This downloadable slidedeck, presented in a regional grand rounds series, focuses on increasing awareness about current and emerging treatment options for patients with newly diagnosed and recurrent ovarian cancer.

2. Your Input Is Very Important!
 Sign-In Sheets:
– Your attendance counts
– Please sign-in
 Chair’s Practice Patterns Research
– Research data identifying common practices
– Understanding knowledge gaps and training
needs

3. DISCLAIMER
Participants have an implied responsibility to use the newly acquired information to enhance
patient outcomes and their own professional development. The information presented in this
activity is not meant to serve as a guideline for patient management. Any procedures,
medications, or other courses of diagnosis or treatment discussed or suggested in this
activity should not be used by clinicians without evaluation of their patients’ conditions and
possible contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USE
This educational activity may contain discussion of published and/or investigational uses of
agents that are not indicated by the FDA. University of California, Irvine School of Medicine
(UCI-SOM) and Institute for Medical Education & Research (IMER), do not recommend the
use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not
necessarily represent the views of University of California, Irvine School of Medicine (UCI-
SOM) and IMER. Please refer to the official prescribing information for each product for
discussion of approved indications, contraindications, and warnings.

4. Disclosure of Conflicts of Interest
Robert F. Ozols, MD
Reported a financial interest/relationship or affiliation in
the form of: Consultant, AstraZeneca Pharmaceuticals
LP, Johnson & Johnson Pharmaceutical Research &
Development, LLC.

5. Learning Objectives
L
Upon completion of this activity, participants
should be better able to:

 Outline evidence-based clinical decisions incorporating currently
approved standard chemotherapeutic and biologic treatments for
ovarian cancer
 Describe emerging clinical trial information that may facilitate
individual treatment planning for ovarian cancer
 Explain the rationale for and implications of the use of novel
therapies in ovarian cancer
 Discuss effective designs of treatment plans based upon
individualized patient characteristics and other relevant clinical
factors
 Identify ways to counsel patients on the availability of clinical trial
participation when warranted

6. Activity Agenda
 Activity Overview (5 mins)
 Current Treatments in Ovarian Cancer (25 mins)
– Case study 1: Integrating personalized approaches into
treatment planning and management for first-line therapy
• Updates on currently approved therapeutics
 Emerging Treatments in Ovarian Cancer (25 mins)
– Case study 2: Optimally managing recurrent ovarian cancer in
relation to platinum sensitivity/resistant disease
• Novel therapies – Rationale for targets, relevant data, and impact on
therapeutic landscape
• Evidence-based updates and results from data presented at
2011 oncology meetings
 Questions and Answers (5 mins)

7. Community and Academic
Ground Rounds: Transforming
Treatment in Ovarian Cancer

8. Newly Diagnosed Advanced
Ovarian Cancer
Courtesy of Bradley J. Monk, MD, FACOG, FACS.

9. Ovarian Carcinoma:
Incidence and Mortality
 Incidence in US women
– 21,990 cases in 2011
– Ninth most common cancer
– Second most common gynecologic cancer
– 1.4% lifetime risk of developing ovarian cancer
 Mortality in US women
– 15,460 deaths in 2011
– Fifth most common cause of cancer death
– Fourth leading cause of cancer deaths in women aged 40–59
yrs
– Most common cause of death due to gynecologic cancer
– 1.0% lifetime risk of dying of ovarian cancer
US = United States.
ACS, 2011.

10. Stage Distribution and 5-yr Relative
Survival by Stage at Diagnosis
(2001–2007, all races)
LNs = lymph nodes.
Howlader et al, 2011.

11. Results of Treatment:
Advanced Disease
Parameter Small Volume Large Volume
Response (%) 95 75
Clinical CR (%) 95 50
Pathologic CR (%) 50 25
PFS (mos) 25 18
Survival (mos) 50 36
10-yr Survival (%) 30–40 15–20
CR = complete response; PFS = progression-free survival.
Gynecologic Oncology Group Database (courtesy of J. Tate Thigpen, MD).

12. Results of Treatment:
Advanced Disease (cont.)
Parameter (%) Small Volume Large Volume
1980: 10-yr survival 7 0
1990: 10-yr survival 20 10
2008: 10-yr survival 30–40 15–20
Gynecologic Oncology Group Database (courtesy of J. Tate Thigpen, MD).

