This document summarizes targeted therapies for ovarian cancer, including anti-angiogenic agents and PARP inhibitors. It discusses several studies evaluating bevacizumab, an anti-VEGF monoclonal antibody, in the first-line and recurrent platinum-sensitive settings. The GOG218 and ICON7 trials showed improved progression-free survival when bevacizumab was added to chemotherapy as first-line treatment. The OCEANS trial found that adding bevacizumab to chemotherapy significantly prolonged progression-free and overall survival compared to chemotherapy alone for platinum-sensitive recurrent ovarian cancer. Adverse events with bevacizumab were consistent with its known safety profile.

1. Targeted Therapy In Ovarian
Cancer
Atlal Abusanad, MD, MSc, CIP, FRCPC
No Disclosure

2. Outline
• Anti-angiogenic agents
– VEGF MoAb
• First line setting
• Recurrent setting
– TKIs of VEGF Receptors
– Other AAA (e.g. vascular disrupting agents)
• PARP inhibitors
• EGFR/HER2 inhibitors

3. Mechanisms of tumor neovascularization
Spannuth WA et al. (2008) Angiogenesis as a strategic target for ovarian cancer therapy
Nat Clin Pract Oncol doi:10.1038/ncponc1051

4. Anti-VEGF/VEGFR in ovarian cancer:
The rational
• VEGF receptor(s) and VEGF ligand(s) are both
over-expressed in ovarian cancer
• VEGF pathways are strongly associated with
the development of malignant ascites,
malignant pleural effusions, and
carcinomatosis
• VEGF pathway over-expression is a negative
prognostic factor in ovarian cancer

5. Beva-ci-zu-mab

6. Bevacizumab Early Phase Trials
*Burger RA, et al. J Clin Oncol 2007; 25: 5165–5171; **Garcia AA, et al. J Clin Oncol
2008; 26: 76–82, ***Cannistra SA, et al. J Clin Oncol 2007; 25: 5180–5186

7. First line setting : GOG218
• Stratification variables
– GOG performance status
– stage/debulking status Bevacizumab 15mg/kg q3w
15 months
Paclitaxel (P) 175mg/m2
Carboplatin (C) AUC6
Carboplatin (C) AUC6
Paclitaxel (P) 175mg/m2
Carboplatin (C) AUC6
Paclitaxel (P) 175mg/m2
Placebo q3w
Placebo q3w
Front-line: epithelial
OV, PP or FT cancer
● Stage III optimal
(macroscopic)
● Stage III
suboptimal
● Stage IV
N=1,873
I
II
III
Arm
1:1:1
Burger, et al. NEJM 2011 (Supplementary information)
OV = ovarian; PP = primary peritoneal
FT = fallopian tube; Bev = bevacizumab
Bev 15mg/kg
R
A
N
D
O
M
I
S
E

8. GOG-0218: significantly increased PFS with
continued bevacizumab compared with
standard chemotherapy
I
CP + Pl
→ Pl
(n=625)
Median PFS (months) 10.6
Stratified analysis HR
(95% CI)
p value one-sided (log rank)
II
CP + B15
→ Pl
(n=625)
11.6
0.89
(0.78–1.02)
0.0437a
III
CP + B15
→ B15
(n=623)
14.7
0.70
(0.61–0.81)
<0.0001a
*p value boundary = 0.0116
Data cut-off date: 25 February 2010
0 6 12 18 24 30 36 42 48
Time (months)
1.0
0.8
0.6
0.4
0.2
0
PFSestimate
CP + B15 → Pl
CP + Pl → Pl
CP + B15  B15

9. Data cut-off date: 26 August 2011 SmPC.
CP + Pl → Pl 625 595 558 506 447 322 202 117 55 27 13 1 -
CP + B15 → Pl 625 598 561 487 442 303 191 109 54 28 11 1 -
CP + B15 → B15 623 588 561 519 462 321 202 115 62 26 9 0 -
GOG-0218: final OS Kaplan-Meier
curves (ITT)
CP + Pl
→ Pl
(n=625)
CP + B15
→ Pl
(n=625)
CP + B15
→ B15
(n=623)
Deaths, n (%)
299
(47.8%)
309
(49.4%)
270
(43.3%)
Median, months 40.6 38.8 43.8
Stratified OS HR* (95% CI)
1.07
(0.91–1.25)
0.88
(0.75-1.04)
Stratified 1-sided log-rank p value 0.2197 0.0641
Overall survival (months)
0 6 66 72
1.0
0.8
0.6
0.4
Proportionsurviving
12 18 24 30 36 42 48 54 60
0.2
0.0
*Relative to CPP

