1. Ovarian Cancer: Standards of Care and New Opportunities
Robert L. Coleman, M.D.
Professor & Vice Chair, Clinical Research
Department of Gynecologic Oncology
M.D. Anderson Cancer Center

2. Ovarian Cancer: Liner Notes
Globally 7th most incident and lethal cancer
New cases: 225,000 annually
Deaths: 140,000 annually
Burden of disease is greater in developed countries
The incidence increases with age
Almost 75% of cases present with advanced stage III / IV disease
Risk of relapse of advanced stage disease is as high as 70%
CA Cancer, 2013 2

3. Ovarian Cancer: Natural History
Progression
Death
Diagnosis
Evaluation
? SLL
Secondary
Surgery
Symptoms
Chemotherapy #1
Chemo #2
Chemo #3+
Maintenance
Supportive
Care
Staging
Progression-Free Survival
(12-28 mos)
Post Progression Survival
(12-38 mos)
Duration

5. Surgical Management of Primary Ovarian Cancer
Theoretical:
Reduced the volume of hypoxic, poorly perfused cells
Host immunocompetence is improved with lower tumor burden
Recruitment of residual cells into G1 potentiating the effects of cytotoxic therapy
Removal of chemoresistant clones
Practical:
“Biology vs Brawn”

6. The Impact of Residual Tumor: What Is Optimal Debulking?
% Progression-free Survival
HR (95%CI) mm vs. 0 mm: (2.26;2.81) >10 mm vs mm: 1.36 (1.24;1.50)
log-rank: p <
0 mm
1-10 mm
> 10 mm
Generated from 3 prospective Phase III trials (OVAR 3,5, & 7)
N = 3126 pts
% Overall Survival
HR (95%CI) mm vs. 0 mm: (2.37; 3.07) >10 mm vs mm: 1.34 (1.21; 1.49)
log-rank: p <
0 mm
1-10 mm
> 10 mm
DuBois, Cancer (2009)115:1234

7. Primary Approach: What’s Best?
PDS: 12 mos
NACT: 12 mos
HR: ( )
PFS
PDS: 29 months
IDS: 30 months
HR: (0.85, 1.14) OS
N Engl J Med (2010) 363:943

8. Neoadjuvant Chemotherapy in Ovarian Cancer
9/21/10
1/20/11

9. Primary Approach: What’s Best?
PDS: 12 mos
NACT: 12 mos
HR: ( )
PFS
PDS: 29 months
IDS: 30 months
HR: (0.85, 1.14) OS
N Engl J Med (2010) 363:943

10. CHORUS Chemotherapy Or Upfront Surgery
OV.21
CHORUS Chemotherapy Or Upfront Surgery
Neoadjuvant Chemotherapy
X 3-4 courses
Randomized
IV-Arm IP-Arm
Pac/Carbo + Pac/Carbo (IP) +
Pac (d8) Pac (IP, d8)
ICON-8
Pre-randomization
Strata for NACT or PDS
Randomized
Standard
Pac/Carbo
Exp A
DD-Pac/Carbo
Exp B
DD - Pac/DD-Carbo
RCOG

11. Principle Approach: Iº Therapy
Chemotherapy OS
Cytoxan/Cisplatin
- - - Paclitaxel/Cisplatin
PFS
GOG-172
Cisplatin 75 mg/m2
Paclitaxel 135 mg/m2
Day1: IV Paclitaxel 135 mg/m2
Day 2: IP Cisplatin 100mg/m2
Day 8: IP Paclitaxel 60 mg/m2
GOG-158
Cisplatin 75 mg/m2
Paclitaxel 135 mg/m2
Carboplatin AUC 7.5
Paclitaxel 175 mg/m2
GOG-111
Cisplatin 75 mg/m2
Cytoxan 750mg/m2
Paclitaxel 135 mg/m2
McGuire New Engl J Med (1996) 334:1
Ozols, J Clin Oncol (2003) 21:3194
Armstrong New Engl J Med (2006) 354:34