13. First-Line Therapy
Global Standard Treatment
Surgery With Maximum
Cytoreduction Effort
IV Platinum + Taxane Chemotherapy
(Carboplatin + Paclitaxel) x 6
IV = intravenous.
Pfisterer & Ledermann, 2006.
Courtesy of Bradley J. Monk, MD, FACOG, FACS.

14. Basis for Current Standard:
Systemic Therapy
 Studies showing paclitaxel/cisplatin superior to
cyclophosphamide/cisplatin
– GOG Protocol 111
– EORTC-NCIC OV 10
 Studies showing paclitaxel/carboplatin at least
equivalent to paclitaxel/cisplatin in efficacy
– AGO Trial
– GOG Protocol 158
GOG = Gynecologic Oncology Group; EORTC = European Organisation for Research and Treatment of Cancer;
NCIC = National Cancer Institute of Canada; AGO = Arbeitsgemeinschaft Gynäkologische Onkologie.
Ozols, 2008; Ozols et al, 2003; McGuire et al, 1996; Piccart et al, 2000; Du Bois et al, 2004.

15. Case Study 1
Integrating Personalized Approaches Into
Treatment Planning and Management for
First-Line Therapy

16. Case Study 1
A 65-yr-old woman with diet controlled
diabetes and a past history (18 mos ago) of
an uncomplicated myocardial infarction
presents to her PCP with a 1-mos history of
increasing abdominal bloating and pain
 Work-up reveals a 10-cm pelvic mass and
extensive intra-abdominal ovarian cancer
PCP = primary care physician.

17. Based on Existing Evidence-Based
Data, What Options Might Be
Considered at This Point?
1) Surgery + “standard” q3wk carboplatin + paclitaxel
2) Surgery + “standard” q3wk carboplatin + wkly paclitaxel
3) Neoadjuvant chemotherapy followed by surgery
4) Surgery + IP chemotherapy
5) Surgery + “standard” carboplatin + paclitaxel +
bevacizumab
IP = intraperitoneal.

18. JGOG: Dose-Dense Wkly Paclitaxel
 EOC or PP
Pac 180 mg/m2
 Stage II–IV I x 6–9
Carb AUC = 6
 No prior therapy
 Stratified: Residual disease,
stage, and histology
 Primary end point: PFS
Carb AUC = 6
 Secondary end point: OS II Pac 80 mg/m2/wk x 3 x 6–9
 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer
patients completed all protocol therapy
 Improved PFS with dose-dense wkly paclitaxel
Accrual: 637 patients (ITT)
EOC = epithelial ovarian cancer; PP = primary peritoneal cancer; OS = overall survival;
JGOG = Japanese Gynecologic Oncology Group; ITT = intent-to-treat; AUC = area under curve.
Isonishi et al, 2008.

19. JGOG: Dose-Dense Wkly Paclitaxel
(cont.)
Isonishi et al, 2008.

20. Justification for Neoadjuvant
Chemotherapy
1. Extensive intra-abdominal ovarian cancer preventing,
or increasing the risk for an unsuccessful “optimal”
cytoreduction
2. Elderly patient or woman with significant comorbidity
(eg, history of CHF) substantially increasing the risk
associated with major abdominal surgery
CHF = congestive heart failure.
Weinberg et al, 2010.

21. NACT + IDS Vs. PDS
Ovarian, Tubal, or Peritoneal Cancer
FIGO Stage IIIC/IV (N = 670)
Randomization
PDS NACT
3 x platinum-based CT 3 x platinum-based CT
IDS IDS if no PD
(not obligatory)
≥ 3 x platinum-based CT ≥ 3 x platinum-based CT
Primary End Point: OS
Secondary End Points: PFS, QOL, AEs
NACT = neoadjuvant chemotherapy; IDS = interval debulking surgery; PDS = primary debulking surgery;
FIGO = International Federation of Gynaecology and Obstetrics; CT = chemotherapy; PD = progressive
disease; QOL = quality of life; AEs = adverse events.
Vergote et al, 2008, 2010.