10. QoL conclusions
• Bevacizumab-containing therapy produced statistically
significant QOL disruption during chemotherapy
– this difference was small and below the MID
• QOL was not adversely or favourably affected by prolonged
bevacizumab delivery
• Relative to placebo, adding bevacizumab does not appear to
improve or impair QOL

11. Adverse event (grade when limited), n (%)
Arm I
CP + Pl → Pl
(n=601)
Arm II
CP + B15 → Pl
(n=607)
Arm III
CP + B15 → B15
(n=608)
Gastrointestinal events* (grade ≥2) 7 (1.2) 17 (2.8) 16 (2.6)
Hypertension (grade ≥2) 43 (7.2)
‡
100 (16.5)
‡
139 (22.9)
‡
Proteinuria (grade ≥3) 4 (0.7) 4 (0.7) 10 (1.6)
Pain (grade ≥2) 250 (41.7)
‡
252 (41.5)
‡
286 (47.1)
‡
Neutropenia (grade ≥4) 347 (57.7) 384 (63.3) 385 (63.3)
Febrile neutropenia 21 (3.5) 30 (4.9) 26 (4.3)
Venous thromboembolism 35 (5.8) 32 (5.3) 41 (6.7)
Arterial thromboembolism 5 (0.8) 4 (0.7) 4 (0.7)
Wound disruption 17 (2.8) 22 (3.6) 18 (3.0)
CNS bleeding 0 0 2 (0.3)
Non-CNS bleeding (grade ≥3) 5 (0.8) 8 (1.3) 13 (2.1)
RPLS 0 1 (0.2) 1 (0.2)
*Perforation/fistula/necrosis/leak
‡p<0.05; RPLS = reversible posterior leucoencephalopathy syndrome
GOG-0218: adverse events consistent with those
previously reported with bevacizumab
NEJM
data
Burger, et al. NEJM 2011

12. First line setting : ICON7Schema
Stratification variables:
• Stage and extent of debulking (I–III debulked ≤1 cm vs I–III debulked >1 cm vs IV and
inoperable stage III)
• Timing of intended treatment start (≤4 vs >4 weeks after surgery)
• GCIG group
Paclitaxel 175 mg/m2
Carboplatin AUC 5 or 6
Carboplatin AUC 5 or 6
Paclitaxel 175 mg/m2
18 cycles (12 months)
R
Bevacizumab 7.5 mg/kg q3w
1:1
AUC = area under the curve; OC = epithelial ovarian, primary peritoneal or fallopian tube cancer
n=1528
Dec 2006 to Feb 2009
• FIGO stage I–IIA
(clear cell or grade 3)
or FIGO stage IIB–IV
• Surgically debulked
histologically
confirmed OC
4
Perren, et al. NEJM 2011

13. ICON7: Primary PFS analysis (2010)
Primary PFS
analysis (2010)
100
75
50
25
0
Alivewithoutprogression(%)
Time (months)
0 3 6 9 12 15 18 21 24 27 30
17.3 19.0
HR = 0.81
(95% CI 0.70–0.94)
p=0.0041 10.5 15.9
Time (months)
100
75
50
25
0
Alivewithoutprogression(%)
0 3 6 9 12 15 18 21 24 27 30
Perren TJ, et al. N Engl J Med 2011
Control Research
All patients High risk

