Olaparib Delays Progression in gBRCAm Metastatic Pancreatic Cancer

Olaparib in
patients with
gBRCAm
metastatic
pancreatic cancer
Chandan Das
Medical Oncology
PGIMER, Chandigarh

Overview
• Introduction to Pancreatic Cancer
• Maintenance in Ca Pancreas
• The role of BRCA in Pancreatic Cancer
• The POLO trial
• Study Design
• Results
• Safety data

Epidemiology :Globocan 2020
Gaidhani RH, Balasubramaniam G. An epidemiological review of pancreatic cancer with special reference to India. Availablefrom: https://dx.doi.org/10.25259/IJMS_92_2020

Patients with pancreatic cancer have a poor prognosis, the
majority will die within the first year of diagnosis
• 1. Pancreatic cancer. www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer/survival (accessed May 2019); 2. Cancer of the Pancreas (Invasive)
https://seer.cancer.gov/archive/csr/1975_2014/results_merged/sect_22_pancreas.pdf (accessed May 2019); 3. David M et al. Br J Cancer. 2009;101:215–8; 4. Kuroda T et al. BMC Gastroenterol. 2013;13:134; 5. Siegel RL et al. CA Cancer J Clin.
2016;66:7–30; 6. Yu J et al. Gut. 2015;64:1783-9
Pancreatic cancer is generally diagnosed at a late stage, and there are limited treatment options3-6
20.8%
3.3% 1.1%
35.3%
8.5% 4.1%
0
20
40
60
80
100
1 year 5 year 10 year
Survival
rate
(%)
Time after diagnosis
UK US
1 year
UK US
5 years
UK US
10 years

Moreover, there have been no improvement in survival rates for
patients with pancreatic cancer in the last four decades
• *Arrows represent change in net survival at 1, 5 and 10 years after diagnosis for all tumour types combined in England for adults (15-99 years) and trends in age-adjusted net survival for selected tumours (all patients) between 1971–72
to 2010–11
• Quaresma M et al. Lancet 2015;385:1206–18
1971 >>>>>>>> 2011
Change in survival
rates over 40
years*
All cancers
Pancreas
Ovarian
Kidney
Bladder
Breast
Malignant
melanoma
Prostate
Lung
0% 25% 50% 100%
75% 0% 25% 50% 100%
75% 0% 25% 50% 100%
75%
Survival
1-year survival rate 10-year survival rate
5-year survival rate

There is a significant unmet need to prolong disease control as part of
first-line treatment for patients with pancreatic cancer
•*LA or metastatic unresectable pancreatic cancer; **Metastatic pancreatic cancer.
•mPFS values in graphic; mPFS varies between studies due to study design, inclusion/exclusion criteria and patient demographics.
•5-FU=5-fluorouracil
• 1. Burris HA et al. J Clin Oncol. 1997;15(6):2403؎2413.; 2. Conroy T, et al. N Engl J Med. 2011;364(19):1817-1825; 3. Von Hoff DD et al. N Engl J Med 2013; 369:1691-1703
Existing regimens: Time from original diagnosis to progression
Randomised
6.4 months2
1.0 month1
3.3–3.7 months2,3
Gemcitabine**
5-FU*
mFOLFIRINOX**
Gemcitabine + nab-paclitaxel**
5.5 months3

Overview
• Maintenance strategies in ca pancreas
• The POLO trial
• Study Design
• Results
• Safety data

