PFS2
Primary endpoint
• Investigator-assessed
PFS
Secondary endpoints
• TFST
• PFS2
• TSST
• OS
• HRQoL
• Safety and tolerability
• PFS2 was immature at the time of primary PFS analysis (DCO 22 March 2019)
• The prespecified final PFS2 analysis was planned for ≈53% data maturity or
1 year after primary analysis (DCO 22 March 2020)
• PFS2 by biomarker status was a post hoc analysis
6

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A multiple testing procedure was employed in PAOLA-1
DCO=data cut-off; ITT=intent to treat; PFS=progression-free survival; PFS2=time to second progression or death; OS=overall survival; RECIST=Response Evaluation Criteria in Solid Tumours
1. Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428; 2. Ray-Coquard I, et al. N Engl J Med. 2019;381:Supplementary appendix;
3. Ray-Coquard I, et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain
4. Gonzalez-Martin A, et al. Presented at ESMO Virtual Congress 2020. 19-21 September. Abstract #LBA33; 5. Ray-Coquard I, et al. N Engl J Med. 2019;381:Clinical Study Protocol.
First patient in:
10 July 20151,2
Last patient in:
1 September 20173
Primary DCO:
22 March 20191
2015 2016 2017 2018 2019 2020
Final PFS2 DCO:
22 March 20204
PFS
PFS2
OS
Hierarchical testing procedure in the ITT3-5
Primary endpoint, tested at the 2-sided p<0.05
Final PFS2 at ~ 53% maturity (~411 events) or after a maximum duration of 1 year following the PFS analysis3
Final OS analysis ~60% maturity or after a 3-year duration from the main PFS analysis, whichever occurs first2
If statistically significant
If statistically significant
7

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Baseline patient characteristics were well balanced between arms
*No deleterious mutation, including tumour BRCA wild-type, a variant of uncertain significance, or an unknown result
†Neoadjuvant treatment may have included bevacizumab
CR=complete response; FIGO=Fédération Internationale de Gynécologie et d'Obstétrique; NED=no evidence of disease; PR=partial response
3. Ray-Coquard I, et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain.
Olaparib + bevacizumab
(n=537)
Placebo + bevacizumab
(n=269)
Age, median years (range) 61 (32–87) 60 (26–85)
tBRCAm status, n (%)
tBRCAm
No tBRCAm*
161 (30)
376 (70)
80 (30)
189 (70)
FIGO stage, n (%)
III
IV
378 (70)
159 (30)
186 (69)
83 (31)
History of cytoreductive
surgery, n (%)
Upfront surgery
Residual macroscopic disease
No residual macroscopic disease
271 (50)
111 (41)
160 (59)
138 (51)
53 (38)
85 (62)
Interval cytoreductive surgery†
228 (42)
65 (29)
163 (71)
110 (41)
35 (32)
75 (68)
No surgery 38 (7) 21 (8)
Response after surgery/platinum-
based chemotherapy, n (%)
NED
CR
PR
290 (54)
106 (20)
141 (26)
141 (52)
53 (20)
75 (28)
8

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Summary
1. Bookman MA, et al. J Clin Oncol. 2009;27:1419–1425; 2. Burger RA, et al. N Engl J Med. 2011;365:2473–2483; 3. Perren TJ, et al. N Engl J Med. 2011;365:2484–2496;
4. du Bois A, et al. Cancer. 2009;115(6):1234-1244; 5. Ledermann JA, et al. Ann Oncol. 2013;24(Suppl 6):vi24-32; 6. Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428
There is a significant need for better frontline treatment to improve outcomes for women with ovarian cancer1-5
PAOLA-1 is a Phase III trial investigating the addition of olaparib maintenance therapy (vs. placebo) to
bevacizumab in newly diagnosed advanced ovarian cancer patients treated with chemotherapy6
PAOLA-1 is designed closely with the academic community to reflect clinical practice6
Baseline patient characteristics were well balanced between arms6
9

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PFS in the ITT population
Data cut-off March 2019

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Olaparib plus bevacizumab significantly improved PFS vs. placebo plus
bevacizumab in the ITT population
PFS by investigator assessment. Analysis per eCRF. Data maturity=59%
Median duration of follow-up for primary analysis: olaparib, 22.7 months; placebo, 24.0 months
Data cut-off: 22 March 2019
Bev=bevacizumab; CI=confidence interval; eCRF=electronic case report file; HR=hazard ratio; inv=investigator-assessed; ITT=intent to treat; PFS=progression-free survival
1. Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428; 2. Ray-Coquard I, et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain.
PFS by BICR was consistent with investigator-assessed PFS, indicating robustness of the result
Olaparib +
bevacizumab
n=537
Placebo +
bevacizumab
n=269
Events, n (%) 280 (52) 194 (72)
Median PFS,
months (inv)
22.1 16.6
HR 0.59
95% CI 0.49–0.72
p<0.001
Median time from first cycle
of chemotherapy to
randomisation = 7 months2
Months since randomisation
537
269
513
252
461
226
433
205
403
172
374
151
279
109
240
83
141
50
112
35
55
15
37
9
12
1
3
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
1
0
0
Primary endpoint:
investigator-assessed PFS
Patients
free
from
disease
progression
and
death
(%)
100
80
60
40
20
0
No. at risk
Olaparib + bev
Placebo + bev
11

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Results of pre-specified PFS subgroup analyses evaluating clinical
characteristics were consistent with the primary PFS analysis
CI=confidence interval; CR=complete response; CT=chemotherapy; ECOG=Eastern Cooperative Oncology Group;
FIGO=Fédération Internationale de Gynécologie et d'Obstétrique; HR=hazard ratio; NED=no evidence of disease;
PFS=progression-free survival; PR=partial response
Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428.
Subgroup
Olaparib +
bevacizumab
Placebo +
bevacizumab
HR (95% Cl)
No. of events/no. of patients (%)
All 280/537 (52) 194/269 (72) 0.59 (0.49–0.72)
Age group
<65 years old 171/332 (52) 126/182 (69) 0.61 (0.49–0.77)
≥65 years old 109/205 (53) 68/87 (78) 0.55 (0.41–0.75)
FIGO stage
III 184/378 (49) 125/186 (67) 0.64 (0.51–0.80)
IV 96/159 (60) 69/83 (83) 0.49 (0.36–0.67)
ECOG baseline
0 193/378 (51) 132/189 (70) 0.63 (0.50–0.78)
1 85/153 (56) 61/76 (80) 0.51 (0.37–0.71)
Cytoreductive surgery outcome
Debulking surgery with no residual macroscopic disease 135/323 (42) 104/160 (65) 0.54 (0.42–0.71)
Debulking surgery with residual macroscopic disease 113/176 (64) 71/88 (81) 0.63 (0.47–0.85)
No debulking surgery 32/38 (84) 19/21 (90) 0.56 (0.32–1.01)
Timing of cytoreductive surgery
Upfront 116/271 (43) 92/138 (67) 0.52 (0.40–0.69)
Interval debulking 132/228 (58) 83/110 (75) 0.66 (0.50–0.87)
No debulking surgery 32/38 (84) 19/21 (90) 0.57 (0.32–1.02)
Response to first-line CT
NED 119/290 (41) 92/141 (65) 0.53 (0.40–0.70)
CR 54/106 (51) 42/53 (79) 0.44 (0.29–0.66)
PR 107/141 (76) 60/75 (80) 0.86 (0.63–1.19)
2
1
0.5
0.2
Placebo +
bevacizumab better
Olaparib +
bevacizumab better
12

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PFS in the HRD-positive patient population