22. NACT + IDS Vs. PDS (cont.)
ITT Analysis
HR = hazard ratio.
Vergote et al, 2010.

23. NACT + IDS Vs. PDS (cont.)
Surgical Characteristics PDS NACT  IDS
(n = 329) (n = 339)
Postoperative mortality 2.5% 0.7%
(< 28 days)
Postoperative fever grade 3/4 8.1% 1.7%
Fistula (bowel/GU) 1.2% / 0.3% 0.3% / 0.6%
Operative time (mins) 180 180
RBC transfusion 51% 53%
Hemorhage grade 3/4 7.4% 4.1%
Venous grade 3/4 2.6% 0%
GU = genitourinary; RBC = red blood cell.
Vergote et al, 2008, 2010.

24. Primary Therapy: IP
Median PFS HR Median OS HR
(mos) (mos)
IV IP IV IP
0.76
GOG 104 — — — 41 49 (p = .02)
0.78 0.81
GOG 114 22 28 (p = .01) 52 63 (p = .05)
0.80 0.75
GOG 172 18.3 23.8 (p = .05) 50 66 (p = .03)
Alberts et al, 1996; Markman et al, 2001; Armstrong et al, 2006.

25. GOG 172: Ovarian (Optimal III)
 EOC
 Optimal stage III
 No prior therapy
 Elective second-look
Pac 135 mg/m2 (24 hrs)
I Cis 75 mg/m2 Day 2
Pac 135 mg/m2 (24 hrs) IV Day 1
II Cis 100 mg/m2 IP Day 2
Pac 60 mg/m2 IP Day 8
Open: 23-March-98
Closed: 29-January-01
Accrual: 415 patients (evaluable)
Armstrong et al, 2006.

26. GOG Protocol 172
RR of death = 0.75 (95% CI: 0.58, 0.97) p = .03
By Treatment Group
1.0
0.9
IP median OS = 65.6 mos
0.8
0.7
0.6 IV median OS = 49.7 mos
Proportion Surviving
0.5
0.4
0.3
0.2
Rx Group Lost to Alive Dead Total
0.1 Rx Group Follow-up Alive Dead Total
IV
IV 5 78 127 93 210 117 210
0.0 IP
IP 11 93 101 117 205 88 205
0 12 24 36 48 60
Months on Study
RR = response rate; CI = confidence interval.
Adapted from Armstrong et al, 2006.

27. GOG Protocol 172: Toxicity
IV IP
Grade (N = 210; %) (N = 201; %)
3/4 Leukopeniaa 64 76
3/4 Platelet 4 12
3/4 GIa 24 46
3/4 Renala 2 7
3/4 Neurologic eventa 9 19
3/4 Fatiguea 4 18
3/4 Infectiona 6 16
3/4 Metabolica 7 27
3/4 Paina 1 11
No difference in QOL at 12 mos
p ≤ .05
a
GI = gastrointestinal.
Armstrong et al, 2006.

28. GOG 218: Schema
Arm
C AUC 6
P 175 mg/m2
I
Front-Line (CP)
EOC, PP, or FT Placebo
• Stage III optimal
(macroscopic) 1:1:1 C AUC 6
• Stage III
suboptimal P 175 mg/m2
II
• Stage IV (CP + Bev)
Bev 15 mg/kg Placebo
N = 1,800
(planned)
C AUC 6
Stratification variables
– GOG PS P 175 mg/m2
III
– Stage/debulking status (CP + Bev
 Bev)
Bev 15 mg/kg
Cytotoxic Maintenance 15 mos
FT = fallopian tube; PS = performance status;
(6 cycles) (16 cycles)
C = carboplatin; P = paclitaxel.
Burger et al, 2010.

29. GOG 218: Patient Disposition
Arm I Arm II Arm III
CP CP + Bev CP + Bev Bev
Characteristic (n = 625) (n = 625) (n = 623)
Median (range) number Bev/placebo cycles 11 (0–22a) 12 (0–22a) 14 (0–21)
On treatment at time of analysis, n (%) 86 (14) 82 (13) 117 (19)
Completed regimen, n (%) 100 (16) 104 (17) 148 (24)
Discontinued study treatment, n (%)
Disease progression 299 (48) 264 (42) 164 (26)
AEs 69 (11) 86 (14) 94 (15)
Cycles 1–6 57 (9) 73 (12) 59 (9)
Cycle ≥ 7 12 (2) 13 (2) 35 (6)
Deaths 8 (1) 7 (1) 13 (2)
Patient refusal 44 (7) 55 (9) 50 (8)
Other 19 (3) 27 (4) 37 (6)
 Percentages may not total 100% due to rounding or categorization
One patient in each group received Bev/placebo in Cycle 1.
a
Burger et al, 2010.