Maintenance in Ca Pancreas
8
Olaparib for
mBRCA

Maintenance trial in Ca Pancreas
9

Overview
• The POLO trial
• Study Design
• Results
• Safety data

It is estimated that 5–7% of all patients with pancreatic cancer
have germline BRCA mutations*
• *Deleterious or suspected deleterious mutations
• **Ashkenazi Jewish population
• 1. Holter S et al. J Clin Oncol. 2015;33:3124-3129; 2. Golan T et al. Poster related to abstract 4115, presented at ASCO 2018; 3. Zhen DB et al. Genet Med. 2015;17:569–577; 4. Hu C et al. Cancer Epidemiol Biomarkers Prev. 2016;25:207–
211; 5. Shindo K et al. J Clin Oncol. 2017;35:3382–3390; 6. Waddell N et al. Nature. 2015;518(7540):495–501; 7. Aguirre AJ et al. Cancer Discov. 2018;8:1096–1111; 8. Raphael BJ, et al. Cancer Cell. 2017;32:185–203; 9. Goggins M et al.
Cancer Res. 1996;56:5360--5364; 10. Lal G et al. Cancer Res. 2000;15;60:409–416
The prevalence of gBRCAm varies by geography and ethnic group1-10
gBRCAm prevalence in the general
pancreatic cancer population is estimated
to equal:
Approximately
1 in 15
gBRCAm1–6
1:3
BRCA1m:BRCA2m
Approximate
ratio1–9
BRCA2 mutations are more prevalent
than BRCA1 mutations1–9
Germline BRCA mutations may be
increased in:1,10
People with
family history
Some ethnic
groups**

However, evidence suggests BRCAm is predictive of better
outcomes to platinum-based therapy
• gBRCAm=germline BRCA mutation; HR-DDR=Homologous recombination repair DNA damage response; LA=locally advanced; mOS= median overall survival; NCCN=National Comprehensive Cancer Network; PC=pancreatic cancer
•
1. Golan T et al. Br J Cancer. 2014;111(6):1132–1138; 2. Pishvaian M et al. Poster presented at ASCO GI 2019. Abstract #191; 3. Phlilip, P. A. et al.. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2009; 27:5660–5669
OS by platinum treatment for gBRCAm pancreatic
cancer (Stages III-IV, n=43)1
OS by platinum treatment for HR-DDR mutated advanced pancreatic
cancer (N=445 LA/metastatic*)2
Non-platinum
N=21
Non-platinum
N=19
Platinum
N=54
Platinum
N=22
0.75 years 0.76 years
1.8 years 2.37 years

Double-
stranded
DNA break
Single-stranded
DNA break
Unrepaired
SSB
Translesional
synthesis
Nucleotide
excision
repair
Mismatch
repair
Base
excision
repair
DNA
PARylation
PARP
Non-
homologous
end-joining
Low fidelity
Homologous
recombination
High fidelity
DNA-PKcs
PARP inhibitor
DNA damage
Double-Stranded and Single-Stranded Break
Repair With PARP Inhibitors
Lee. Ann Oncol. 2014;25:32.

Olaparib in Ca Pancreas: Phase II trial
16
Kaufmann et al Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation J Clin Oncol 2015 Jan 20;33(3):244-50.

POLO (Pancreas Cancer Olaparib Ongoing) trial
• *Planned N=145; **There was no crossover as part of the study design; †Modified RECIST 1.1
BICR=blinded independent central review; bid=twice daily; DCR=disease control rate; ECOG=Eastern Cooperative Oncology Group; HRQoL=health related quality of life; mPAC=metastatic pancreatic cancer; ORR=objective response rate; OS=overall
survival; PARPi=poly (ADP ribose) polymerase inhibitor; PFS=progression free survival; PFS2=time to secondary progression; po=by mouth; PS=performance status; TDT=time to study treatment discontinuation or death; TFST=time to first
subsequent therapy; TSST=time to second subsequent therapy
•
Golan T et al. Article and supplementary appendix online ahead of print. New Engl J Med. 2019.
A double blind study in patients who have not progressed on first-line platinum-based therapy
Primary endpoint
• PFS (BICR)†
Secondary endpoints
• OS
• PFS2
• TFST
• TSST
• TDT
• ORR (BICR)†
• DCR (BICR)†
• HRQoL
• Safety and tolerability
No stratification
Randomisation
3:2
N=154*
• Metastatic pancreatic adenocarcinoma
• gBRCAm
• ECOG PS 0 or 1
• ≥16 weeks of first-line platinum-based
chemotherapy for mPAC with no
evidence of disease progression. No limit
to duration of chemotherapy.
• No persistent CTCAE Grade ≥2 toxicities
from current therapy, excluding alopecia
and CTCAE Grade 3 peripheral
neuropathy
Treatment until
progression**
Olaparib
300 mg po bid
n=92
Placebo
po bid
n=62