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Approximately 50% of patients in PAOLA-1 were HRD-positive*
*HRD-positive determined by tBRCAm and/or Myriad myChoice® CDx genomic instability score ≥42
Reasons for HRD status unknown: 4.2% missing; 2.1% fail; 11.3% inconclusive
CDx=companion diagnostic test; HRD=homologous recombination deficiency; tBRCAm=mutation in tumour BRCA
Ray-Coquard I, et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain.
Around half of HRD-positive* patients were tBRCAm
tBRCAm
n=235; 29%
Genomic instability score ≥42,
excluding tBRCAm
n=152; 19%
HRD status unknown
n=142; 18%
HRD-negative n=277; 34%
HRD-positive*
n=387; 48%
14

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Baseline patient characteristics were also well balanced between arms
in the HRD-positive* subgroup
*HRD-positive defined as tBRCAm and/or Myriad myChoice® CDx genomic instability score ≥42
†Neoadjuvant treatment may have included bevacizumab
CDx=companion diagnostic; CR=complete response; FIGO=Fédération Internationale de Gynécologie et d'Obstétrique; HRD=homologous recombination deficiency;
NED=no evidence of disease; PR=partial response; tBRCAm=mutation in tumour BRCA
Ray-Coquard I, et al. N Engl J Med. 2019;381:Supplementary appendix
(n=255)
(n=132)
Age, median years (range) 58 (32–77) 58 (35–82)
tBRCAm status, n (%)
tBRCAm
No tBRCAm
150 (59)
105 (41)
65 (49)
67 (51)
FIGO stage, n (%)
III
IV
182 (71)
73 (29)
90 (68)
42 (32)
History of cytoreductive
surgery, n (%)
Upfront surgery
145 (57)
55 (38)
90 (62)
79 (60)
30 (38)
49 (62)
Interval cytoreductive surgery†
100 (39)
24 (24)
76 (76)
45 (34)
13 (29)
32 (71)
No surgery 10 (4) 8 (6)
Response after surgery/platinum-
based chemotherapy, n (%)
NED
CR
PR
150 (59)
52 (20)
53 (21)
71 (54)
26 (20)
35 (27)
15

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Pre-specified subgroup analysis showed substantial PFS benefit in
HRD-positive* (including tBRCAm) patients
Data maturity=46%. The percentages of patients progression-free at 12 months and 24 months have been calculated based on Kaplan-Meier estimates
*HRD-positive determined by tBRCAm or Myriad myChoice® CDx genomic instability score ≥42. †This median is unstable due to a lack of events – less than 50% maturity.
CDx=companion diagnostic test; CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficiency; inv=investigator-assessed; (m)PFS=(median) progression-free survival; tBRCAm=mutation in tumour BRCA
The clinically meaningful improvement in mPFS (20 months) may increase with longer follow-up
HRD+
48%
Olaparib +
bevacizumab
n=255
Placebo +
bevacizumab
n=132
Events, n (%) 87 (34) 92 (70)
Median PFS,
months (inv)
37.2† 17.7
HR 0.33
95% CI 0.25–0.45
0 3
No. at risk
Placebo
Olaparib 255
132
252
128
6 9 12 15 18 21 24 27 30 33 36 39 42
242
117
236
103
223
91
213
79
169
54
155
44
103
28
85
18
46
8
29
5
11
1
3 0
1 0
100
80
60
40
20
0
Patients
free
from
disease
progression
and
death
(%)
66%
29%
89%
71%
45
16

© AstraZeneca 2021
Pre-specified subgroup analysis showed PFS benefit in
HRD-positive*, non-tBRCAm patients
Data maturity=55%. The percentages of patients progression-free at 12 months and 24 months have been calculated based on Kaplan-Meier estimates
*HRD-positive determined by Myriad myChoice® CDx genomic instability score ≥42. †This median is unstable due to a lack of events – less than 50% maturity.
CDx=companion diagnostic test; CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficiency; inv=investigator-assessed; PFS=progression-free survival; tBRCAm= mutation in tumour BRCA
Olaparib +
bevacizumab
n=97
Placebo +
bevacizumab
n=55
Events, n (%) 43 (44) 40 (73)
Median PFS,
months (inv)
28.1† 16.6
HR 0.43
95% CI 0.28–0.66
0 3
No. at risk
Placebo
Olaparib
6 9 12 15 18 21 24 27 30 33 36 39 42
100
80
60
40
20
0
Patients
free
from
disease
progression
and
death
(%)
45 HRD+,
non-
tBRCAm
19%
97
55
96
54
90
48
86
41
79
37
75
32
54
19
48
15
30
11
29
8
16
3
12
2
4
0
2 0
52%
26%
83%
69%
17

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Summary
~50% of patients in PAOLA-1 were HRD-positive*
In these patients, olaparib added to bevacizumab resulted in a substantial PFS benefit (median >3 years) vs. placebo
plus bevacizumab
*HRD-positive defined as BRCAm and/or genomic instability score ≥42 in the Myriad myChoice® CDx
BRCAm=mutation in BRCA; CDx=companion diagnostic; HRD=homologous recombination deficiency; PFS=progression-free survival
Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428
18

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© AstraZeneca 2021
PFS in the HRD-positive population
according to clinical risk status

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In HRD-positive* patients, olaparib + bevacizumab improved PFS vs.
bevacizumab alone regardless of patients’ clinical risk status
Olaparib +
bevacizumab
n=78
Placebo +
bevacizumab
n=43
Events, n (%) 10 (13) 25 (58)
Median PFS, months NR 22.1
HR 0.15
95% CI 0.07–0.30
Stage III patents with PDS and no
residual disease
Stage III patients with PDS and
residual disease, patients who
received NACT, Stage IV patients
Higher risk Lower risk
No. at risk
Olaparib + bev
Placebo + bev
177
89
175
86
166
78
161
66
150
59
140
47
109
31
95
24
63
16
50
11
27
5
15
2
5
0
0 78
43
77
42
76
39
75
37
73
32
73
32
60
23
60
20
40
12
35
7
19
3
14
3
6
1
3
1
0
0
Patients
free
from
disease
progression
and
death
(%)
100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
86%
68%
23%
56%
100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
96%
76%
90%
43%
Olaparib +
bevacizumab
n=177
Placebo +
bevacizumab
n=89
Events, n (%) 77 (44) 67 (75)
Median PFS, months 36.0† 16.0
HR 0.39
95% CI 0.28–0.54
20
In the HRD-positive, non-BRCAm subgroup, the HR for median PFS with olaparib + bevacizumab vs. placebo + bevacizumab was 0.51 (95% CI 0.31–0.83) and 0.19 (95% CI 0.06–0.55) in the higher- and lower-
risk subgroup respectively2
*HRD-positive defined as BRCAm and/or genomic instability score ≥42 in the Myriad myChoice® CDx assay
†Median unstable due to lack of events
Bev=bevacizumab; BRCAm=BRCA mutation; CDx=companion diagnostic; CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficiency; NACT=neoadjuvant chemotherapy; NR=not
reached; PDS=primary debulking surgery; PFS=progression-free survival
Harter P, et al. Presented at IGCS Annual Global Meeting 2020. 10-13 September. Plenary presentation #1207. 2. AstraZeneca Data of File 2021.