12. International Phase III ExperienceCP
CPG
CPPLD
CTCP
CGCP
PLD-C CE
Total
GOG0182-ICON5
864
862
861
4312
SCOTROC
538
539
1077
AGO-GINECO
635
647
1282
NSGO-EORTC-NCIC-GEICO
444
443
887
MITO
170
156
326
AGO-GINECO-GERCOR-NSGO
882
860
1742
NCIC-EORTC-GEICO OV16
410
409
819
MITO-2
820
Regimen Total:
4353
1724
1272
1426
1090
11265
No Significant Effect
More ≠ Better
Different ≠ Better

13. Moving The Bar: Primary Therapy
Establishing a Front-Line Adjuvant Standard
Moving The Bar: Primary Therapy
Dose-dense therapy
IP Chemotherapy
Biologics: Anti-angiogenesis, PARPi, angiopoeitin inhibitors

14. Dose Dense: Weekly Therapy
Ovarian Epithelial, PP, FT
FIGO Stage II-IV
Stratification;
Residual disease: <1cm, > 1cm
FIGO Stage： II vs. III vs. IV
Histology： clear cell/mucinous vs serous/others R
　Paclitaxel 180mg/m2
　Carboplatin AUC 6.0
　 q 21 days (6-9 cycles)
Dose density: 60 mg/m2/wk
　Paclitaxel 80mg/m2, days 1, 8, 15
　Carboplatin AUC 6.0, day 1
　 q 21 days (6-9 cycles)
Dose density: 80 mg/m2/wk (+33%)
Katsumata, Lancet 2009

15. JGOG 3016: Long-Term Follow-Up
Katsumata N, ASCO Abstract 5003, 2012

16. iPocc JGOG Trial: Schema Epithelial Ovarian Cancer
Stages II-IV
Including Bulky Tumor
RANDOMIZATION
Paclitaxel 80 mg/m2 IV Day 1,8,15
Carboplatin AUC 6 IV
Q21, 6-8 Cycles
Paclitaxel 80 mg/m2 IV Day 1,8,15
Carboplatin AUC 6 IP
Q21, 6-8 Cycles
Dose dense−TCiv
Dose dense−TCip
Primary Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOL
Accrual Goal: 746 pts / 511 events

17. GOG-0218 study schema I II III Arm 15 months Paclitaxel 175 mg/m2
Establishing a Front-Line Adjuvant Standard
2008
GOG-0218 study schema
15 months
Paclitaxel 175 mg/m2
Carboplatin AUC 6
Placebo I
Arm
Cytotoxic (6 cycles)
Maintenance
(16 cycles)
(CP + PLA → PLA)
Previously untreated epithelial ovarian, primary peritoneal, or fallopian tube cancer
Stage III optimal (macroscopic)
Stage III
suboptimal
Stage IV
n=1873
Stratification variables:
GOG performance status
Stage/debulking status
RANDOM I
Z E
1:1:1
Carboplatin AUC 6
Paclitaxel 175 mg/m2
Placebo
Bevacizumab
15 mg/kg II
(CP + BEV
→ PLA)
Bevacizumab 15 mg/kg
Carboplatin AUC 6
Paclitaxel 175 mg/m2
III
(CP + BEV  BEV)
Burger et al. N Engl J Med 2011;365: 17 17

18. Establishing a Front-Line Adjuvant Standard
Schema
Carboplatin AUC 5/6
Stratification variables:
Stage & extent of debulking: I–III debulked ≤1cm vs stage I–III debulked >1 cm vs stage IV and inoperable stage III
Timing of intended treatment start ≤4 vs >4 weeks after surgery
GCIG group
1:1
Paclitaxel 175 mg/m2 R
Carboplatin AUC 5/6
n=1528*
Paclitaxel 175 mg/m2
Bevacizumab 7.5 mg/kg q3w
18 cycles
*Dec 2006 to Feb 2009
Academic-led, industry-supported trial to investigate use of bevacizumab and to support licensing
Perrin, N Engl J Med 2011;365:

19. Anti-VEGF Targeting: Frontline
PFS
GOG 218
ICON7
HR: 0.87
17.4vs 19.8 mos
Median D: 2.4 mos
HR: 0.73
10.4 vs 13.9 mos
Median D: 3.5 mos
Burger, NEJM (2011) 365:2473
Perren, NEJM (2011) 365:2484

