Transforming Treatment in Ovarian Cancer

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Chair’s Practice Patterns Research– Research data identifying common practices

– Understanding knowledge gaps and training needs

DISCLAIMERDISCLAIMERParticipants 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 USEDISCLOSURE OF UNLABELED USEThis 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.

Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestRobert F. Ozols, MDRobert F. Ozols, MD

Reported a financial interest/relationship or affiliation in the form of: Consultant, AstraZeneca Pharmaceuticals LP, Johnson & Johnson Pharmaceutical Research & Development, LLC.

Learning ObjectivesLearning ObjectivesUpon completion of this activity, participants Upon completion of this activity, participants

should be better able to: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

Activity AgendaActivity 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)

Community and Academic Community and Academic Ground Rounds: Transforming Ground Rounds: Transforming Treatment in Ovarian CancerTreatment in Ovarian Cancer

Courtesy of Bradley J. Monk, MD, FACOG, FACS.

Newly Diagnosed Advanced Newly Diagnosed Advanced Ovarian CancerOvarian Cancer

Ovarian Carcinoma: Ovarian Carcinoma: Incidence and MortalityIncidence 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 cancerUS = United States.ACS, 2011.

Stage Distribution and 5-yr Relative Stage Distribution and 5-yr Relative Survival by Stage at DiagnosisSurvival by Stage at Diagnosis

(2001–2007, all races)(2001–2007, all races)

LNs = lymph nodes.Howlader et al, 2011.

Results of Treatment: Results of Treatment: Advanced DiseaseAdvanced Disease

CR = complete response; PFS = progression-free survival.Gynecologic Oncology Group Database (courtesy of J. Tate Thigpen, MD).

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

Results of Treatment: Results of Treatment: Advanced Disease (cont.)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).

First-Line Therapy First-Line Therapy Global Standard TreatmentGlobal Standard Treatment

IV Platinum + Taxane Chemotherapy(Carboplatin + Paclitaxel) x 6

IV = intravenous.Pfisterer & Ledermann, 2006.Courtesy of Bradley J. Monk, MD, FACOG, FACS.

Surgery With Maximum Cytoreduction Effort

Basis for Current Standard: Basis for Current Standard: Systemic TherapySystemic 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.

Case Study 1Case Study 1Integrating Personalized Approaches Into Integrating Personalized Approaches Into Treatment Planning and Management for Treatment Planning and Management for

First-Line TherapyFirst-Line Therapy

Case Study 1Case 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.

Based on Existing Evidence-Based Based on Existing Evidence-Based Data, What Options Might Be Data, What Options Might Be Considered at This Point? 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.

JGOG: Dose-Dense Wkly PaclitaxelJGOG: Dose-Dense Wkly Paclitaxel

EOC or PP Stage II–IV No prior therapy Stratified: Residual disease,

stage, and histology Primary end point: PFS Secondary end point: OS

Pac 180 mg/m2 Carb AUC = 6

Carb AUC = 6Pac 80 mg/m2/wk x 3

Accrual: 637 patients (ITT)

I

II

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.

x 6–9

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

Isonishi et al, 2008.

JGOG: Dose-Dense Wkly Paclitaxel JGOG: Dose-Dense Wkly Paclitaxel (cont.)(cont.)

Justification for Neoadjuvant Justification for Neoadjuvant ChemotherapyChemotherapy

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.

Ovarian, Tubal, or Peritoneal CancerFIGO Stage IIIC/IV (N = 670)

Primary End Point: OSSecondary End Points: PFS, QOL, AEs

Randomization

PDS NACT

3 x platinum-based CT

IDS if no PDIDS (not obligatory)

≥ 3 x platinum-based CT≥ 3 x platinum-based CT

3 x platinum-based CT

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.

NACT + IDS Vs. PDSNACT + IDS Vs. PDS

HR = hazard ratio.Vergote et al, 2010.