14. Numberatrisk
Control 764 484 294 239 198 66
Research 764 604 314 226 182 54
1.00
0.75
0.50
0.25
0
Proportionalivewithoutprogression
Time(months)
0 6 12 18 24 30 36 42 48 54 60
PFS(2013update)
Control Research ∆
Events,n(%) 526(69) 554(73)
Restrictedmean,
months
27.7 29.2 +1.6
Median,months 17.5 19.9 +2.4
Log-ranktest p=0.25
HR(95%CI) 0.93(0.83–1.05)
Non-proportionality test:p<0.0001
BEVexposure 19.917.5
8
CTscansasclinicallyindicated
Numberatrisk
Control 254 109 43 24 18 6
Research 248 175 53 32 23 5
1.00
0.75
0.50
0.25
0
Proportionalivewithoutprogression
Time(months)
0 6 12 18 24 30 36 42 48 54 60
PFS(2013update):
Highrisk(n=502)
Control Research ∆
Events 228 223
Restrictedmean,
months
15.9 20.0 +4.1
Median,months 10.5 16.0 +5.5
Log-ranktest p=0.001
HR(95%CI) 0.73(0.61–0.88)
Non-proportionality test: p<0.0001
16.0
10.5
13
StageIIIsuboptimallydebulked,anystageIVor nodebulkingsurgery
BEVexposure
PFS (2013 update) PFS (2013 update):
High risk (n=502)

15. Final OS by risk groups

16. 6.2
2.5 2.1 1.3 0.4
11.6
4.1 1.5
0.4
0
29.1
2.0
9.2
25.9
4.4 5.0
1.7
1.3
39.6
6.7
3.6
0.4 0
28.3
2.8
12.5
ICON7: adverse events (all grades) consistent with
those previously reported with bevacizumab
ATE = arterial thromboembolism; CHF = congestive heart failure
RPLS = reversible posterior leucoencephalopathy syndrome
VTE = venous thromboembolism
CP (n=753)
CP + B7.5  B7.5 (n=745)
Patients(%)
40
30
20
10
0
Perren, et al. ESMO 2010

17. RECURRENT PLATINUM SENSITIVE
OVARIAN CANCER

18. OCEANS: study schema
Stratification variables:
•Platinum-free interval
(6–12 vs >12 months)
•Cytoreductive surgery for recurrent disease (yes vs no)
Placebo q3w until progression
Bevacizumab 15mg/kg q3w until progression
Platinum-sensitive
recurrent epithelial
ovarian, primary
peritoneal or fallopian
tube cancer
• Measurable disease
• ECOG 0/1
• No prior chemotherapy
for recurrent ovarian
cancer
• No prior Bev
(n=484)
CG + Pl
CG for 6 (up to 10) cycles
G 1000 mg/m2, d1 & 8
C AUC 4
C AUC 4
G 1000 mg/m2, d1 & 8
CG + Bev
AUC=area under the curve; Bev=bevacizumab; C=carboplatin;
ECOG=Eastern Cooperative Group; G=gemcitabine; P=placebo Aghajanian et al. ASCO 2011

19. OCEANS: primary analysis of PFS
CG + Pl
(n=242)
CG + Bev
(n=242)
Events, n (%) 187 (77.3) 151 (62)
Median PFS, months
(95% CI)
8.4
(8.3–9.7)
12.4
(11.4–12.7)
Stratified analysis HR
(95% CI)
Log-rank p-value
0.484
(0.388–0.605)
<0.0001
Proportionprogressionfree
242 177 45 11 3 0
242 203 92 33 11 0
CG + Pl
CG + Bev
No. at risk:
1.0
0.8
0.6
0.4
0.2
0
0 6 12 18 24 30
Time (months)
Aghajanian et al. ASCO 2011

20. 100
80
60
40
20
0
OCEANS: objective response
Aghajanian et al. ASCO 2011
Duration of
response
CG + Pl
(n=139)
CG +
Bev
(n=190)
Median,
months
7.4 10.4
HR (95% CI) 0.534
(0.408–0.698)
p<0.0001a
%
78.5
57.4 PR = 61
PR = 48
CR = 17
CR = 9
Difference: 21.1%
p<0.0001
aCompared for descriptive purposes only
CG + Pl
(n=242)
CG + Bev
(n=242)

21. 0 6 12 18 24 30 36 42 48 54 60
Proportionsurviving
Months
OCEANS: third interim OS
analysisa
GC + Pl
(n=242)
GC + Bev
(n=242)
Events, n (%) 142 (58.7) 144 (59.5)
Median OS, months
(95% CI)
33.7
(29.3‒38.7)
33.4
(30.3‒35.8)
HR (95% CI)
Log-rank P value
0.960 (0.760–1.214)
p=0.7360
aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3
months in BV arm, with 286 deaths (59.1% of patients)
1.0
0.8
0.6
0.4
0.2
0
242 221 159 77 23 0
242 226 171 78 27 0
CG + Pl
CG + Bev
No. at risk:
235
239
190
201
117
127
44
48
7
7
Aghajanian et al. ESMO 2012