The most comprehensive dataset to date for gBRCA mutations in
metastatic pancreatic cancer
• *Percentageof patientswithpreviouslyunknownBRCAmstatus
• Testedbetween October2014 and December2017 – Numbers are different from ITT populationin thePOLO studywhichcontinuedto screen patients
•
1. Golan T et al., Poster related to abstract 4115, presented at ASCO 2018; 2. Golan T et al. Article and supplementary appendix online ahead of print. New Engl J Med. 2019.
gBRCAm
159 patients
96.3% of
patients with
known gBRCAm
were white
Newly identified
gBRCAm
130 patients
Newly identified
gBRCAm excluding
the US and Israel
85 patients
2206
patients
screened
6.0%*
7.2% 5.1%*
Highest prevalence
in US, Israel and
France
Final data from all 3315
patients screened were
consistent with this interim
analysis. The overall mutation
rate was 7.4%2

POLO is a global study :12 countries worldwide
• Golan T et al. Article and supplementary appendix online ahead of print. New Engl J Med. 2019.
Country, n (%)
Total
N=154
US 32 (20.8)
France 24 (15.6)
Israel 23 (14.9)
Germany 20 (13.0)
Italy 16 (10.4)
Spain 11 (7.1)
UK 9 (5.8)
Republic of Korea 6 (3.9)
Belgium 5 (3.2)
Canada 3 (1.9)
Netherlands 3 (1.9)
Australia 2 (1.3)
Canada
US
Italy
Israel
Republic ofSouth
Korea
TheNetherlands
Belgium
Germany
UK
France
Spain

Enrolment : 4 year period between January 2015 and January
2019
• *Last date known to be alive for patients who had not died at the time of the analysis
• BICR=blinded independent central review; OS=overall survival; PFS=progression-free survival
First patient
enrolled
January 2015
Last patient
enrolled
January 2019
Data cut-off for
primary PFS
analysis
15 January 2019
2015 2016 2017 2018 2019
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3
• Primary events achieved: 104 PFS by BICR events (target=87)
• OS events achieved: 71 OS events

Baseline patient characteristics
• *Myriad result. n=3 and n=1 patient were missing testing results in the olaparib and placebo arms, respectively.
• Some patients were missing information in the olaparib and placebo arms. Data cut-off: 15 January 2019
• ECOG=Eastern Cooperative Oncology Group; PS=performance status
• 1. Golan T et al. Article and supplementary appendix online ahead of print. New Engl J Med. 2019.; 2. Kindler H et al., Abstract LBA4 presented at ASCO 2019
Olaparib
N=92
Placebo
N=62
Total
N=154
Median age, years (range) 57.0 (37-84) 57.0 (36-75) 57.0 (36-84)
Age at randomisation, n (%)
<65 years 64 (69.6) 49 (79.0) 113 (73.4)
≥65 years 28 (30.4) 13 (21.0) 41 (26.6)
Sex, n (%)
Male 53 (57.6) 31 (50.0) 84 (54.5)
Female 39 (42.4) 31 (50.0) 70 (45.5)
BRCA mutation status, n (%)*
BRCA1 29 (31.5) 16 (25.8) 45 (29.2)
BRCA2 62 (67.4) 46 (74.2) 108 (70.1)
Both 1 (1.1) 0 1 (0.6)
ECOG PS, n (%)
0 65 (70.7) 38 (61.3) 103 (66.9)
1 25 (27.2) 23 (37.1) 48 (31.2)
Median time from diagnosis to randomisation, months (range) 6.9 (3.6-38.4) 7.0 (4.1-30.2) 6.9 (3.6-38.4)
Duration of first-line chemotherapy
Median, months (range) 5.0 (2.5-35.2) 5.1 (3.4-20.4) -
16 weeks to 6 months, n (%) 61 (66.3) 40 (64.5) 101 (65.6)
>6 months, n (%) 30 (32.6) 21 (33.9) 51 (33.1)