© AstraZeneca 2021
21
Summary
Olaparib + bevacizumab improved PFS vs. bevacizumab alone in HRD-positive* patients and regardless of
these patients’ clinical risk status
In HRD-positive* patients at lower risk for disease progression, olaparib + bevacizumab reduced the risk of
progression by 85% vs. placebo + bevacizumab
BRCAm=mutation in BRCA; CDx=companion diagnostic; HRD=homologous recombination deficiency; PFS=progression-free survival
. Harter P, et al. Presented at IGCS Annual Global Meeting 2020. 10-13 September. Plenary presentation #1207
21
In higher-risk HRD-positive* patients, olaparib added to bevacizumab delivered a median PFS of 3 years

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© AstraZeneca 2021
Final PFS2 analyses

© AstraZeneca 2021
Olaparib plus bevacizumab significantly reduced the risk of second
progression vs. placebo plus bevacizumab in the ITT population
Data maturity=53%
Median duration of follow-up: olaparib, 35.5 months; placebo, 36.5 months
Data cut-off: March 2020
Bev=bevacizumab; CI=confidence interval; HR=hazard ratio; ITT=intent to treat; PFS2=time from randomisation to second progression or death
27% of patients in the placebo
arm and 9% in the olaparib arm
received a PARP inhibitor as
their first subsequent treatment
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
537
269
527
266
515
258
491
245
459
226
434
215
408
206
376
190
339
171
309
149
263
131
217
106
150
72
97
40
72
27
22
9
14
4
3
1
0
0
Patients
free
from
second
disease
progression
and
death
(%)
100
80
60
40
20
0
0
Olaparib +
bevacizumab
n=537
Placebo +
bevacizumab
n=269
Events, n (%) 260 (48) 164 (61)
Median PFS2,
months
36.5 32.6
HR 0.78
95% CI 0.64–0.95
P=0.0125
Olaparib + bev
Placebo + bev
No. at risk
23

© AstraZeneca 2021
A substantial PFS2 benefit was also seen in HRD-positive* patients
regardless of BRCAm status
*HRD-positive determined by tBRCAm or Myriad myChoice® CDx genomic instability score ≥42; †HRD-negative determined by non-BRCAm and Myriad myChoice® CDx genomic instability score <42;
‡This median is unstable due to a lack of events – less than 50% maturity
Bev=bevacizumab; BRCAm=mutation in BRCA; CDx=companion diagnostic; CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficiency; PFS2=time to progression on subsequent therapy;
tBRCAm=tumour BRCA mutation
Olaparib +
bevacizumab
n=255
Placebo +
bevacizumab
n=132
Events, n (%) 85 (33) 70 (53)
Median PFS2, months 50.3‡ 35.3
HR 0.56
95% CI 0.41–0.77
Olaparib +
bevacizumab
n=97
Placebo +
bevacizumab
n=55
41 (42) 33 (60)
50.3‡ 30.1
HR 0.60
95% CI 0.38–0.96
Olaparib +
bevacizumab
n=282
Placebo +
bevacizumab
n=137
175 (62) 94 (69)
26.3 28.1
HR 0.98
95% CI 0.77–1.27
HRD-positive,* including tBRCAm HRD-positive,* excluding tBRCAm HRD-negative†/unknown
Olaparib plus bev
Patients
free
from
second
disease
progression
and
death
(%)
0
20
40
60
80
100
255
132
253
130
252
127
247
125
239
117
230
111
223
109
211
99
196
93
184
83
161
71
137
61
102
44
70
26
54
17
17
8
11
4
3
1
0
0
Ola + bev
Pla + bev
Placebo plus bev
No of patients at risk:
0
20
40
60
80
100
97
55
96
54
95
53
92
52
87
49
83
44
81
43
77
40
67
36
63
30
53
27
46
23
31
15
24
8
20
3
7
1
5
0
1 0
0
20
40
60
80
100
282
137
274
136
263
131
244
120
220
109
204
104
185
97
165
91
143
78
125
66
102
60
80
45
48
28
27
14
18
10
5
1
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
0 3 6 12 15 18 21 24 27 30 33 39 42 45 48 51 54
0 3 6 12 15 18 21 24 27 30 33 39 42 45 48 51 54 9
9 36
36
Placebo plus bev Placebo plus bev
Olaparib plus bev
Olaparib plus bev
24

© AstraZeneca 2021
Summary
After 3 years’ follow-up, a statistically significant increase in PFS2 demonstrated that the benefit of olaparib +
bevacizumab extends beyond progression despite cross-over to subsequent PARPi
The PFS2 improvement in the HRD-positive* subgroup (HR 0.56) suggests clinically meaningful long-term benefit was
observed in patients with a BRCAm and/or genomic instability
BRCAm=BRCA mutation; CDx=companion diagnostic; HR=hazard ratio; HRD=homologous recombination deficiency; PARPi=PARP inhibitor; PFS2=time to progression on subsequent therapy
25

© AstraZeneca 2021
© AstraZeneca 2021
Safety, tolerability and HRQoL

© AstraZeneca 2021
Adverse events were generally mild to moderate and manageable
through dose adjustments
Primary analysis DCO: 22 March 2019. Median duration of follow-up for primary analysis: olaparib, 22.7 months; placebo, 24.0 months
*At the final PFS2 DCO (March 2020, median duration of follow-up: olaparib, 35.5 months; placebo, 36.5 months), the median duration of treatment was unchanged. 112 (21%) patients in the
olaparib arm had discontinued treatment vs. 15 (6%) in the placebo arm4
AE=adverse event; DCO=data cut-off
3. Ray-Coquard I, et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain;
4. Gonzalez-Martin A, et al. Presented at ESMO Virtual Congress 2020. 19-21 September. Abstract #LBA33
n=535
n=267
Median duration of treatment with olaparib/placebo,* months (range)
Median duration of treatment with bevacizumab since randomisation*, months (range)
17.3 (0.0–33.0)
11.0 (0.7–21.4)
15.6 (0.1–26.2)
10.6 (0.7–17.1)
All grade AEs, n (%) 531 (99) 256 (96)
Grade ≥3 AEs, n (%) 303 (57) 136 (51)
Serious AEs, n (%) 167 (31) 83 (31)
AEs leading to death, n (%) 1 (<1) 4 (2)
AEs leading to dose interruption of olaparib or placebo, n (%) 291 (54) 65 (24)
AEs leading to dose reduction of olaparib or placebo, n (%) 220 (41) 20 (7)
AEs leading to treatment discontinuation of olaparib or placebo,* n (%) 109 (20) 15 (6)
27

© AstraZeneca 2021
The AE profile of olaparib in PAOLA-1 was consistent with previous trials
of olaparib
Secondary data cut-off: March 2020. Median duration of follow-up: olaparib, 35.5 months; placebo, 36.5 months
All-grade grouped-term thrombocytopenia occurred in 8% of olaparib plus bevacizumab patients and 3% of placebo plus bevacizumab patients; grade ≥3 grouped-term thrombocytopenia occurred
in 2% of olaparib plus bevacizumab patients and <1% of placebo plus bevacizumab patients
*Grouped terms.
AE=adverse event; bev=bevacizumab; UTI=urinary tract infection
1. Gonzalez-Martin A, et al. Presented at ESMO Virtual Congress 2020. 19-21 September. Abstract #LBA33; 2. Moore K, et al. N Engl J Med 2018;379:2495-505;
3. Pujade-Lauraine E, et al. Lancet Oncol. 2017;18:1274-84; 4. Ledermann J, et al. Lancet Oncol. 2014;15:852-61
Olaparib + bev: All grades (frequency ≥10%)
Olaparib + bev: Grade ≥3
Placebo + bev: Grade ≥3
Placebo + bev: All grades (frequency ≥10%)
0 10 20 30 40 50 60
0
10
20
30
40
50
60
Nausea 53 2 22
1
Fatigue/asthenia 53 5 32
1
Hypertension 46 19 60
31
Vomiting 22 1 11
2
Abdominal pain 20 1 20
2
Anaemia* 41 18 10
<1
Neutropenia* 18 6 16
3
Constipation 10 10
<1
UTI 15 <1 10
<1
Lymphopenia* 24 7 9
1
Arthralgia 22 1 24
1
Diarrhoea 18 2 17
2
Leukopenia* 18 2 10
1
Headache 14 <1 13
1
Proteinuria 6 1 15
<1
Treatment-emergent AEs (%)
28