20. Anti-VEGF Targeting: Frontline
Overall Survival
GOG 218
ICON7
Burger, NEJM (2011) 365:2473
Perren, NEJM (2011) 365:2484

21. GOG-0218 and ICON7:
Restricted Means Estimate – Benefit During Exposure Only?
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 6 12 18 24 30 36
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 6 12 18 24 30 36
14 vs 17
3 months’ difference
13.3 vs 16.5
3 months’ difference
Research Arm
Research Arm
GOG-0218
ICON7 (III suboptimal and IV subgroup) 2 4 6 8 10 12 14 16 18 20 24 30 36
-15
-10 -5 5 10 15 20 25 30 6 12 18 24 36
Research Arm
Research Arm
Time (months)
Time (months) 21

22. Maintenance to Progression
GOG Ovarian Strategy: 262
Bevacizumab q 3 wk
(If chosen)
Maintenance to Progression
IV Paclitaxel 80 mg/m2 weekly
IV Carboplatin AUC 6 q 3 wk
IV Bevacizumab 15 mg/kg (optional)
262
Suboptimal
(> 1 cm Residual)
Neoadjuvant allowed
CT Perfusion Scan
IV Paclitaxel 175 mg/m2
IV Carboplatin AUC 6
IV Bevacizumab 15 mg/kg (optional)
N: 702/625 (OPEN only for ACRIN Component
Primary endpoint: PFS

23. IV Paclitaxel 80 mg/m2 days 1, 8, 15
Phase III GOG 252 Schema
Cycles 1-6*
Cycles 7-22*
IV Paclitaxel 80 mg/m2 days 1, 8, 15
IV Carboplatin AUC 6 day 1
Bevacizumab 15 mg/kg q3w†
IP Carboplatin AUC 6 day 1
IV Paclitaxel 135 mg/m2 day 1
IP Cisplatin 75 mg/m2 day 2
IP Paclitaxel 60 mg/m2 day 8
RANDOMIZATION
N = 1250
Bevacizumab 15 mg/kg q3w
Bevacizumab 15 mg/kg q3w
Bevacizumab 15 mg/kg q3w
N: 1554 (CLOSED)
Primary endpoint: PFS
*Each cycle is 3 weeks; †Begin cycle 2.
Walker JL. Am Soc Clin Oncol Ed Book. 2009:

24. Other Pursuits in Front-Line Therapy
VEGF TKI’s
Nintedanib (BIBF1120)
PARPi
Veliparib (OVM1102)
Angiopoeitin inhibitors
TRINOVA-3: Trebananib (AMG-386)

25. Bottom Line… Determine good candidates for surgery
Potential for better selection tools, e.g. Laparoscopy
Optimal radical resection
Goal: R0
Adjuvant therapy
IP and dose dense are my favorite options
Good place for clinical trial

26. Maintenance: The Stakes are High!
Progression
Death
Diagnosis
Evaluation
? SLL
Secondary
Surgery
Symptoms
Chemotherapy #1
Chemo #2
Chemo #3+
Maintenance
Supportive
Care
Staging
What we know…
Rate of response is high (CR + PR) >75%
Second assessment operations find disease > 40% of CR’s
Clinical CR’s have >50% recurrence risk at 2 years
Pathological CR’s have >40% risk at 2 years
Option applies to CR’s and documented PR’s

27. Maintenance Therapy Scorecard
Maintenance Beneficial?
Strategy No
Yes
Prolonged Initial Therapy ✓
Short Duration / Non-Cross Resistant Chemotherapy
High-Dose Chemotherapy
Intraperitoneal
Interferon-
Anti-CA-125 Ab
Biologic Agent (MMPI, bevacizumab*) ✓*
Paclitaxel (6 months)
Paclitaxel (1 year) ✓#
Erlotinib