The liver was the most common site of metastasis prior to
chemotherapy in both treatment groups
• Full analysis set
• Data cut-off: 15 January 2019
Most patients did not have a biliary stent
Olaparib
N=92
n (%)
Placebo
N=62
n (%)
Total
N=154
n (%)
Site of metastasis prior
to chemotherapy
Liver 61 (66.3) 48 (77.4) 109 (70.8)
Lung 10 (10.9) 5 (8.1) 15 (9.7)
Peritoneum 10 (10.9) 5 (8.1) 15 (9.7)
Other 14 (15.2) 8 (12.9) 22 (14.3)
Biliary stent
Present 1 (1.1) 4 (6.5) 5 (3.2)
Absent 91 (98.9) 58 (93.5) 149 (96.8)

Patients were well balanced in terms of their response to first-line
therapy
• Some patients were missing information in the olaparib and placebo arms.
Data cut-off: 15 January 2019
• PR/CR=partial response/complete response; SD=stable disease.
FOLFIRINOX variants were the most common first-line therapy, with approximately one third of patients
receiving more than 6 months of treatment Olaparib
N=92
Placebo
N=62
Total
N=154
Previous chemotherapy,
n (%)
FOLFIRINOX variants 79 (86.9) 50 (80.6) 129 (83.8)
Gemcitabine/cisplatin 2 (2.2) 3 (4.8) 5 (3.2)
Other 10 (10.9) 8 (12.9) 18 (11.7)
Type of previous
chemotherapy, n (%)
Doublets 15 (16.3) 10 (16.1) 25 (16.2)
Triplets 73 (79.3) 46 (74.2) 119 (77.3)
Other 3 (3.2) 5 (8.1) 8 (5.2)
Median time from diagnosis to randomisation, months (range) 6.9 (3.6-38.4) 7.0 (4.1-30.2) 6.9 (3.6-38.4)
Time on first-line treatment
until randomisation
Median, months (range) 5.0 (2.5-35.2) 5.1 (3.4-20.4) -
16 weeks to 6 months, n (%) 61 (66.3) 40 (64.5) 101 (65.6)
>6 months, n (%) 30 (32.6) 21 (33.9) 51 (33.1)
Best response on first-line
treatment, n (%)
SD 45 (48.9) 31 (50.0) 76 (49.4)
PR/CR 46 (50.0) 30 (48.4) 76 (49.4)

Olaparib significantly improved PFS reducing the risk of progression or
death by 47% compared with placebo
• PFS by BICR assessment, data maturity = 68%
• Data cut-off: 15January 2019
• BICR=blinded independent central review; CI=confidence interval; HR=hazard ratio; PFS=progression free survival
•
Median PFS was improved by 3.6 months with olaparib treatment compared to placebo
Median PFS was almost
doubled, with a 95%
improvement over placebo
Olaparib
(N=92)
Placebo
(N=62)
Events, n (%) 60 (65.2) 44 (71.0)
Median PFS, months
(BICR) 7.4 3.8
Median difference +3.6
HR=0.53
95% CI (0.35-0.82)
p=0.004
Number of patients at risk
Olaparib 92 69 50 41 34 24 18 17 14 10 10 8 8 7 5 3 3 3 3 2 1 1 1 0
Placebo 62 39 23 10 6 6 4 4 4 2 2 2 2 1 1 0
Probability
of
progression
free
survival
1.0
0
0.2
0.4
0.6
0.8
0 2 6 14 18 22 26 28 32 36
Time from randomisation (months)
10 24 30 40 46
0.9
0.1
0.3
0.5
0.7
4 8 12 16 20 34 38 42 44
Olaparib 300 mg bid (N=92)
Placebo bid (N=62)

Twice as many patients were progression-free following olaparib
treatment compared to placebo at all timepoints assessed
• BICR analysis
• Data cut-off: 15 January 2019.
• PFS=progression-free survival
30% more patients were progression-free at 6 months following randomisation to olaparib
maintenance compared to placebo
53.0
33.7
27.6
22.1
23.0
14.5
9.6 9.6
0
20
40
60
80
100
6 months 12 months 18 months 24 months
%
free
of
progression
or
death
Placebo (N=62)