© AstraZeneca 2021
Haematological adverse events were consistent with previous trials
of olaparib
Secondary data cut-off: March 2020. Median duration of follow-up: olaparib, 35.5 months; placebo, 36.5 months
*Grouped terms
AE=adverse event
1. Gonzalez-Martin A, et al. Presented at ESMO Virtual Congress 2020. 19-21 September. Abstract #LBA33; 2. Moore K, et al. N Engl J Med 2018;379:2495-505;
3. Pujade-Lauraine E, et al. Lancet Oncol. 2017;18:1274-84; 4. Ledermann J, et al. Lancet Oncol. 2014;15:852-61
n=535
n=267
Haematological AEs, %
All grade Grade ≥3 All grade Grade ≥3
Anaemia* 41 18 10 <1
Lymphopenia* 24 7 9 1
Neutropenia* 18 6 16 3
Thrombocytopenia 8 2 3 <1
Leukopenia* 18 2 10 1
29

© AstraZeneca 2021
No new cases of MDS/AML/AA were reported in an updated analysis1-3
Final PFS2 DCO: 22 March 2020. Median duration of follow-up: olaparib, 35.5 months; placebo, 36.5 months
*3 of the 4 patients in the placebo plus bevacizumab group who developed MDS/AML/AA received a PARP inhibitor as first subsequent treatment before onset of AML
†At primary PFS analysis, new primary malignancies in the olaparib plus bevacizumab group were acute lymphocytic leukaemia (n=1), breast cancer (n=2), lung cancer (n=1), myeloma (n=1), squamous skin cancer
(n=1), and pancreatic cancer (n=1), and in the placebo group were breast cancer (n=2) and thyroid cancer (n=1). Additional new primary malignancies reported at final PFS2 analysis in the olaparib plus bevacizumab
group were breast cancer (n=5), squamous skin cancer (n=1), and colon cancer (n=1), and in the placebo group were breast cancer (n=1) and malignant neoplasm (n=1)
AA=aplastic anaemia; AE=adverse event; AML=acute myeloid leukaemia; DCO=data cut off; ILD=interstitial lung disease; MDS=myelodysplastic syndrome; PARPi=PARP inhibitor; PFS=progression free survival;
PFS2=time to second progression or death
3. Gonzalez-Martin A, et al. Presented at ESMO Virtual Congress 2020. 19-21 September. Abstract #LBA33;
4. Banerjee S, et al. Presented at ESMO Virtual Congress 2020. 19-21 September. Abstract #811MO
The incidence of MDS/AML was consistent with other trials of olaparib in newly-diagnosed disease4
Primary analysis1,2 Final PFS2 analysis3
AEs of special interest for the PARPi
class in PAOLA-1, n (%)
Olaparib +
bevacizumab
n=535
Placebo +
bevacizumab
n=267
Olaparib +
bevacizumab
n=535
Placebo +
bevacizumab
n=267
MDS/AML/AA* 6 (1.1) 1 (<1) 6 (1.1) 4 (1.5)*
New primary malignancies† 7 (1.3) 3 (1.1) 14 (2.6) 5 (1.9)
Pneumonitis/ILD/bronchitis 6 (1.1) 0 6 (1.1) 0
30

© AstraZeneca 2021
No clinically meaningful or statistically significant difference in HRQoL
was seen between treatment arms
A minimal clinically important difference is defined as ±10 points
CI=confidence interval; GHS=global health score; HRQoL=health-related quality of life; QoL=quality of life
Olaparib +
bevacizumab
Placebo +
bevacizumab
n 498 246
Adjusted
mean
change
from
baseline
−1.33 −2.89
95% CI,
p
−2.47 to −0.19,
p=0.022
−4.52 to −1.26,
p=0.0005
Estimated
difference
1.56
95% CI,
p
−0.42 to 3.55,
p=0.123
Mean
change
from
baseline
in
GHS/QoL
score
15
10
5
0
−5
−10
−15
0 12 24 36 48 60 72 84 96
Weeks since randomisation
No. at risk
Placebo
Olaparib 508
249
458
228
432
207
396
199
393
185
352
171
342
166
308
151
252
123
31

© AstraZeneca 2021
Summary
AEs with olaparib and bevacizumab were generally mild to moderate and manageable through
dose adjustments1,2
The AE profile of olaparib in PAOLA-1 was consistent with previous trials of olaparib1-5
After 36 months’ follow-up, the incidence of MDS/AML/AA in the olaparib and bevacizumab arm remained
consistent with the primary analysis (1%)1,2
No clinically meaningful or statistically significant difference in HRQoL was seen between treatment arms1
AA=aplastic anaemia; AE=adverse event; AML=acute myeloid leukaemia; HRQoL=health-related quality of life; MDS=myelodysplastic syndrome
1. Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428; 2. Gonzalez-Martin A, et al. Presented at ESMO Virtual Congress 2020. 19-21 September. Abstract #LBA33;
3. Moore K, et al. N Engl J Med 2018;379:2495-505; 4. Pujade-Lauraine E, et al. Lancet Oncol. 2017;18:1274-84; 5. Ledermann J, et al. Lancet Oncol. 2014;15:852-61
32

© AstraZeneca 2021
© AstraZeneca 2021
Summary

© AstraZeneca 2021
Summary
BRCAm=BRCA mutation; CDx=companion diagnostic test; HR=hazard ratio; HRD=homologous recombination deficiency; HRQoL=health-related quality of life; PARPi=PARP inhibitor;
PFS=progression-free survival; PFS2=time to progression on subsequent therapy
1. Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428; 2. Gonzalez-Martin A, et al. Presented at ESMO Virtual Congress 2020. 19-21 September. Abstract #LBA33;
3. Lynparza 150mg Film-Coated Tablets, SmPC, 2020.
PAOLA-1 is the only Phase III randomised trial to investigate the addition of a PARPi (olaparib) to active treatment
with bevacizumab in the newly diagnosed setting, with the intent of achieving maximum therapeutic benefit1
In HRD-positive* patients, olaparib added to bevacizumab substantially improved PFS vs. placebo added to
bevacizumab with a median PFS >3 years (HR 0.33)1
The tolerability of olaparib in PAOLA-1 was well characterised and consistent with previous knowledge, and there was
no detriment in HRQoL1,3
In a representative patient population, unselected by biomarker status or surgical outcomes, olaparib + bevacizumab
significantly improved PFS and PFS2 vs. placebo + bevacizumab1,2
34

© AstraZeneca 2021
© AstraZeneca 2021
Appendix

© AstraZeneca 2021
© AstraZeneca 2021
Patient baseline characteristics and disposition

© AstraZeneca 2021
Baseline patient characteristics were well balanced between arms
*ECOG performance was missing for six patients in the olaparib arm and four patients in the placebo arm
†Two patients had low grade serous carcinoma with a BRCAm
‡Other includes clear cell, undifferentiated and other histology
ECOG=Eastern Cooperative Oncology Group; tBRCAm=mutation in tumour BRCA
(n=537)
(n=269)
ECOG performance status*,
n (%)
0
1
378 (70)
153 (28)
189 (70)
76 (28)
Primary tumour location, n (%)
Ovary
Fallopian tubes
Primary peritoneal
456 (85)
39 (7)
42 (8)
238 (88)
11 (4)
20 (7)
Histology, n (%)
Serous†
Endometrioid
Other‡
519 (97)
12 (2)
6 (1)
253 (94)
8 (3)
8 (3)
37