22. OCEANS: AEs of special interest
ATE=arterial thromboembolic event; CHF=congestive heart failure; GI=gastrointestinal;
RPLS=reversible posterior leukoencephalopathy syndrome; VTE=venous thromboembolic event
aTwo GI perforations occurred 69 days after last BV dose
Patients, %
CG + Pl
(n=233)
CG + Bev
(n=247)
ATE, all grades 1 3
VTE, grade ≥3 3 4
CNS bleeding, all grades <1 1
Non-CNS bleeding, grades ≥3 1 6
CHF, grades ≥3 1 1
Neutropenia, grade ≥3 56 58
Febrile neutropenia, grade ≥3 2 2
Hypertension, grade ≥3 <1 17
Fistula/abscess, all grades <1 2
GI perforation, all grades 0 0
a
Proteinuria, grade ≥3 1 9
RPLS, all grade 0 1
Wound-healing complication, grades ≥3 0 1
Aghajanian et al. ASCO 2011

23. PD = progressive disease
aEpithelial ovarian, primary peritoneal, or fallopian tube cancer; bOr 10 mg/kg q2w;
c15 mg/kg q3w, permitted on clear evidence of progression
AURELIA Platinum Resistant Ovarian
Cancer: trial design
Stratification factors:
• Chemotherapy selected
• Prior anti-angiogenic therapy
• Treatment-free interval
(<3 vs 3‒6 months from previous platinum
to subsequent PD)
Platinum-resistant OCa
• ≤2 prior anticancer
regimens
• No history of bowel
obstruction/abdominal
fistula, or clinical/
radiological evidence of
rectosigmoid involvement
Treat to
PD/toxicity
Treat to
PD/toxicity
Investigator’s
choice
(without BEV)
Optional BEV
monotherapyc
BEV 15 mg/kg q3wb
+ chemotherapy
Chemotherapy
R
1:1
Chemotherapy options (investigator’s choice):
• Paclitaxel 80 mg/m2 days 1, 8, 15, & 22 q4w
• Topotecan 4 mg/m2 days 1, 8, & 15 q4w
(or 1.25 mg/m2, days 1–5 q3w)
• PLD 40 mg/m2 day 1 q4w
ASCO 2012

24. AURELIA: PFS
Median duration of follow-up: 13.9 months (CT arm) vs 13.0 months (BEV + CT arm)
CT
(n=182)
BEV + CT
(n=179)
Events, n (%) 166 (91%) 135 (75%)
Median PFS, months
(95% CI)
3.4
(2.2‒3.7)
6.7
(5.7‒7.9)
HR (unadjusted)
(95% CI)
Log-rank p value
(2-sided, unadjusted)
0.48
(0.38‒0.60)
<0.001
Time (months)
182 37 8 1 0
179 88 18 1 0
CT
BEV + CT
No. at risk:
93
140
20
49
1
4
0
1
3.4 6.7
Pujade-Lauraine, et al. ASCO 2012
Estimatedprobability
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30

25. Subgroup
No. of
patients
Median PFS, months
HR*
BEV + CT
better
CT
betterCT BEV + CT
All patients 361 3.4 6.7 0.48
Age, years <65
≥65
228
133
3.4
3.5
6.0
7.8
0.49
0.47
PFI, months† <3
3‒6
96
257
2.1
3.6
5.4
7.8
0.53
0.46
Measurable disease, cm No (<1)
Yes (1‒<5)
Yes (≥5)
74
126
161
3.7
3.3
3.3
7.5
7.5
6.0
0.46
0.50
0.47
Ascites Yes
No
113
248
2.5
3.5
5.6
7.6
0.40
0.48
Chemotherapy Paclitaxel
PLD
Topotecan
115
126
120
3.9
3.5
2.1
10.4
5.4
5.8
0.46
0.57
0.32
Subgroup analysis of PFS
*Unadjusted. †Missing n=8
0.2 0.3 0.5 1 2 3 4 5
Pujade-Lauraine, et al. ASCO 2012