POLO: Illustrative summary of first-line treatment
Time on first-line
chemotherapy
Metastatic
disease
diagnosis
Olaparib
N=92
Placebo
N=62
PFS on maintenance
treatment (median)
PFS HR=0.53
95% CI (0.35-0.82);
p=0.004
Approximately
one year since
mPAC diagnosis
Approximately six
months since
mPAC diagnosis
3.8 months
5.1 months
(3.4-20.4)
4-8
weeks
7.4 months
5.0 months
(2.5-35.2)
4-8
weeks
R
12 month

PFS benefit with olaparib was consistent across the prespecified pt
subgroups, including patients with PR/CR or SD at baseline
• BICR analysis
• CR=complete response; NED=no evaluable disease; PFS=progression-free survival;
• PR=partial response; SD=stable disease
POLO was not
powered to
demonstrate
differences
between
subgroups
Olaparib Placebo
All patients 0.53 (0.35-0.82) 60/92 (65.2) 44/62 (71.0)
Previous chemotherapy
FOLFIRINOX variants
Other
0.54 (0.35-0.84)
0.76 (0.27-2.32)
50/79 (63.3)
8/10 (80.0)
35/50 (70.0)
6/8 (75.0)
Absence of biliary stent 0.54 (0.36-0.82) 59/91 (64.8) 40/58 (69.0)
Type of previous chemotherapy
Doublets
Triplets
0.59 (0.24-1.50)
0.51 (0.32-0.82)
12/15 (80.0)
45/73 (61.6)
8/10 (80.0)
33/46 (71.7)
Time on first-line treatment before randomisation
16 weeks-6 months
> 6 months
0.69 (0.43-1.12)
0.35 (0.17-0.72)
42/61 (68.9)
18/30 (60.0)
29/40 (72.5)
15/21 (71.4)
Best response on first-line treatment
PR / CR
SD
0.62 (0.35-1.12)
0.50 (0.29-0.87)
30/46 (65.2)
30/45 (66.7)
20/30 (66.7)
24/31 (77.4)
Measurable vs. non-measurable disease / NED at baseline
Measurable
Non-measurable or NED
0.57 (0.37-0.88)
0.45 (0.4-1.57)
53/78 (67.9)
7/13 (53.8)
39/52 (75.0)
5/6 (83.3)
gBRCA mutation type (by Myriad)
BRCA1
BRCA2
0.40 (0.20-0.85)
0.63 (0.39-1.02)
20/29 (69.0)
38/59 (64.4)
12/16 (75.0)
32/45 (71.1)
Age at randomisation
< 65 years
≥ 65 years
0.45 (0.28-0.72)
1.02 (0.45-2.60)
39/64 (60.9)
21/28 (75.0)
37/49 (75.5)
7/13 (53.8)
Sex
Male
Female
0.46 (0.27-0.80)
0.66 (0.37-1.19)
33/53 (62.3)
27/39 (69.2)
23/31 (74.2)
21/31 (67.7)
Race
White 0.59 (0.39-0.90) 55/82 (67.1) 41/59 (69.5)
0.01 1 10
0.1
Hazard ratio (95% CI)

Most patients who received a PARP inhibitor as a subsequent line
of therapy received olaparib
• PARP=poly (ADP ribose) polymerase
• 1. Golan T et al. Article and supplementary appendix online ahead of print. New Engl J Med. 2019; 2. AstraZeneca data on file (2019)
Almost all of these patients were in the placebo arm, with the exception of one patient in the
olaparib arm who received a PARP inhibitor as a fifth-line therapy1
Olaparib
N=92
Placebo
N=62
Total
N=154
Received PARP inhibitor1, n (%) 1 (1.1) 9 (14.5) 10 (6.5)
Line of subsequent therapy2, n
(%)
Second 0 2 (3.2) 2 (1.3)
Third 0 6 (9.7) 6 (3.9)
Fourth 0 1 (1.6) 1 (0.6)
Fifth 1 (1.1) 1 (1.6) 2 (1.3)
Patients in placebo arm who subsequently received olaparib1, n (%) - 7 (11.3) 7 (4.5)