© AstraZeneca 2021
Baseline patient characteristics were also well balanced between arms
in the HRD-positive* subgroup
*HRD-positive defined as tBRCAm and/or Myriad myChoice® CDx genomic instability score ≥42
†ECOG performance was missing for four patients in the olaparib arm and five patients in the placebo arm
‡Other defined as clear cell (n=1, olaparib plus bevacizumab), undifferentiated (n=1, olaparib plus bevacizumab; n=3, placebo plus bevacizumab) or other (n=2, olaparib plus bevacizumab;
n=1, placebo plus bevacizumab) ECOG=Eastern Cooperative Oncology Group; HRD=homologous recombination deficiency
Ray-Coquard I, et al. N Engl J Med. 2019;381:Supplementary appendix
(n=255)
(n=132)
ECOG performance status,†
n (%)
0
1
190 (75)
61 (24)
100 (76)
21 (16)
Primary tumour location, n (%)
Ovary
Fallopian tubes
Primary peritoneal
217 (85)
24 (9)
14 (5)
118 (89)
5 (4)
9 (7)
Histology, n (%)
Serous
Endometrioid
Other‡
242 (95)
9 (4)
4 (2)
124 (94)
4 (3)
4 (3)
38

© AstraZeneca 2021
Disease progression was the most common reason for discontinuation
in the overall population
*Other includes lost to follow-up, missing and other
RECIST=Response Evaluation Criteria in Solid Tumours; TEAE=treatment-emergent adverse event
1. Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428; 2. Ray-Coquard I, et al. N Engl J Med. 2019;381:Supplementary appendix.
(n=537)
(n=269)
Randomised, n 537 269
Treated, n (%) 535 (99.6) 267 (99.3)
Discontinued study treatment, n (%)
Disease progression per RECIST
Disease progression non-RECIST
TEAE
Patient decision
Death
Other*
331 (62)
182 (34)
14 (3)
109 (20)
4 (1)
1 (<1)
21 (4)
194 (72)
155 (58)
13 (5)
15 (6)
4 (1)
3 (1)
6 (2)
Median duration of treatment, months
Olaparib/placebo
Bevacizumab
17.3
11.0
15.6
10.6
39

© AstraZeneca 2021
© AstraZeneca 2021
PFS according to BRCA and HRD status

© AstraZeneca 2021
The Myriad myChoice® CDx test defines patients with a BRCAm and/or
a genomic instability score ≥42 as HRD-positive1,2
*The genomic instability score is calculated from 3 components reflecting tumour genome rearrangements. LOH are regions of intermediate size (>15 Mb and <whole chromosome) in the tumour genome;
LST are chromosome breaks (translocations, inversions or deletions) in adjacent segments of DNA ≥10 Mb; and TAI is defined as the number of regions with allelic imbalance which extend to the sub-telomere but do not
cross the centromere
BRCAm=mutation in BRCA; CDx=companion diagnostic; HRD=homologous recombination deficiency; LOH=loss of heterozygosity; LST=large-scale state transitions; TAI=telomeric allelic imbalance; tBRCA=tumour BRCA
1. Myriad myChoice HRD Technical Specifications. Available at: https://myriad-web.s3.amazonaws.com/myChoice/downloads/myChoiceHRDTechSpecs.pdf (accessed September 2020);
2. Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428
HRD-negative is defined as absence of a BRCAm and a genomic instability score <42
tBRCA mutation
Genomic instability
Assessed by LOH, TAI and LST*
Score out of 100
Yes / No
BRCAm
Non-BRCAm Score <42
HRD-positive:
HRD-negative:
Score ≥42
and/or
and
Testing in newly diagnosed
ovarian cancer
41

© AstraZeneca 2021
Pre-specified subgroup analyses showed PFS benefit in both tBRCAm
and non-tBRCAm patients
Analysis per eCRF. The percentages of patients progression-free at 12 months and 24 months have been calculated based on Kaplan-Meier estimates. Data maturity: 38% in tBRCAm subgroup, 67% in non-tBRCAm subgroup
*Includes tBRCAm status unknown. †This median is unstable due to a lack of events – less than 50% maturity
CI=confidence interval; eCRF=electronic case report form; HR=hazard ratio; inv=investigator-assessed; PFS=progression-free survival; tBRCAm=mutation in tumour BRCA
1. Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428; 2. Ray-Coquard I et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain
However, a greater PFS benefit was observed in the tBRCAm vs. the non-tBRCAm subgroup
Olaparib +
bevacizumab
n=157
Placebo +
bevacizumab
n=80
Events, n (%) 41 (26) 49 (61)
Median PFS, months 37.2† 21.7
HR 0.31; 95% CI 0.20–0.47
tBRCAm
0 3
380
189
359
174
6 9 12 15 18 21 24 27 30 33 36 39 42 45
311
154
285
139
259
113
236
99
162
68
130
47
65
28
54
22
24
8
18
5
5
0
2 0
Patients
free
from
disease
progression
and
death
(%)
100
80
60
40
20
0
0 3
No. at risk
Placebo
Olaparib 157
80
154
78
6 9 12 15 18 21 24 27 30 33 36 39 42 45
150
72
148
66
144
59
138
52
117
41
110
36
76
22
58
13
31
7
19
4
7
1
1
1
0
0
39%
76%
76%
94%
Non-tBRCAm* Olaparib +
bevacizumab
n=380
Placebo +
bevacizumab
n=189
Events, n (%) 239 (63) 145 (77)
Median PFS, months 18.9 16.0
HR 0.71; 95% CI 0.58–0.88
100
80
60
40
20
0
42

© AstraZeneca 2021
Subgroup analysis in HRD-negative* or unknown patients
Data maturity=70%. *HRD-negative determined by non-BRCAm and Myriad myChoice® CDx genomic instability score <42
CDx=companion diagnostic test; CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficiency; inv=investigator-assessed; PFS=progression-free survival
Olaparib +
bevacizumab
n=282
Placebo +
bevacizumab
n=137
Events, n (%) 193 (68) 102 (74)
Median PFS,
months (inv)
16.9 16.0
HR 0.92
95% CI 0.72–1.17
0 3
No. at risk
Placebo
Olaparib
6 9 12 15 18 21 24 27 30 33 36 39 42
100
80
60
40
20
0
Patients
free
from
disease
progression
and
death
(%)
45
282
137
261
124
219
109
197
102
180
81
161
72
110
55
85
39
38
22
27
17
9
7
8
4
1
0
0
HRD- or
unknown
52%
43

© AstraZeneca 2021
Pre-specified subgroup analysis in HRD-negative* patients
Olaparib +
bevacizumab
n=192
Placebo +
bevacizumab
n=85
Events, n (%) 145 (76) 66 (78)
Median PFS,
months (inv)
16.6 16.2
HR 1.00
95% CI 0.75–1.35
0 3
No. at risk
Placebo
Olaparib
6 9 12 15 18 21 24 27 30 33 36 39 42
100
80
60
40
20
0
Patients
free
from
disease
progression
and
death
(%)
45
Data maturity=76%. *HRD-negative determined by non-BRCAm and Myriad myChoice® CDx genomic instability score <42
CDx=companion diagnostic test; CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficiency; inv=investigator-assessed; PFS=progression-free survival
HRD-
34%
192
85
175
79
145
68
128
63
115
52
102
47
67
34
49
20
20
8
13
8
6
3
5
2
1
0
0
44