26. OS: ITT population
Data cut-off: 25 January 2013. Median duration of follow-up: 27.4 months in both arms
*2-sided log-rank, unadjusted; OS = overall survival
CT
BEV + CT
No. at risk:
CT
(n=182)
BEV + CT (n=179)
Events, n (%) 136 (75) 128 (72)
Median OS,
months (95% CI)
13.3
(11.9‒16.4)
16.6
(13.7‒19.0)
HR (unadjusted)
(95% CI)
0.85
(0.66‒1.08)
p=0.174*
182 130 98 63 29 12 1 0
179 148 106 75 39 13 1 0
0 6 12 18 24 30 36 42
Time (months)
100
75
50
25
0
Overallsurvival(%)
Witteveen, et al. ECC 2013

27. Median OS by chemotherapy cohort
Chemotherapy
cohort
BEV + CT CT alone HR
(95% CI)
BEV + paclitaxel 22.4 months
(n=60)
13.2 months
(n=55)
0.64
(0.41–1.01)
BEV +
topotecan
13.8 months
(n=57)
13.3 months
(n=63)
1.12
(0.73–1.73)
BEV + PLD 13.7 months
(n=62)
14.1 months
(n=64)
0.94
(0.63–1.42)

28. Incidence of paracentesis during study therapy: subgroup of
patients with ascites at baseline (31% of study cohort)
Data not shown for cycles with <10 patients in one or both arms
0
2
4
6
8
10
12
14
16
18
20
All cycles Screening 1 2 3 4 5 6
CT (n=54)
BEV + CT (n=59)
Patients(%)
Cycle number
CT
BEV + CT
No. at risk:
54 54 36 17
59 59 52 37
54
59
48
57
26
44
13
32
Kristensen, et al. IGCS 2012

29. Grade ≥3 adverse events of special interest, n (%)
CT
(n=181)
BEV + CT
(n=179)
Hypertension 2 (1.1) 13 (7.3)
Grade ≥2 12 (6.6) 36 (20.1)
Proteinuria 0 3 (1.7)
Grade ≥2 1 (0.6) 19 (10.6)
GI perforation 0 3 (1.7)
Grade ≥2 0 4 (2.2)
Fistula/abscess 0 2 (1.1)
Grade ≥2 0 4 (2.2)
Bleeding 2 (1.1) 2 (1.1)
Thromboembolic event
Arterial
Venous
8 (4.4)
0
8 (4.4)
9 (5.0)
4 (2.2)
5 (2.8)
Wound-healing complication 0 0
RPLS 0 1 (0.6)
CHF 1 (0.6) 1 (0.6)
Cardiac disorders (excluding CHF) 0 0
AURELIA: adverse events of special
interest
Pujade Laurraine et al. ASCO 2012
RPLS = reversible posterior leukoencephalopathy syndrome
CHF = congestive heart failure

30. Summary : Bevacizumab & Ovarian Ca
CancerClinical Setting Trial Name Result Impact on practice?
First Line therapy ICON 7
GOG-0218
PFS improved 3
mo
No OS advantage
No
? High risk patients
Recurrent –
platinum
sensitive
OCEANS
PFS improved
3 mo
No OS
advantage
No
Recurrent -
Platinum
resistant
AURELIA
PFS improved
3 mo
OS is not
statistically
significant
palliative benefit and PFS in a
challenging group
? Trend toward improved OS
in a subgroup