23% of patients with measurable disease at baseline had a
response to olaparib treatment
• *In patients with measurable disease at baseline
• Analysis performed by logistic regression. OR >1 favours olaparib.
• BICR=blinded independent central review; CI=confidence interval; CR=complete response; DCR=disease control rate; DoR=duration of response; IQR=interquartile range; OR=odds ratio; ORR=objective response rate; PR=partial response
• 1. Golan T et al. Article and supplementary appendix online ahead of print. New Engl J Med. 2019.; 2. Golan T et al. Abstract LBA001, presented at WCGIC 2019; 3. AstraZeneca data on file (2019)
Median duration of response in these patients was over 2 years1
Olaparib
N=92
Placebo
N=62
ORR in patients with measurable disease at baseline, n/N (%)1
18/78 (23.1) 6/52 (11.5)
OR=2.30 (95% CI 0.89-6.76)
CR*, n/N (%)1
PR*, n/N (%)1
2/78 (2.6)
16/78 (20.5)
0/52
6/52 (11.5)
DCR, n (%)2 49 (53.3) 23 (37.1)
Median time to onset of response from randomisation, months (IQR)1,3 5.4 (3.6-5.6) 3.6 (1.9-5.8)
Median DoR from onset of response, months (95% CI)1 24.9 (14.8-NC) 3.7 (2.1-NC)

Over half of patients on olaparib had disease control at 16 weeks
• Disease control defined as complete or partial response (by modified RECIST v1.1) at ≥1 visit, or stable or no evidence of disease for ≥15 weeks
• *By modified RECIST v1.1, four olaparib arm and five placebo arm patients were not evaluable; **Applicable to patients entering the study with no evidence of disease
• Golan T et al. Abstract LBA001, presented at WCGIC 2019
19.6%
n=18
48.9%
n=45
5.4%; n=5
21.7%
n=20
9.7%
n=6
54.8%
n=34
27.4%
n=17
100
50
0
40
30
20
10
60
70
80
90
Progression
No evidence
of disease**
Stable disease
≥7 weeks
Response
Olaparib Placebo
53.3%
n=49
37.1%
n=23
Olaparib Placebo
Disease control rate at 16 weeks
Best objective response*

Most patients went onto receive subsequent therapy after the end
of study treatment
• *Subsequent therapies may be reported as regimens or as individual drugs and in some cases are reported both ways
• †Other chemotherapy regimen’ includes platinum-based combinations (listed) and non-platinum-containing chemotherapy regimens.
• No cross over to olaparib was permitted as part of the study.
Olaparib
N=92
Placebo
N=62
Total
N=154
Remaining on treatment at data cut off, n (%) 30 (32.6) 8 (12.9) 38 (24.7)
Received subsequent anti-cancer therapy*, n (%) 45 (48.9) 46 (74.2) 91 (59.1)
Subsequent platinum chemotherapy, n
(%)
Carboplatin 4 (4.3) 4 (6.5) 8 (5.2)
Cisplatin 10 (10.9) 12 (19.4) 22 (14.3)
Oxaliplatin 9 (9.8) 4 (6.5) 13 (8.4)
PARP inhibitor, n (%)
Olaparib 0 7 (11.3) 7 (4.5)
Rucaparib 1 (1.1) 1 (1.6) 2 (1.3)
Veliparib 0 1 (1.6) 1 (0.6)
Subsequent other chemotherapy
regimen†, n (%)
FOLFIRINOX 17 (18.5) 18 (29.0) 35 (22.7)
FOLFOX 2 (2.2) 5 (8.1) 7 (4.5)
Gemcitabine/cisplatin 1 (1.1) 1 (1.6) 2 (1.3)
GEMOX 1 (1.1) 0 1 (0.6)