© AstraZeneca 2021
Pre-specified subgroup analysis in the HRD-unknown subgroup
Olaparib +
bevacizumab
n=90
Placebo +
bevacizumab
n=52
Events, n (%) 48 (53) 36 (69)
Median PFS,
months (inv)
22.1 14.6
HR 0.71
95% CI 0.46–1.10
0 3
No. at risk
Placebo
Olaparib
6 9 12 15 18 21 24 27 30 33 36 39 42
100
80
60
40
20
0
Patients
free
from
disease
progression
and
death
(%)
45
Data maturity=59%
CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficiency; inv=investigator-assessed; PFS=progression-free survival
3. Ray-Coquard I, et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain; 4. AstraZeneca data on file (2019).
HRD
unknown
18%
90
52
86
45
74
41
69
39
65
29
59
25
43
21
36
19
18
14
14
9
3
4
3
4
3
2
0
0
45

© AstraZeneca 2021
Summary of key subgroup PFS data
*HRD-positive determined by tBRCAm or Myriad myChoice® CDx genomic instability score ≥42
†HRD-negative determined by non-tBRCAm and Myriad myChoice® CDx genomic instability score <42
BICR=blinded independent central review; CDx=companion diagnostic test; HR=hazard ratio; HRD=homologous recombination deficiency; inv=investigator-assessed; ITT=intent to treat;
mPFS=median progression-free survival; tBRCAm=tumour mutation in BRCA
Ray-Coquard I, et al. N Engl J Med. 2019;381:2416-2428.
Difference in
mPFS (months)
PFS HR
5.5 (inv)
(BICR: 7.8)
0.59 (inv)
(BICR: 0.63)
15.5 0.31
19.5 0.33
0.9 0.92
0 5 10 15 20 25 30 35 40
HRD-negative†/
unknown
HRD-positive*
tBRCAm
ITT
HRD-negative†
/unknown
46

© AstraZeneca 2021
Exploratory analyses evaluated investigator-assessed PFS in higher- and
lower-risk patient subgroups
ITT=intent to treat; NACT=neoadjuvant chemotherapy; PDS=primary debulking surgery; PFS=progression-free survival
Harter P, et al. Presented at IGCS Annual Global Meeting 2020. 10-13 September. Plenary presentation #1207
Higher risk (74% of ITT)
Stage III patients with PDS and residual
disease, patients who had received NACT,
Stage IV patients
Lower risk (26% of ITT)
Stage III patients with PDS and
no residual disease
Olaparib + bevacizumab, n=138
Placebo + bevacizumab, n=73
Olaparib + bevacizumab, n=399
Placebo + bevacizumab, n=196
48

© AstraZeneca 2021
In higher-risk* patients, >5 months PFS benefit was seen with olaparib +
bevacizumab vs. placebo + bevacizumab
*Stage III patients with PDS and residual disease, patients who had received NACT, Stage IV patients
Bev=bevacizumab; CI=confidence interval; HR=hazard ratio; NACT=neoadjuvant chemotherapy; PDS=primary debulking surgery; PFS=progression-free survival
Harter P, et al. Presented at IGCS Annual Global Meeting 2020. 10-13 September. Plenary presentation #1207
Olaparib +
bevacizumab
n=399
Placebo +
bevacizumab
n=196
Events, n (%) 239 (60) 154 (79)
Median PFS,
months
20.3 14.7
HR 0.60
95% CI 0.49–0.74
Olaparib plus bev
Placebo plus bev
75%
60%
37%
21%
Patients
free
from
disease
progression
and
death
(%)
No. at risk
Olaparib + bev
Placebo + bev
399
196
381
180
336
157
313
139
287
114
259
95
188
67
153
48
86
31
68
21
31
9
19
4
6
0
0
100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
49

© AstraZeneca 2021
Lower risk patients* received a greater absolute magnitude of benefit
with the addition of olaparib than with placebo + bevacizumab1
*Stage III patints with PDS and no residual disease
†Median unstable due to lack of events
Bev=bevacizumab; CI=confidence interval; HR=hazard ratio; PDS=primary debulking surgery; PFS=progression-free survival
1. Harter P, et al. Presented at IGCS Annual Global Meeting 2020. 10-13 September. Plenary presentation #1207; 2. Gonzalez-Martin A, et al. N Engl J Med. 2019; 381:Clinical Study Protocol
Olaparib +
bevacizumab
n=138
Placebo +
bevacizumab
n=73
Events, n (%) 41 (30) 40 (55)
Median PFS,
months
39.3† 22.9
HR 0.46
95% CI 0.30–0.72
Patients
free
from
disease
progression
and
death
(%)
No. at risk
Olaparib + bev
Placebo + bev
100
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Note that this subgroup
represents a population
of patients excluded
from the PRIMA study2
!
138
73
132
72
125
69
120
66
116
58
115
56
91
42
87
35
55
19
44
14
24
6
18
5
6
1
3
1
0
0
Olaparib plus bev
Placebo plus bev
88%
73%
82%
46%
50

© AstraZeneca 2021
A substantial PFS2 benefit was seen in HRD-positive* patients
†This median is unstable due to a lack of events – less than 50% maturity
bev=bevacizumab; CDx=companion diagnostic; CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficiency; PFS2=time to progression on subsequent therapy;
tBRCAm=tumour BRCA mutation
Olaparib plus bev
255
132
253
130
252
127
247
125
239
117
230
111
223
109
211
99
196
93
184
83
161
71
137
61
102
44
70
26
54
17
17
8
11
4
3
1
0
0
52
Olaparib +
bevacizumab
n=255
Placebo +
bevacizumab
n=132
Events, n (%) 85 (33) 70 (53)
Median PFS2,
months
50.3† 35.3
HR 0.56
95% CI 0.41–0.77
Olaparib + bev
Placebo + bev
No. at risk Months since randomisation
100
80
60
40
20
0
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
0
Patients
free
from
second
disease
progression
and
death
(%)

© AstraZeneca 2021
A significant delay in TSST supported the PFS2 benefit seen with
olaparib plus bevacizumab vs. placebo plus bevacizumab
*TSST analysis not adjusted for multiplicity
Data maturity=53%
Bev=bevacizumab; CI=confidence interval; HR=hazard ratio; ITT=intent to treat; PFS2=time from randomisation to second progression or death; TSST=time to second subsequent therapy or death
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Patients
free
from
second
disease
progression
and
death
(%)
100
80
60
40
20
0
0
Olaparib +
bevacizumab
n=537
Placebo +
bevacizumab
n=269
Events, n (%) 266 (50) 164 (61)
Median TSST,
months
38.2 31.5
HR 0.78
95% CI 0.64–0.95
P=0.0115*
Olaparib + bev
Placebo + bev
No. at risk
537
269
528
267
520
260
505
247
469
232
442
218
421
207
394
191
329
149
297
135
245
113
184
75
127
49
86
31
39
17
19
5
6
1
1
0
364
172
53

© AstraZeneca 2021
The greatest TSST benefit for olaparib vs. placebo was seen in
HRD-positive* patients
†HRD-negative determined by non-BRCAm and Myriad myChoice® CDx genomic instability score <42
CDx=companion diagnostic; CI=confidence interval; HR=hazard ratio; HRD=homologous recombination deficiency; tBRCAm=tumour BRCA mutation; TSST=time to second subsequent treatment
Biomarker subgroup
TSST HR
(95% CI)
tBRCAm 0.48 (0.31–0.75)
HRD-positive* 0.48 (0.35–0.66)
HRD negative†/unknown 1.05 (0.82–1.36)
54