31. VEGFR TKI
• AGO-OVAR16
Incorporation of
Pazopanib in
Maintenance Therapy of
Ovarian Cancer

32. PARP Inhibitors

33. Randomized, open-label, Phase II study in patients with
platinum-sensitive, advanced serous ovarian cancer
Patients with:
• Platinum-sensitive
advanced ovarian
cancer
• A serous histology
or serous
component
• Measurable disease
• 3 previous
platinum-containing
regimens
• Progression free for
6 months following
completion of last
platinum-containing
regimen
Olaparib 200 mg bid*
(d1–10 every 21 days)
+ paclitaxel 175 mg/m2
(iv, d1)
+ carboplatin AUC4
(iv, d1)
Paclitaxel 175 mg/m2
(iv, d1)
+ carboplatin AUC6
(iv d1)
Randomization
(1:1)
All patients
followed for
objective
radiologic
progression
and survival
Maintenance
phase
Olaparib 400 mg bid
continuously
Maintenance
phase
No further study
treatment
Completion of
4–6 x 21-day cycles
of chemotherapy
Arm BArm A
n=81
n=81
n=66
n=55
Multinational study; 43 sites in 12 countries
* Capsule formulation
• Statistically significant PFS improvement (HR 0.35, P<0.00001)
• Interim OS analysis: HR=0.94; 95% CI, 0.63–1.39; P=0.75
Ledermann J et al. N Engl J Med 2012;366:1382–1392
0
0.6
0.8
0.9
0
0.1
0.2
0.3
0.4
0.5
0.7
1.0
3 6 9 12 15 18
Probabilityof
progression-freesurvival
Time from randomization (months)
Hazard ratio 0.35
(95% CI, 0.25–0.49)
P<0.00001
Randomized treatment
Placebo
Olaparib 400 mg bid monotherapy
• Statistically significant PFS improvement (HR 0.35, P<0.00001)
• Interim OS analysis: HR=0.94; 95% CI, 0.63–1.39; P=0.75
Ledermann J et al. N Engl J Med 2012;366:1382–1392
0
0.6
0.8
0.9
0
0.1
0.2
0.3
0.4
0.5
0.7
1.0
3 6 9 12 15 18
Probabilityof
progression-freesurvival
Time from randomization (months)
Hazard ratio 0.35
(95% CI, 0.25–0.49)
P<0.00001
Randomized treatment
Placebo
Olaparib 400 mg bid monotherapy
Ledermann J et al. N Engl J Med 2012;366:1382–1392

35. PFS & OS in BRCAm
52
53

36. Conclusion
• Olaparib 200 mg bid (10 days) + P + C (AUC4)
followed by olaparib 400 mg bid maintenance
monotherapy resulted in:
• – Significant PFS improvement vs P + C (AUC6)
alone in platinum-sensitive relapsed ovarian
cancer (HR=0.51)
– Median PFS improvement of 2.6 months vs P + C
(AUC6) alone
• Combination phase: both arms had generally
similar toxicity profiles

37. EGFR/HER2 Inhibitors
Rationale: ErbB targeted therapy in
refractory/resistant ovarian cancer
n ErbB+ DRUG ORR SD
Bookman 2003 837 95 Herceptin 7%* 39%
Schilder 2005 27 27 Gefitininb 3% 15%
Gordon 2005 34 34 Erlotinib 6% 44%
Campos 2005 105 82+ CI-1003 0% 34%/26%
Friberg 2006 13 NK Erlot + Bev 15% ° 54%
Seiden 2007 75 37 Matuzumab 0% 8%
Schilder 2007 25 26 Catuximab 0% 8%
Gordon 2007 117 28 Pertuzumab 4% 7%
PRESENTED BY: Ignace Vergote

38. Targeted Therapy In Ovarian Cancer:
Conclusion
• Bevacizumab is the first anti-VEGF agent to
show improved PFS and manageable S/E
profile in Ovarian Ca.
• VEGFR TKI(s) showed improved outcomes but
simultaneous increased toxicity
• Several AAA(s) are in development
• Up to date, No anti-EGFR/HER2 agents
showed improved outcomes

39. Targeted Therapy In Ovarian Cancer:
Conclusion
• OS is the gold standard outcome in assessing new agent
efficacy, However
– Longer F/U periods are required
– Large number of patients is required
– Post-progression treatments
– Crossover
• Alternative endpoints (PFS, QoL, RR or combined) need to
be better defined and utilized
• Surrogacy between PFS and OS in Ovarian cancer is to be
established
• Better-selection of patients is essential
• Better molecular characterization of ovarian cancer is
crucial to direct therapy

40. “And mankind have not been given of knowledge except
a little.”
} ‫ا‬َ‫م‬ َ‫و‬‫ا‬‫َّل‬ِ‫إ‬ ِ‫م‬ْ‫ِل‬‫ع‬ْ‫ال‬ َ‫ِن‬‫م‬ ْ‫م‬ُ‫ت‬‫ِي‬‫ت‬‫و‬ُ‫أ‬ً‫ِيل‬‫ل‬َ‫ق‬ {