30. GOG 218: Select AEs
Onset Between Cycle 2 and 30 Days After Date of Last Treatment
Arm I Arm II Arm III
CP CP + Bev CP + Bev  Bev
AE (grade when limited), n (%)
(n = 601) (n = 607) (n = 608)
GI eventsa (grade ≥ 2) 7 (1.2) 17 (2.8) 16 (2.6)
Hypertension (grade ≥ 2) 43 (7.2)b 100 (16.5)b 139 (22.9)b
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 thromboembolic event 35 (5.8) 32 (5.3) 41 (6.7)
Arterial thromboembolic event 5 (0.8) 4 (0.7) 4 (0.7)
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.
a
p < .05
b
HTN = hypertension; CNS = central nervous system; RPLS = reversible posterior leukoencephalopathy syndrome.
Burger et al, 2010.

31. GOG 218: Select AEs (cont.)
Treatment Phase
Arm I Arm II Arm III
Select AEs (n)
CP CP + Bev CP + Bev → Bev
(grade when limited)
Patients (n) (n = 601) (n = 483) (n = 607) (n = 457) (n = 608) (n = 464)
Cycles (n) 2,906 4,059 2,911 4,204 2,891 4,677
Cytotoxic Maintenance Cytotoxic Maintenance Cytotoxic Maintenance
Treatment phasea (Cycles 2–6) (Cycles ≥ 7) (Cycles 2–6) (Cycles ≥ 7) (Cycles 2–6) (Cycles ≥ 7)
GI eventsb (grade ≥ 2) 6 1 16 1 15 1
HTN (grade ≥ 3) 3 7 24 12 25 38
Proteinuria (grade ≥ 3) 2 2 4 0 0 10
Pain (grade ≥ 3) 28 23 42 31 46 37
Neutropenia (grade ≥ 4) 345 2 382 2 385 0
Febrile neutropenia 21 0 30 0 26 0
Venous thromboembolic event 26 9 27 5 27 14
Arterial thromboembolic event 4 1 1 3 3 1
CNS bleeding 0 0 0 0 0 2
Non-CNS bleeding (grade ≥ 3) 3 2 8 0 10 3
RPLS 0 0 1 0 0 1
Onset within 30 days of last treatment.
a
Perforation/fistula/necrosis/leak.
b
Burger et al, 2010.

32. GOG 218: Investigator-Assessed
PFS Arm I Arm II Arm III
CP CP + Bev CP + Bev  Bev
1.0 (n = 625) (n = 625) (n = 623)
423 418 360
0.9 Patients with event (n; %)
(67.7) (66.9) (57.8)
Median PFS (mos) 10.3 11.2 14.1
Proportion PFS (%)
0.8 0.908 0.717
Stratified analysis HR
(95% CI) (0.759–1.040) (0.625–0.824)
0.7
One-sided p value (log rank) .080a < .0001a
0.6
0.5
0.4
0.3
CP (Arm I)
+ Bev (Arm II)
0.2 + Bev  Bev maintenance (Arm III)
0.1
0 12 24 36
0 Time (Mos Since Randomization)
a
p = .0116
Burger et al, 2010.

33. GOG 218: Subgroup Analyses of PFS
CP + Bev  Bev (Arm III) Vs. CP (Arm I)
Experimental Arm
(CP + Bev  Bev; Control Arm
HR Arm III) Better (CP; Arm I) Better
Stage III optimal (n = 434) 0.618
Stage III suboptimal (n = 496) 0.763
Stage IV (n = 318) 0.698
PS 0 (n = 616) 0.710
PS 1/2 (n = 632) 0.690
Age < 60 yrs (n = 629) 0.680
Age 60–69 yrs (n = 409) 0.763
Age ≥ 70 yrs (n = 210) 0.678
0.33 0.5 0.67 1.0 1.5 2.0
3.0
Treatment HR
Burger et al, 2010.