© AstraZeneca 2021
OS data remained immature after ~36 months follow-up
Data maturity=38%
Bev=bevacizumab; CI=confidence interval; HR=hazard ratio; NR=not reached; OS=overall survival
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Patients
who
survived
(%)
100
80
60
40
20
0
0
Olaparib +
bevacizumab
n=537
Placebo +
bevacizumab
n=269
Events, n (%) 195 (36) 108 (40)
Median OS,
months
NR 45.8
HR 0.93
95% CI 0.74–1.18
p=0.56
Olaparib + bev
Placebo + bev
No. at risk
537
269
528
267
526
264
515
261
499
250
475
240
458
227
436
218
392
197
366
185
306
158
245
119
167
81
110
58
53
33
25
11
8
3
2
1
416
206
55

© AstraZeneca 2021
A significant PFS benefit from olaparib was seen in the ITT population
using time to earliest progression by RECIST, CA-125 or death*
56
*Whichever occurred first
Data cut-off: 22 March 2019. Median duration of follow-up for PFS by RECIST/CA-125: Olaparib + bev, 24.2 months; placebo + bev, 24.7 months
bev=bevacizumab; CA-125=cancer antigen 125; CI=confidence interval; HR=hazard ratio; ITT=intent-to-treat; PFS=progression-free survival; RECIST=response evaluation criteria in solid tumors
Hietanen S, et al. Presented at the SGO Virtual Annual Meeting 2021; 19–25 March
Olaparib +
bevacizumab
n=537
Placebo +
bevacizumab
n=269
Events, n (%) 284 (53) 198 (74)
Median PFS,
months
22.1 15.4
HR 0.58
95% CI 0.48–0.70
0 3
No. at risk
Placebo + bev
Olaparib + bev
6 9 12 15 18 21 24 27 30 33 36 39 42
100
80
60
40
20
0
Patients
free
from
disease
progression
and
death
(%)
45
537
269
494
238
443
207
410
180
380
154
353
137
302
107
238
81
162
54
116
37
72
19
42
11
14
2
6
1
0
0
73%
58%
47%
28%

© AstraZeneca 2021
Response to maintenance treatment was measured in the 216* (27%) of
patients with evidence of disease after front-line treatment1
*216 patients with evidence of disease by RECIST and/or CA-125 ≥2 x ULN at baseline were analysed for response by RECIST criteria (n=202) and/or CA-125 criteria (n=45)
CA-125=cancer antigen 125; ORR=objective response rate; RECIST=Response Evaluation Criteria in Solid Tumors; ULN=upper limit of normal
1. Colombo N, et al. Presented at ESMO Virtual Congress 2020. 19-21 September. Abstract #812MO; 2. Sørensen SM, et al. Acta Obstet Gynecol Scand. 2019;98(1):34-43
These patients had evidence of disease after front-line surgery and platinum-based chemotherapy plus
bevacizumab, and would therefore be expected to have poor prognosis1,2
Patients with evidence of
disease after front-line
treatment, measurable for ORR
Patients without evidence of
disease after front-line treatment,
not measurable for ORR
57

© AstraZeneca 2021
Olaparib improved ORR vs. placebo when added to bevacizumab in
patients with evidence of disease at baseline
Exploratory endpoint: ORR by RECIST among 202 patients with evidence of disease (target and/or non-target lesions, and/or CA-125 ≥2 x ULN at baseline)
*HRD-positive defined as BRCAm and/or Myriad myChoice® genomic instability score ≥42
†HRD-negative defined as non-BRCAm and Myriad myChoice® genomic instability score <42
Bev=bevacizumab; BRCAm=mutation in BRCA; CA-125=cancer antigen 125; CR=complete response; HRD=homologous recombination deficiency; ORR=objective response rate; PR=partial response;
RECIST=Response Evaluation Criteria in Solid Tumors; ULN=upper limit of normal
Colombo N, et al. Presented at ESMO Virtual Congress 2020. 19-21 September. Abstract #812MO
Addition of olaparib to bevacizumab enhanced the clinical response to first-line treatment.
The ORR was highest in patients with BRCAm or HRD-positive* disease
25
18
57
26
43
22 21
14 13 11
5
7
7
16
10
9 11
7
4
0
20
40
60
80
100
Olaparib
+ bev
Placebo
+ bev
Olaparib
+ bev
Placebo
+ bev
Olaparib
+ bev
Placebo
+ bev
Olaparib
+ bev
Placebo
+ bev
Olaparib
+ bev
Placebo
+ bev
ORR
(%)
64%
(18/28)
42%
(8/19)
53%
(26/49)
31%
(10/32)
32%
(6/19)
21%
(3/14) 13%
(7/56)
15%
(4/27)
OVERALL
(n=202)
BRCAm
(n=47)
HRD-positive*
BRCAm included (n=81)
HRD-positive*
non-BRCAm (n=33)
HRD-negative†
(n=83)
30%
(39/129) 25%
(18/73)
CR
PR
CR
PR
Olaparib +
bevacizumab
Placebo +
bevacizumab
58

© AstraZeneca 2021
tBRCAm
29%
tBRCAm
29%
HRD ≥42, non-BRCAm
19%
*HRD status was assessed using the Myriad myChoice® CDx assay. HRD-positive was defined as a BRCAm and/or genomic instability score ≥422
†HRRm status was assessed using a pre-defined panel of 13 genes
BRCAm=BRCA mutation; CDx=companion diagnostic; HRD=homologous recombination deficiency; HRRm=homologous recombination repair gene mutation; tBRCAm=tumour BRCA mutation
1. Pujade-Lauraine E, et al. Presented at the SGO Virtual Annual Meeting 2021; 19–25 March;
2. Ray-Coquard I, et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain
An exploratory analysis assessed the utility of non-BRCA HRRm as a
predictive biomarker for efficacy of olaparib + bevacizumab in PAOLA-11
HRD-unknown
18%
HRD-negative
34%
HRRm (non-BRCAm)
2%
1%
3%
60
19% of patients were HRD-positive*
excluding BRCAm2
6.7% of patients in PAOLA-1 had a
non-BRCA HRRm†1

© AstraZeneca 2021
Gene panel
Non-BRCA HRRm, n (%)
(N=806)
Exploratory gene panels
Pre-defined (13 genes) 54 (6.7)
Expanded (18 genes) 72 (8.9)
Restricted (5 genes) 30 (3.7)
Published gene panels
Used in Study 19 (26 genes) 79 (9.8)
Used in ARIEL3 (19 genes) 61 (7.6)
Used in NOVA (11 genes) 44 (5.5)
HRRm gene panels identified between 3.7% and 9.8% of PAOLA-1
patients as non-BRCA HRRm
HRRm=homologous recombination repair gene mutation
Pujade-Lauraine E, et al. Presented at the SGO Virtual Annual Meeting 2021; 19–25 March
61

© AstraZeneca 2021
The presence of a HRRm was not predictive of PFS benefit with olaparib
+ bevacizumab vs. placebo + bevacizumab
62
bev=bevacizumab; CI=confidence intervals; HR=hazard ratio; HRRm=homologous recombination repair gene mutation; NC=not calculated; PFS=progression-free survival
Pujade-Lauraine E, et al. Presented at the SGO Virtual Annual Meeting 2021; 19–25 March
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Time from randomisation (months)
0
10
20
30
40
50
60
70
80
90
100
Probability
of
PFS
(%)
34
No. at risk
32 27 26 24 24 17 15 9 8 4 3 1 0
Olaparib + bev
Placebo + bev 20 19 18 17 15 11 9 7 7 5 1 1 0 0
No PFS benefit was seen with olaparib + bevacizumab in HRRm
patients identified using a pre-defined panel of 13 genes
Pre-defined
Expanded
Restricted
Used in Study 19
Used in ARIEL3
Used in NOVA
0.25 0.50 1.00 2.00 4.00
Exploratory
panels
NC
HR (95% CI)
0.95 (0.49–1.94)
1.01 (0.55–1.95)
NC (<20 events)
0.92 (0.51–1.73)
1.35 (0.65–3.14)
1.83 (0.76–5.43)
3
Published
panels
Favours placebo + bev
Favours olaparib + bev
HR (95% CI)
No benefit for olaparib + bevacizumab was seen regardless
of the panel used
Pre-defined
Expanded
Restricted
Used in Study 19
Used in ARIEL3
Used in NOVA