OS data are not mature
• Data maturity = 46%
• CI=confidence interval; HR=hazard ratio; OS=overall survival
Median OS in the olaparib arm was 18.9 months compared to 18.1 months in the placebo arm
OS data maturity at DCO was 46%.
There was no evidence of detriment
and final OS analysis will occur at
approximately 106 events
Olaparib
(N=92)
Placebo (N=62)
Events, n (%) 41 (44.6) 30 (48.4)
Median OS, months 18.9 18.1
HR=0.91
95% CI (0.56-1.46)
p=0.68
Probability
of
overall
survival
1.0
0
0.2
0.4
0.6
0.8
0 2 6 14 18 22 26 28 32 36
Time from randomisation (months)
10 24 30 40 46
0.9
0.1
0.3
0.5
0.7
4 8 12 16 20 34 38 42 44
Placebo bid (N=62)
Olaparib 92 87 80 71 61 51 46 39 31 28 20 16 14 12 9 6 5 4 4 4 2 1 1 0
Placebo 62 60 56 50 44 32 29 27 20 18 14 10 8 8 6 6 4 1 1 1 1 1 1 0

There was a trend towards benefit in PFS2 but the difference was not
significant
• PFS2 by investigator assessment, data maturity = 46%
CI=confidence interval; HR=hazard ratio; PFS2=time from randomisation to second progression (PFS2 is defined as time from the date of randomisation to the earliest of the progression event subsequent to that used for the primary variable
PFS or death)
Median PFS2 was 13.2 months in the olaparib arm compared with 9.2 months in the placebo arm1,2
Olaparib
(N=92)
Placebo (N=62)
Events, n (%)1 41 (44.6) 30 (48.4)
Median PFS2, months1 13.2 9.2
HR=0.76
95% CI (0.46-1.23)1
p=0.26
Probability
of
progression
free
survival
2
1.0
0
0.2
0.4
0.6
0.8
0.9
0.1
0.3
0.5
0.7
Placebo bid (N=62)
92 82 65 56 43 32 27 22 19 13 12 11 8 7 5 4 3 3 3 2 1 1 1 0
62 54 43 36 24 17 12 7 5 4 4 4 3 2 2 1 0
Olaparib
Placebo
PFS2 data were 46% mature at data
cut off1
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50

18.1
9.2
3.8
18.9
13.2
7.4
0 2 4 6 8 10 12 14 16 18 20
mOS
PFS2
mPFS
Placebo (N=62)
Summary of time to endpoints
PFS2
(46% maturity)
OS
(46% maturity)
HR=0.76
95% CI (0.46-1.23)
p=0.26
HR=0.91
95% CI (0.56-1.46)
p=0.68
PFS by BICR assessment; PFS2 by investigator assessment
Data cut-off: 15January 2019
CI=confidence interval; HR=hazard ratio; OS=overall survival; PFS=progression-free survival; PFS2=time from randomisation to second progression
1. Golan T et al. Article and supplementary appendix online ahead of print. New Engl J Med. 2019; 2. Kindler H et al., Abstract LBA4 presented at ASCO 2019
PFS
(68% maturity)
HR=0.53
95% CI (0.35-0.82)
p=0.004
Median, months

There was no difference in change in HRQoL from baseline over the
first six months of treatment between arms
• Global HRQoL is measured on a 100 point scale; A 10-point change is considered clinically meaningful.
• CI=confidence interval; HRQoL=health-related quality of life; MMRM=mixed model for repeated measures.
Olaparib treatment had no detrimental effect upon patient HRQoL
Global HRQoL Olaparib (n=84) Placebo (n=54)
Adjusted mean change from baseline
(SE) [95% CI]
−1.20 (±1.42) [−4.01 to 1.62] 1.27 (±1.95) [−2.58 to 5.12]
Estimated difference (95% CI) –
MMRM
−2.47 (−7.27 to 2.33)

Global
HRQoL
over time
was similar
between
arms
• Kindler H et al., Abstract LBA4 presented at ASCO 2019
37