34. GOG 218: OS Analysis
At Time of Final PFS Analysis (January 2010)
1.0
0.9
0.8
Proportion Alive (%)
0.7
0.6 Arm I Arm II Arm III
CP CP + Bev CP + Bev  Bev
0.5 (n = 625) (n = 625) (n = 623)
Patients with 156 150 138
0.4
events (n; %) (25.0) (24.0) (22.2)
0.3 Median (mos) 39.3 38.7 39.7
0.2 HRa 1.036 0.915
(95% CI) (0.827–1.297) (0.727–1.152)
0.1
One-sided p value .361 .252
0
0 12 24 36 48
Time (Mos Since Randomization)
No. at risk 625/625/623 442/432/437 173/162/171 46/39/40
Stratified analysis.
a
Burger et al, 2010.

35. ICON7: Study Design
C AUC 6a
Primary end point:
Front-Line A P 175 mg/m2 PFS
m
EOC, PP, or FT Ar
Secondary end
• Stage I/IIA (grade 3)
• Stage IIB/C points: OS, RR,
• Stage III QOL, safety,
• Stage IV
Ar cost-effectiveness,
N = 1,520 (planned) m C AUC 6a translational
B
P 175 mg/m2 No IRC present
 Stratification variables Bev 7.5 mg/kg
– Stage/surgery 12 mos
– Time since surgery
– GCIG group
Might vary based on GCIG group.
a
GCIG = Gynecologic Cancer Intergroup; IRC = independent review committee.
Kristensen et al, 2011.

36. Key Differences Between
GOG 218 and ICON7
Trial GOG 218 ICON7
 Double-blinded, placebo-controlled  Open-label
Setting/  3-arm study  2-arm study
Design  Bev for 15 mos  Bev for 12 mos
 Bev dose: 5 mg/kg/wk  Bev dose: 2.5 mg/kg/wk
 Stage III (suboptimal)  Stage I or IIA (grade 3/clear cell
Patient
 Stage III (optimal, visual/palpable) histology)
Population
 Stage IV  Stages IIB–IV (all)
 Defined final OS analysis (end
Additional  OS analysis (formal testing at time of PFS)
2012)
End Point  IRC
 No IRC
Burger et al, 2010; Kristensen et al, 2011.

37. ICON7 Schema
Carboplatin AUC 5/6 Stratification Variables
1:1 Paclitaxel 175 mg/m2  Stage and extent of debulking:
 I–III debulked ≤ 1 cm
R  Stage I–III debulked > 1 cm
Carboplatin AUC 5/6  Stage IV and inoperable stage III
N = 1,528a
 Timing of intended treatment start
Paclitaxel 175 mg/m2
≤ 4 vs. > 4 wks after surgery
 GCIG group
BEV 7.5 mg/kg q3wks
18 cycles
 Academic-led, industry-supported trial to investigate use of Bev
and to support licensing
December 2006 to February 2009.
a
Kristensen et al, 2011.

38. ICON7 PFS: Updated
17.4
19.8
Control
Research
Kristensen et al, 2011.

39. PFS: “High Risk” Subgroup (Ad Hoc Analysis)
High Risk: Stage IIIC Suboptimal/Stage IV Control Research
1.00 (n = 234) (n = 231)
Proportion Alive Without Progression (%)
Events, n (%) 173 (74) 158 (68)
Median (mos) 10.5 15.9
0.75 Log-rank test p < .001
HR (95% CI) 0.68 (0.55–0.85)
Restricted mean 13.3 16.5
0.50
0.25
Control
Research
10.5 15.9
0
Time
0 3 6 9 12 15 18 21 24 27 30 (mos)
Number At Risk
Control 234 205 98 36 14 2
Research 231 213 159 56 10 1
Kristensen et al, 2011.

40. Interim Analysis of Overall Survival
Kristensen et al, 2011.

41. Case Study 2
Optimally Managing Recurrent
Ovarian Cancer

42. Case Study 2
 A 54-yr-old woman with ovarian cancer attains a
clinically-defined CR to primary
carboplatin/paclitaxel chemotherapy
 10 mos following the completion of
chemotherapy abdominal pain returns and a
repeat CT scan reveals the presence of diffuse
small IP masses
 What are the current antineoplastic drug options
and the direction of future research in this
clinical setting?

43. The Traditional Treatment Paradigm
Recurrence After First-Line Chemotherapy
Platinum Platinum
Refractory/Resistant Sensitive
< 6 Mos > 6 Mos
Non-Platinum Chemotherapy
Single Agent Doublet
Ushijima, 2010.