© AstraZeneca 2021
The most common AE leading to dose reductions was anaemia
Primary analysis data cut-off: 22 March 2019. Median duration of follow-up for primary analysis: olaparib, 22.7 months; placebo, 24.0 months
AE=adverse event
AstraZeneca data on file (2019).
AEs leading to dose
reduction, n (%)
n=535
n=267
Any 220 (41.1) 20 (7.5)
Anaemia 99 (18.5) 0
Nausea 40 (7.5) 2 (0.7)
Fatigue 21 (3.9) 2 (0.7)
Diarrhoea 8 (1.5) 4 (1.5)
Thrombocytopenia 8 (1.5) 0
Neutrophil count decreased 4 (0.7) 0
Platelet count decreased 4 (0.7) 0
Stomatitis 4 (0.7) 0
Vomiting 4 (0.7) 0
Abdominal pain 3 (0.6) 1 (0.4)
Headache 3 (0.6) 1 (0.4)
Myalgia 3 (0.6) 1 (0.4)
Neutropenia 3 (0.6) 1 (0.4)
64

Fachkurzinformation Olaparib Filmtabletten
65
BEZEICHNUNG DES ARZNEIMITTELS
Lynparza 100 mg Filmtabletten, Lynparza 150 mg Filmtabletten
Pharmakotherapeutische Gruppe: Antineoplastische Mittel, andere antineoplastische Mittel;ATC Code: L01XX46
QUALITATIVE UND QUANTITATIVE ZUSAMMENSETZUNG
Lynparza 100 mg Filmtabletten. Jede Filmtablette enthält 100 mg Olaparib.
Lynparza 150 mg Filmtabletten. Jede Filmtablette enthält 150 mg Olaparib.
Sonstiger Bestandteil mit bekannter Wirkung: Dieses Arzneimittel enthält 0,24 mg Natrium pro 100-mg-Tablette und 0,35 mg Natrium pro 150-mg-Tablette.
Sonstige Bestandteile:
Tablettenkern:Copovidon, Hochdisperses Siliciumdioxid, Mannitol (Ph.Eur.), Natriumstearylfumarat (Ph.Eur.)
Filmüberzug
Hypromellose, Macrogol (400), Titandioxid (E171), Eisen(III) hydroxid-oxid x H2O (E172), Eisen(II,III)-oxid (E172) (nur 150-mg-Tabletten)
ANWENDUNGSGEBIETE
Ovarialkarzinom
Lynparza wird angewendet als Monotherapie für die:
• Erhaltungstherapie von erwachsenen Patientinnen mit einem fortgeschrittenen (FIGO-Stadien III und IV) BRCA1/2-mutierten (in der Keimbahn und/oder somatisch), high-grade epithelialen Ovarialkarzinom, Eileiterkarzinom oder primären
Peritonealkarzinom, die nach einer abgeschlossenen Platin-basierten Erstlinien-Chemotherapie ein Ansprechen (vollständig oder partiell) haben.
• Erhaltungstherapie von erwachsenen Patientinnen mit einem Platin-sensitiven Rezidiv eines high-grade epithelialen Ovarialkarzinoms, Eileiterkarzinoms oder primären Peritonealkarzinoms, die auf eine Platin-basierte Chemotherapie
ansprechen (vollständig oder partiell).
Lynparza in Kombination mit Bevacizumab wird angewendet für die:
• Erhaltungstherapie von erwachsenen Patientinnen mit einem fortgeschrittenen (FIGO-Stadien III und IV) high-grade epithelialen Ovarialkarzinom, Eileiterkarzinom oder primären Peritonealkarzinom, die nach einer abgeschlossenen Platin-
basierten Erstlinien-Chemotherapie in Kombination mit Bevacizumab ein Ansprechen (vollständig oder partiell) haben und deren Tumor mit einem positiven Status der homologen Rekombinations-Defizienz (HRD) assoziiert ist. Der Status HRD-positiv ist
definiert entweder durch eine BRCA1/2-Mutation und/oder genomische Instabilität (siehe Abschnitt 5.1 der Fachinformation).
Mammakarzinom
Lynparza wird als Monotherapie für die Behandlung von erwachsenen Patienten mit BRCA1/2 Mutationen in der Keimbahn angewendet, die ein HER2-negatives, lokal fortgeschrittenes oder metastasiertes Mammakarzinom haben. Die Patienten sollten
zuvor mit einem Anthrazyklin und einem Taxan im (neo)adjuvanten oder metastasierten Setting behandelt worden sein, es sei denn, die Patienten waren für diese Behandlungen nicht geeignet (siehe Abschnitt 5.1 der Fachinformation). Patienten mit
Hormonrezeptor (HR)-positivem Mammakarzinom sollten außerdem eine Krankheitsprogression während oder nach einer vorherigen endokrinen Therapie aufweisen oder für eine endokrine Therapie nicht geeignet sein.
Adenokarzinom des Pankreas
Lynparza wird angewendet als Monotherapie für die Erhaltungstherapie von erwachsenen Patienten mit Keimbahn-BRCA1/2-Mutationen, die ein metastasiertes Adenokarzinom des Pankreas haben und deren Erkrankung nach einer mindestens 16-
wöchigen Platin-haltigen Behandlung im Rahmen einer Erstlinien-Chemotherapie nicht progredient war.
Prostatakarzinom
Lynparza wird angewendet als Monotherapie für die Behandlung von erwachsenen Patienten mit metastasiertem kastrationsresistentem Prostatakarzinom und BRCA1/2-Mutationen (in der Keimbahn und/oder somatisch), deren Erkrankung nach
vorheriger Behandlung, die eine neue hormonelle Substanz (new hormonal agent) umfasste, progredient ist.
GEGENANZEIGEN
Überempfindlichkeit gegen den Wirkstoff oder einen der in Abschnitt 6.1 der Fachinformation genannten sonstigen Bestandteile. Stillen während der Behandlung und 1 Monat nach Einnahme der letzten Dosis (siehe Abschnitt 4.6 der Fachinformation).
INHABER DER ZULASSUNG
AstraZeneca AB, SE 151 85 Södertälje,Schweden
REZEPTPFLICHT/APOTHEKENPFLICHT
Rezept- und apothekenpflichtig, wiederholte Abgabe verboten
STAND DER INFORMATION
11/2020
Informationen zu den Abschnitten besondere Warnhinweise und Vorsichtsmaßnahmen für die Anwendung, Wechselwirkungen mit anderen Arzneimitteln und sonstige Wechselwirkungen, Fertilität, Schwangerschaft und Stillzeit, Nebenwirkungen sowie
den Gewöhnungseffekten sind der veröffentlichten Fachinformation (z. B. Austria Codex) zu entnehmen.
Fachkurzinformation Olaparib Filmtabletten, Stand November 2020

© AstraZeneca 2021
Confidentiality Notice
This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove
it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the
contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 1 Francis Crick Avenue, Cambridge Biomedical Campus,
Cambridge, CB2 0AA, UK, T: +44(0)203 749 5000, www.astrazeneca.com
66

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