Adverse events were generally mild/moderate in the olaparib arm
• *For olaparib, actual treatment duration is reported (total treatment duration – total duration of dose interruptions).
• **No adverse events that occurred during study treatment resulted in death. One stent-related duodenal perforation in an olaparib-treated patient occurred during the 30-day follow-up period after cessation of therapy and was
subsequently fatal.
• Safety Analysis Set
• CTCAE=Common Terminology Criteria for Adverse Events; (S)AE=(Serious) adverse event
Grade ≥3 AEs occurred in 40% of patients in the olaparib arm compared with 23% in the
placebo arm
AE category
Olaparib
N=91
Placebo
N=60
Median treatment duration*, months (range)1 6.0 (0.8-45.3) 3.7 (0.1-30.1)
AnyAE,n(%)1 87 (95.6) 56 (93.3)
Any AE of CTCAE Grade 3 or higher 36 (39.6) 14 (23.3)
Any SAE 22 (24.2) 9 (15.0)
Any AE with outcome of death 0** 0
Any AE leading to discontinuation of treatment 5 (5.5) 1 (1.7)

Consistent
with the
known profile
for olaparib
AE, n (%)
Olaparib
N=91
Placebo
N=60
CTCAE Grade Any grade Grade ≥3 Any grade Grade ≥3
Any 87 (95.6) 36 (39.6) 56 (93.3) 14 (23.3)
Fatigue/asthenia 55 (60.4) 5 (5.5) 21 (35.0) 1 (1.7)
Nausea 41 (45.1) 0 14 (23.3) 1 (1.7)
Anaemia 25 (27.5) 10 (11.0) 10 (16.7) 2 (3.3)
Abdominal pain 26 (28.6) 2 (2.2) 15 (25.0) 1 (1.7)
Diarrhoea 26 (28.6) 0 9 (15.0) 0
Decreased appetite 23 (25.3) 3 (3.3) 4 (6.7) 0
Constipation 21 (23.1) 0 6 (10.0) 0
Vomiting 18 (19.8) 1 (1.1) 9 (15.0) 1 (1.7)
Back pain 17 (18.7) 0 10 (16.7) 1 (1.7)
Arthralgia 14 (15.4) 1 (1.1) 6 (10.0) 0

Only fatigue
resulted in
treatment
discontinuation
for more than
one patient
AE leading to treatment discontinuation*,
Preferred term, n (%)
Olaparib
N=91
Placebo
N=60
Any AE 5 (5.5) 1 (1.7)
Fatigue/asthenia**,† 2 (2.2) 0
Decreased appetite† 1 (1.1) 0
Proteinuria 1 (1.1) 0
Gastric fistula 1 (1.1) 0
Vomiting 1 (1.1) 0
Arthralgia** 1 (1.1) 0
Myalgia** 1 (1.1) 0
Pyrexia 0 1 (1.7)

AEs of special interest were in line with rates seen in previous trials
of olaparib
• *Starting after the follow-up period of 30 days after last dose of study drug; **The case of pneumonitis was not considered to be causally related to the trial intervention by the investigators
• Safety Analysis Set
• AE=adverse event, MDS/AML=myelodysplastic syndrome/acute myeloid leukaemia
It was not mandatory to report these AEs after the standard 30 day off-treatment window in the POLO protocol
MDS/AML
– No events reported
Pneumonitis
– 1 non-serious event in
the olaparib arm**
New primary
malignancies
– 1 event of rectal
cancer in the placebo
arm*
– 1 potential event of
ovarian cancer in the
placebo arm*

Critical Analysis of POLO
• Phase III study
• PFS benefit
• Only modality to exceed
12-month PFS
• Good DCR
• QoL not impired
• Initial 3-month similar PFS rate
• OS benefit unlikely
• Toxicity
• Platinum vs PARP :No answer
42

What to do after 1st line mCa Pancreas
43
Olaparib for BRCA 7.4m
Capecitabine 5m
6.4 m
5.7m
LV5FU 5.7m

Future: Active trials of maintenance therapy in
metastatic pancreatic cancer.

Conclusions
Olaparib maintenance following platinum therapy significantly improves PFS in patients with gBRCA mutated metastatic pancreatic
cancer compared with placebo. Median PFS was improved by 3.6 months
Approximately one fifth of all patients had a response while on olaparib maintenance, the majority of which were durable with a
median duration of response of over two years
Overall survival and PFS2 are not mature
Global quality of life is similar for olaparib and placebo
The safety findings in this study are consistent with the known profile

Olaparib Delays Progression in gBRCAm Metastatic Pancreatic Cancer

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