44. Recurrent Ovarian Cancer:
Definition of Disease Sensitivity
P Time to Recurrence (mos)
R
E
V 0 3 6 12 18 24
I
O
U
S Refractory
T
R
E
A Resistant
T
M Sensitive
E Our Patient
N
T Highly Sensitive
Ushijima, 2010.

45. Major Trials in
Recurrent Ovarian Cancer
 Paclitaxel vs. topotecan
 Topotecan vs. PLD
 Platinum vs. platinum + paclitaxel
 Carboplatin vs. carboplatin + gemcitabine
 Carboplatin + paclitaxel vs. carboplatin + PLD
 PLD vs. PLD + trabectedin
PLD = pegylated liposomal doxorubicin.
ten Bokkel Huinink et al, 1997, 2004; Gordon et al, 2004; Parmar et al, 2003;
Pfisterer et al, 2006; Pujade-Lauraine et al, 2010; Monk et al, 2010.

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47. Recurrence Regimens
NCCN Preferred Agents
Platinum-based combination therapy should be considered for platinum sensitive recurrences.
a
NCCN = National Comprehensive Cancer Network.
NCCN, 2011.

48. Phase III Study (Doublets): CALYPSO
R Paclitaxel 175 mg/m2
A Carboplatin AUC 5
Ovarian Cancer
N q3wks
– First relapse
– Platinum-sensitive D
O Relapse
M
I PLD 30 mg/m2
Z Carboplatin AUC 5
E q4wks Opened: 4/2005
Closed: 10/2007
N = 976
Pujade-Lauraine et al, 2010.

49. PFS: ITT
CD CP
Median PFS (mos) 11.3 9.4
HR (95% CI) 0.82 (0.72, 0.94)
Log-rank p (superiority) .005
p (non-inferiority) < .001
CD = carboplatin-PLD.
Pujade-Lauraine et al, 2010.

50. Intermediate Sensitive: 6–12 mos
CD CP
Median PFS (mos) 9.4 8.8
HR (95% CI) 0.73 (0.58, 0.90)
Log-rank p value (superiority) .004
p value (non-inferiority) < .001
Months from Randomization
Pujade-Lauraine et al, 2010.

51. PFS: Highly Platinum-Sensitive
(PFI > 24 mos)
C-PLD C-P HR p
PFS 12.0 12.3 1.05 .73
mos mos (0.79–1.40)
RR 42% 38% .46
PFI = progression-free interval.
Mahner et al, 2011.

52. CALPYSO: OS Analysis
Marth et al, 2011.

53. Bevacizumab: The First Active
Targeted Agent in Ovarian Cancer
 Case report of single-agent activity
– Monk et al, 2005
 Phase II of single-agent activity
– Burger et al, 2007
 Phase II of combination therapy
– Garcia et al, 2008
 Randomized phase III trial (GOG 218)
– Burger et al, 2010

54. OCEANS: Study Schema
Platinum-Sensitive ROCa CG + Carboplatin AUC 4
PLA Gemcitabine 1,000 mg/m2
 Measurable disease
 ECOG 0/1 Days 1, 8
 No prior chemotherapy
for ROC PLA q3wks Until Progression
 No prior BEV
(N = 484)
Carbopaltin AUC 4
Gemcitabine 1,000 mg/m2
CG + Days 1, 8
Stratification Variables BEV BEV 15 mg/kg q3wks Until Progression
Platinum-free interval
(6–12 vs. > 12 mos) CG for 6 (up to 10) cycles
Cytoreductive surgery for
recurrent disease (yes vs. no)
EOC, PP, or FT cancer.
a
ROC = recurrent ovarian cancer; ECOG = Eastern Cooperative Oncology Group.
Aghajanian et al, 2011.

55. OCEANS: Patient Characteristics
CG + PLA CG + BEV
Characteristic (n = 242) (n = 242)
Median age (yrs) 61 60
(range) (28−86) (38–87)
Age ≥ 65 yrs (%) 38 35
Race (%)
White 92 90
Other 8 10
ECOG PS 0 (%) 76 75
Histologic subtype (%)
Serous 84 78
Mucinous/clear cell 3 5
Other 14 17
Platinum-free interval (%)
6–12 mos 42 41
> 12 mos 58 59
Cytoreductive surgery for recurrent disease (%) 10 12
Aghajanian et al, 2011.