28. Maintenance Trials: Ongoing
EOC, PP, FT cancer
Paclitaxel
X 12 mos
CTI-2103 No
Treatment
Carboplatin
GOG-212
N = 1100 patients
Survival primary endpoints
QOL endpoints
Bevacizumab (GOG 252, 262)
Pazopanib (OVAR-16)
Nintedanib (BIBF 1120)
Trebananib (TRINOVA-3)
CVAC: Muc-1 Dendritic Cell vaccine
PARPi,
pvKLH + OPT-821 [GOG-255] (II° maintenance)
FAKi (GSK ) – GOG concept approved 8/11
NEW

29. Bottom Line…
Experimental but evidence of PFS impact has been demonstrated
I always have the conversation (longest of any counseling session) but it is only infrequently taken by the patient

30. Recurrent Therapy: Ovarian Cancer
Progression
Death
Diagnosis
Evaluation
? SLL
Secondary
Surgery
Symptoms
Chemotherapy #1
Chemo #2
Chemo #3+
Maintenance
Supportive
Care
Staging
What we know (Recurrence):
Nearly all patients will succumb to progression
Options are plentiful
Nothing a “homerun”

31. Treatment Free Interval: Traditional Model
Time from last platinum exposure (TFI)
Treatment
Completion
6 mos
Platinum Resistant/Refractory
Platinum Sensitive
Non-Platinum Treatment
Platinum Retreatment

32. Treatment-Free Interval and Survival
Days
Percentage
0-3 Prog
0-3 Non PD
3-12 mos
12-18 mos
18+ mos
PFS (days) 90
176
174
275
339
OS (days)
217
375
657
957
Response (%) 9 24 35 52 62
Lauraine, Proc ASCO #829, 2002

33. Summary of Phase III Single Agent Trials: Resistant Ovarian Cancer
Control
Experimental N
TTP (wks) P
OS (wks)
Comment
Paclitaxel
Topotecan
226
14 vs 23 NS
43 vs 61
50% Cross-over
Paclitaxel (bolus)
Paclitaxel (weekly)
208
38 vs 26
34 vs 59
Less toxicity w/ weekly
Oxaliplatin 86
14 vs 12
37 vs 42
74% platinum resistant
PLD
481
17 vs 16
57 vs 60
54% resistant; OS benefit in sensitive
214
22 vs 22
56 vs 46
All pts taxane-naïve
Treosulfan
357
22 vs 12
0.001
56 vs 48
0.02
2nd – 3rd line therapy
Gemcitabine
195
16 vs 13
59 vs 55
153
16 vs 20
55 vs 50
resistant
56% platinum resistant
PLD or Topotecan
Canfosfamide
461
19 vs 9
<0.01
59 vs 37 (PLD:62 vs Topo:47)
<0.0001
ASSIST-1 trial All 3rd line
Patupilone
802
16 vs 16
55 vs 57
RR: 8% vs 18% (patupilone)

34. Summary of Phase III Combination Trials: PR
Control
Experimental N
TTP (wks) P
OS (wks)
Comment
PLD
PLD +
Trabectedin
228
16 vs 17.4 NS
N/A
RR: 16 vs 23%
Take home messages:
Many choices
No best cytotoxic agent
Combinations with non-targeted cytotoxics add morbidity only

35. (Paclitaxel weekly, Gemcitabine, Topotecan)
Summary of Phase III Combination Trials: PR
Control
Experimental N
TTP (wks) P
OS (wks)
Comment
PLD
PLD +
Trabectedin
228
16 vs 17.4 NS
N/A
RR: 16 vs 23%
Chemo
(Paclitaxel weekly, Gemcitabine, Topotecan)
Chemo + Bevacizumab
361
14.8 vs 29.1
<0.001
RR: 12% vs 27%
(RECIST)

36. AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC) R A N D O M I Z E
Recurrent EOC
platinum resistant
≤ 2 prior therapies
no clinical or radiologic evidence of bowel involvement
Non-Platinum Chemotherapy
Treat to progression
Non-Platinum Chemotherapy + Bevacizumab 15 mg/kg
Treat to progression
N = 361
Stratified
chemotherapy
PFI (< 3 vs 3-6 mo)
prior anti-angiogenesis
Chemotherapy Options
Paclitaxel 80 mg/m2 d 1,8,15, 22 q28
Topotecan 4 mg/m2 d 1, 8 ,15 q28 or
Topotecan 1.25 mg/m2 d 1-5 q21
PLD 40 mg/m2 d 1 q28
Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