56. OCEANS: Primary Analysis of PFS
CG + PLA CG + BEV
(n = 242) (n = 242)
Events, n (%) 187 (77) 151 (62)
1.0
Median PFS (mos) 8.4 12.4
(95% CI) (8.3–9.7) (11.4–12.7)
Proportion PFS (%)
0.8 Stratified analysis 0.484
HR (95% CI) (0.388–0.605)
Log-rank p value < .0001
0.6
0.4 ORR
GC: 57.4%
0.2 GC+B: 78.5%
p < .0001
0
0 6 12 18 24 30
Number At Risk Time (mos)
CG + PL 242 177 45 11 3 0
CG + BV 242 203 92 33 11 0
Aghajanian et al, 2011.

57. OCEANS: PFS Subgroup Analyses
Median PFS
(mos)
CG +
No. of CG + PLA CG + BEV BEV CG + PLA
Baseline risk factor
patients (n = 242) (n = 242) HR (95% CI) better better
All patients 0.49 (0.40–
484 8.4 12.4
0.61)
Platinum-free interval 0.41 (0.29–
6–12 202 8.0 11.9
(mos) 0.58)
0.55 (0.41–
> 12 282 9.7 12.4
0.73)
Cytoreductive surgery 0.50 (0.24–
Yes 54 7.5 16.7
for recurrent disease 1.01)
0.49 (0.39–
No 430 8.4 12.3
0.62)
Age (yrs) 0.47 (0.36–
< 65 306 8.5 12.5
0.62)
0.50 (0.34–
≥ 65 178 8.4 12.3
0.72)
Baseline ECOG PS 0.47 (0.36–
0 367 8.6 12.5
0.60)
0.61 (0.39–
1 116 8.3 10.6
0.95)
0.2 0.5 1 2 5
HR
Aghajanian et al, 2011.

58. OCEANS: Interim OS
1.0
0.8
Proportion Alive (%)
CG + PLA CG + BEV
0.6 (n = 242) (n = 242)
Events, n (%) 78 (32) 63 (26)
0.4 Median OS (mos) 29.9 35.5
(95% CI) (26.4–NE) (30.0–NE)
Stratified analysis 0.751
0.2 HR (95% CI) (0.537–1.052)
Log-rank p value .094a
0
0 6 12 18 24 30 36 42
Time (mos)
Number At Risk
CG + PL 242 235 195 131 77 26 8 0
CG + BV 242 238 200 146 82 42 8 0
p value does not cross pre-specified boundary of .001
a
NE = not estimable.
Aghajanian et al, 2011.

59. OCEANS: AEs of Special Interest
CG + PLA CG + BEV
Patients (%) (n = 233) (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
HTN, grade ≥ 3 <1 17
Fistula/abscess, all grades <1 2
GI perforation, all grades 0 0a
Proteinuria, grade ≥ 3 1 9
RPLS, all grade 0 1
Wound-healing complication, grades ≥ 3 0 1
Two GI perforations occurred 69 days after last BEV dose.
a
ATE = arterial thromboembolic event; VTE = venous thromboembolic event.
Aghajanian et al, 2011.

60. OCEANS: Preliminary Conclusions
 BEV + carboplatin + gemcitabine followed by
BEV until progression provides a clinically
meaningful benefit over chemotherapy alone in
ROC
– Improved PFS: HR 0.484 (p < .0001);
median 8.4 → 12.4 mos
– Improved ORR and duration of response
– OS data not yet mature
 Safety data consistent with BEV profile
– No GI perforations and no new safety signal
Aghajanian et al, 2011.

61. Novel Therapies and
Future Directions

62. PARP Inhibitors
Suggested Mechanism of Action
Chemotherapy inflicts DNA
damage via adducts and
DNA cross-linking
PARP1
PARP
Inhibitor
Replication
PARP1 fork collapse
Inhibition of Double strand
PARP1 PARP1 DNA break
PARP1 Upregulation
Disables DNA
Base-excision repair of base-excision
DNA damage repair
BRCA1
BRCA2
CELL SURVIVAL CELL DEATH
PARP = poly (ADP-ribose) polymerase; DNA = deoxyribonucleic acid.
O’Shaughnessy et al, 2009.

63. Phase II Study of Olaparib of Patients With
BRCA1 or BRCA2 Mutation
 Two dosages tested in sequential cohorts of patients with
recurrent, measurable disease
 Primary end point: RR
400 mg BID 100 mg BID
n = 33 n = 24
ORR = 33% ORR = 13%
 AEs: Nausea, fatigue, anemia
BRCA = breast cancer gene; BID = twice daily; ORR = overall response rate.
Audeh et al, 2010.

64. Study 19: Aim and Design
 To assess the efficacy of olaparib (OLA) as a maintenance
treatment in patients with platinum-sensitive high grade serous
ovarian cancer
 Randomized, double-blind, placebo-controlled phase II study
 Multinational study; 82 sites in 16 countries
Patient Eligibility
 Platinum-sensitive high grade serous ovarian cancer OLA
400 mg po BID
 ≥ 2 previous platinum regimens
 Last chemotherapy: Platinum-based with a Treatment
maintained response Randomized 1:1 until PD
 Stable CA125 at trial entry
 Randomization stratification factors
– Time to PD on penultimate platinum therapy PLA
po BID
– Objective response to last platinum therapy
– Ethnic descent
po = oral; PD = progressive disease.
Ledermann et al, 2011.

65. Patient Characteristics
Olaparib
400 mg bid Placebo
(n = 136) (n = 129)
Median age, yrs (range) 58 (21–89) 59 (33–84)
Ethnicity, n (%)
Jewish descent 20 (15) 17 (13)
ECOG status, n
0 / 1 / 2 / unknown 110 / 23 / 1 / 2 95 / 30 / 2 / 2
BRCA mutation status, n (%)a
BRCA1 25 (18) 20 (16)
BRCA2 6 (4) 7 (5)
BRCA1 and BRCA2 0 1 (1)
Known negative 18 (13) 20 (16)
Unknown 87 (64) 81 (63)
a
BRCA mutation status was not a requirement.
Ledermann et al, 2011.

66. Progression-Free Survival
Olaparib Placebo
1.0 No. of events: Total patients (%) 60:136 (44.1) 93:129 (72.1)
0.9 Median PFS (mos) 8.4 4.8
Proportion of PFS (%)
0.8
0.7 HR 0.35 (95% CI, 0.25–0.49)
0.6
p < .00001
0.5
0.4
0.3
0.2 Randomized Treatment
0.1 Placebo
Olaparib 400 mg bid
0
0 3 6 9 12 15 18
Time from randomization (mos)
At risk (n)
Olaparib 136 104 51 23 6 0 0
Placebo 129 72 23 7 1 0 0
Ledermann et al, 2011.

67. Preplanned Subgroup Analysis of PFS
Overall
BRCA mutation
BRCA status known
BRCA unknown
Age < 50
Age ≤ 50 to < 65
Age ≥ 65
Race, white
Non-Jewish descent
CR at baseline
PR at baseline
TTP penultimate platinum regimen 6–12 mos
TTP penultimate platinum regimen > 12 mos
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
HR (OLA: PLA) and 95% CI
Favors OLA
Global interaction test showed no evidence of inconsistency across the subgroups (p = .282)
Size of circle is proportional to number of events; grey band represents 95% CI in overall population
PR = partial response; TTP = time to progression.
Ledermann et al, 2011.

68. Confluence of Multiple Advances
Pharmacogenomics
Bioinformatics Translational
Genomics
Personalized
Medicine
Molecular Companion
Biology Diagnostics
Pharmacometabonomics

69. Future Strategies in Ovarian Cancer
Angiogenesis
VEGF/VEGFR
EGFR
mTOR/Akt/PI3K
ER
FR
PARP Targets
CA125
Src
PKC
HSP90
PDGFR
Repackaging Traditional Agents
MoAb
VEGF/R = vascular endothelial growth factor/receptor; EGFR = epidermal growth factor receptor; ER = estrogen receptor;
PDGFR = platelet-derived growth factor receptor; MoAb = monoclonal antibody; mTOR = mammalian target of rapamycin;
PI3K = phosphatidylinositol 3-kinase; FR = folate receptor; PKC = protein kinase C; HSP90 = heat shock protein-90.
Banerjee et al, 2009.