37. AURELIA: Patient Characteristics
CT (n = 182)
BEV + CT (n = 179)
Median age, years 61 62
Serous/adenocarcinoma at diagnosis
152 (84%)
156 (87%)
Histologic grade at diagnosis 1
2/3
9 (5%)
153 (84%)
10 (6%)
147 (82%)
Prior anti-angiogenic therapy
14 (8%)
12 (7%)
2 prior chemotherapy regimens
78 (43%)
72 (40%)
PFI < 3 months
46 (25%)
50 (28%)
ECOG PS
1-2
99 (54%)
80 (44%)
107 (60%)
70 (39%)
Measurable Disease
144 (79%)
143 (80%)
Ascites
54 (30)
59 (34)
Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

38. AURELIA Progression-Free SurvivalC T
BEV + C T
1.0
(n = 182)
(n = 179)
Events, n (%)
166 (91%)
135 (75%)
0.8
Median PFS, months
3.4
6.7
(95% CI)
( )
( )
HR (unadjusted)
0.48
0.6
(95% CI)
( )
Estimated Probability
Log-rnak P
-value
< 0.001
(2-sided, unadjusted)
0.4
0.2
3.4
6.7
0.0 6 12 18 24 30 T
ime (months)
Number at risk C T
182 93 37 20 8 1 1
BEV + CT
179
140 88 49 18 4 1 1
Pujade-Lauraine E, et al. J Clin Oncol. 2012; Suppl. Abstract LBA5002.

39. Subgroup analysis of PFS
No. of patients
Median PFS, months
HRa
BEV + CT better
CT better CT
BEV + CT
All patients
361
3.4
6.7
0.48
Age, years
<65
≥65
228
133
3.5
6.0
7.8
0.49
0.47
PFI, monthsb
<3
3‒6 96
257
2.1
3.6
5.4
0.53
0.46
Measurable disease, cm
No (<1)
Yes (1‒<5)
Yes (≥5) 74
126
161
3.7
3.3
7.5
0.50
Ascites
Yes No
113
248
2.5
5.6
7.6
0.40
Chemotherapy
Paclitaxel
PLD
Topotecan
115
120
3.9
10.4
5.8
0.57
0.32
aUnadjusted. bMissing n=8

40. Summary of best overall response rates
p<0.001a
p<0.001a
p=0.001a
Patients (%)
aTwo-sided chi-square test with Schouten correction

41. AURELIA: Conclusions No alarming safety signals
PLD – HFS, paclitaxel – neuropathy, all: myelosuppression)
Toxicity may relate to exposure (longer on experimental arms)
Bevacizumab augments outcomes (response, PFS) of standard chemotherapy
Paclitaxel may benefit to greater degree
Await OS data
CAVEATS
Not placebo-controlled
Pretreatment characteristics: 80% measurable, 30% ascites, 8% prior AA therapy
Each arm is equivalent to RP2

42. Bottom Line… For platinum-resistant disease, I like:
Weekly paclitaxel ± bevacizumab
PLD
Gemcitabine + cisplatin (q 2 wk infusion)
Try HARD to get onto clinical trial
Lots of options with interesting new agents

43. NCCN Guidelines Version 2013
Therapy for Relapse > 6 months
NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v
Available at:

44. DESKTOP-I: Surgical Endpoint of Surgery at Relapse
no residuals
median OS 45.2 mo
residuals > 10 mm
residuals 1-10 mm
Survival probability
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1 12 24 36 48
Months from Randomization

45. Secondary Cytoreduction: Multivariate Analysis Who Benefits?
Tay, Obstet Gynecol 99:1008, 2002

46. Secondary Cytoreductive Surgery
Goal of surgery: No gross residual disease
DFI
Single Site
Multiple Sites:
No Carcinomatosis
Carcinomatosis
6-12 mos
Suggest SC
Offer SC
No SC
12-30 mos
> 30 mos
DFI = disease-free interval; mos = months; SC = secondary cytoreduction.
Chi DS, et al. Cancer. 2006;106(9): 46 46

47. AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)
EOC, FT, PP
PFI > 6
No prior recurrence chemotherapy
Complete resection seems feasible and positive AGO score:
PS ECOG 0
No ascites > 500 ml
Prior complete debulking or initial FIGO I/II
Secondary Cytoreduction R
Chemo
No surgery
Regimens post-randomization
Carboplatin/paclitaxel
Carboplatin/gemcitabine
Carboplatin/PLD
N = 150/408 planned

48. Recurrent Ovarian, PPT and FT Cancer
GOG-213
Recurrent Ovarian, PPT and FT Cancer
TFI ≥ 6 mos
Surgical Candidate?
Yes No
Randomize
Randomize
Surgery
No Surgery
Carboplatin
Paclitaxel or
Gemcitabine
Carboplatin
Pac or Gem
Bevacizumab
To Chemotherapy
Randomization
Bevacizumab
PI: Coleman

49. SOC I Shanghai Gynecologic Oncology Group
A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer
Platinum-sensitive, first relapse recurrent cancer of the ovaries, fallopian tubes, or peritoneum
PFI > 6 mos No prior chemotherapy for this 1st relapse
Complete secondary cytoreduction predicting score (iMODEL)
FIGO stage
Residual disease after primary surgery
PFI
PS ECOG
CA125
Ascites at recurrence
N=420
Cytoreductive surgery
R A N D
OM I Z E
Platinum-based chemotherapy*
No surgery
Primary outcome: OS
Secondary outcome: PFS, QoL, Complications
Available at: Accessed March 04, 2013.

50. Outcomes in Recurrent Ovarian Cancer: PS
Trial
Treatment
RR (%)
PFS (mo) HR
OS (mo)
ICON 4
(n = 802) C 54 9
0.76
P < 0.001 24
0.82
P = 0.02
C + P 66 12 29
AGO
(n = 366) 31
5.8
0.72
P = 0.003
17.3
0.96
P = 0.73 GC 47
8.6 18
OVA-301
(n = 417)
PLD ?
7.5
0.73
P=0.017
24.1
0.83
P = 0.11
PLD + Trab
9.2
27.0
CALYPSO (n = 976) –
9.4
P = 0.005
33.0
0.99
P = 0.94
C + PLD
11.3
30.7
OCEANS
(n = 484)
GC + PL 57
8.4
0.48
P <
35.2*
1.03*
P = 0.84
GC + BV 79
12.4
33.3
Take home messages:
PFS appears to be impacted from combination therapy
No OS effect to date
Post progression survival is dramatically increasing
*Data still maturing.

51. Bottom Line… For Platinum-sensitive disease, I like:
Secondary cytoreduction if small volume and remote recurrence
However, I try HARD to get on clinical trial as this is a very biased situation
Platinum-based doublets
PLD, Gemcitabine and Paclitaxel with carboplatin
If I give gemcitabine doublet I give with bevacizumab
Lots of new trials coming online here as well

52. Ovarian Cancer: Novel Targets
Matei, Expert Opin Investig Drugs (2007) 16:1227

53. Developmental Therapeutics: Targets
Tumor Cell
Pericyte
Tumor Endothelium
Microenvironment

54. Trebananib: Phase III Studies
TRINOVA-1 Phase III Trial
Weekly paclitaxel + Trebananib
Recurrent ovarian,
FT, PP cancer R
Weekly paclitaxel + placebo
N = 900
Primary Objective: PFS
Secondary Objectives: OS, RR (RECIST and CA-125), Safety, pK, QOL
ClinicalTrials.gov. NCT
TRINOVA-2 Phase III Trial
Pegylated Liposomal Doxorubicin (PLD) + Trebananib
Recurrent ovarian,
FT, PP cancer R
Pegylated Liposomal Doxorubicin (PLD) + placebo

55. EC145 Phase III Randomized Study Design in Patients with Platinum Resistant Ovarian Cancer
Blinded Randomized study comparing EC145 + PLD vs. PLD alone
Platinum Resistant patients
~600 Patients randomized 2:1
Study objectives:
Compare PFS between arms
Independent radiology review
OS in EC20 ++ patients

56. PARP Inhibitors in the Clinic
BRCA +/+
BRCA +/-
1000x
BRCA -/-
Nature 2005

57. Olaparib Development: Lessons Learned
1Phase I
MTD 400 mg BID
Expansion Phase (N=39 BRCA+) = responses
Platinum-sensitive > resistant
Phase II (BRCA+)
Dose effect (100 mg BID vs 400 mg BID)2
PARPi is best measured by PK (AUCss)2
Is as active as PLD (RP2)3
Phase II (BRCA-wt)
HRD exists as somatic event (30%)4
RR seen in BRCA-wt, high grade serous5
Genomic signature may identify these patients6
1Fong, NEJM 2009
2Audeh Lancet 2010
3Kaye, ASCO 2011
4TCGA, 2011
5Gehlmon, Lancet 2011
6Konstantinopoulos, JCO 2010

58. Study 19: Maintenance Olaparib
Patient eligibility:
Platinum-sensitive high-grade serous ovarian cancer
2 previous platinum regimens
Last chemotherapy: platinum-based with a maintained response
Stable CA125 at trial entry
Randomization stratification factors:
Time to disease progression on penultimate platinum therapy
Objective response to last platinum therapy
Ethnic descent
Primary ENDPOINT: PFS
Olaparib 400 mg po bid
Treatment until disease progression
Randomized 1:1
Placebo po bid
Ledermann, N Engl J Med 2012 58

59. Study 19: Secondary Maintenance
Ledermann, N Engl J Med 2012

60. PARP Inhibitors in Clinical Trials
Agent
Administration
Phase
Comments
Olaparib
(AZD-2281)
Oral
I, II, III
Single Agent and Combination, BRCA and non-BRCA, Platinum- sensitive and resistant, Primary and Recurrent
AZD-2461 I
FIH, Solid Tumors
Veliparib
ABT-888
I, II
(GOG-9923, PIS1004, GOG-280)
BMN 673
BRCA mutation carriers, Platinum Sensitive
CEP-9722
Combination, Solid Tumors
E7016
Niraparib
(MK4827)
Single Agent and Combination, BRCA and non-BRCA, Platinum- sensitive and resistant
Rucaparib
(CO-338)
AG014699 IV II
Single Agent, BRCA, Platinum-sensitive and resistant
Iniparib
(BSI-201)
II, III
Combination (Gem/Cis or Carbo), Platinum-sensitive and resistant
Available at:

61. 2013:Phase III Studies in Ovarian Cancer*
Front-line added to chemotherapy then as Maintenance
Bevacizumab (GOG 262 imaging biomarker study)
BIBF 1120 (OVAR 12) - closed
Trebananib (GOG 3001/TRINOVA-3)
Maintenance alone
Polyglutamate paclitaxel (GOG 212)
Pazopanib (OVAR 16) - closed
CVAC (MUC-1)
Platinum-resistant recurrent ovarian cancer
Karenitecin
Trebananib (with Paclitaxel/TRINOVA-1 [closed] or PLD/TRINOVA-2)
Vintafolide (with PLD)
Platinum-sensitive recurrent ovarian cancer
Bevacizumab (with chemotherapy - GOG 213)
Trebananib (with PLD or Paclitaxel)
Trabectedin with PLD (in 6 – 12 month group/INOVATYON)
Water soluble formulation of Paclitaxel
*Phase II studies of PARP inhibitors, and Cabozantinib may lead to FDA approval
PLD = Pegylated Liposomal Doxorubicin

62. Take Home Messages Ovarian cancer is a heterogeneous disease
Molecular sub-classification can describe dependency on different driving/survival mechanisms in otherwise morphologically similar tumors
Consistent patterns of chromosomal change suggests interdependency within individual tumors
Target discovery has led to a flood of clinical trial development
Most promising: angiogenesis, PI3K, HRD, EMT
Lagging are strategic solutions for induced and adaptive responses to treatment and study designs
Need for new composite endpoints (FDA discussions underway)

63. Thanks!