NACT + IDS Vs. PDS (cont.)NACT + IDS Vs. PDS (cont.)ITT AnalysisITT Analysis

NACT + IDS Vs. PDS (cont.)NACT + IDS Vs. PDS (cont.)Surgical Characteristics PDS

(n = 329)NACT IDS

(n = 339)Postoperative mortality (< 28 days)

2.5% 0.7%

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.

Median PFS (mos)

HR Median OS (mos)

HR

IV IP IV IP

GOG 104 — — — 41 490.76

(p = .02)

GOG 114 22 280.78

(p = .01) 52 630.81

(p = .05)

GOG 172 18.3 23.80.80

(p = .05) 50 660.75

(p = .03)

Alberts et al, 1996; Markman et al, 2001; Armstrong et al, 2006.

Primary Therapy: IPPrimary Therapy: IP

GOG 172: Ovarian (Optimal III)GOG 172: Ovarian (Optimal III) EOC Optimal stage III No prior therapy Elective second-look

Open: 23-March-98Closed: 29-January-01Accrual: 415 patients (evaluable)

Pac 135 mg/m2 (24 hrs)Cis 75 mg/m2 Day 2

Pac 135 mg/m2 (24 hrs) IV Day 1Cis 100 mg/m2 IP Day 2Pac 60 mg/m2 IP Day 8

I

II

Armstrong et al, 2006.

GOG Protocol 172GOG Protocol 172

RR = response rate; CI = confidence interval.Adapted from Armstrong et al, 2006.

By Treatment GroupPr

opor

tion

Surv

iving

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months on Study0 12 24 36 48 60

Rx Group Alive Dead Total IV 93 117 210

Alive Dead Total

IP 117 88 205

IV median OS = 49.7 mos

IP median OS = 65.6 mos

RR of death = 0.75 (95% CI: 0.58, 0.97) p = .03

Rx Group Lost to Alive Dead TotalFollow-up

IV 5 78 127 210IP 11 93 101 205

GOG Protocol 172: ToxicityGOG Protocol 172: Toxicity

GradeIV

(N = 210; %)IP

(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 mosap ≤ .05GI = gastrointestinal.Armstrong et al, 2006.

GOG 218: SchemaGOG 218: Schema

Front-Line EOC, PP, or FT

• Stage III optimal (macroscopic)

• Stage III suboptimal• Stage IV

N = 1,800 (planned)

Stratification variables – GOG PS – Stage/debulking status

1:1:1

15 mos

P 175 mg/m2

C AUC 6

Placebo

IArm

Cytotoxic(6 cycles)

Maintenance(16 cycles)

(CP)

C AUC 6

P 175 mg/m2

PlaceboBev 15 mg/kg

II(CP + Bev)

Bev 15 mg/kg

C AUC 6

P 175 mg/m2III

(CP + Bev Bev)

FT = fallopian tube; PS = performance status; C = carboplatin; P = paclitaxel.Burger et al, 2010.

GOG 218: Patient DispositionGOG 218: Patient Disposition

Characteristic

Arm ICP

(n = 625)

Arm IICP + Bev(n = 625)

Arm IIICP + Bev Bev

(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

aOne patient in each group received Bev/placebo in Cycle 1.Burger et al, 2010.

AE (grade when limited), n (%)

Arm ICP

(n = 601)


Arm IIICP + Bev Bev

(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)

GOG 218: Select AEsGOG 218: Select AEsOnset Between Cycle 2 and 30 Days After Date of Last TreatmentOnset Between Cycle 2 and 30 Days After Date of Last Treatment

aPerforation/fistula/necrosis/leak.b p < .05HTN = hypertension; CNS = central nervous system; RPLS = reversible posterior leukoencephalopathy syndrome.Burger et al, 2010.

GOG 218: Select AEs (cont.) GOG 218: Select AEs (cont.) Treatment PhaseTreatment Phase

Select AEs (n)(grade when limited)

Arm ICP

Arm IICP + Bev

Arm IIICP + Bev Bev

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

Treatment phasea Cytotoxic (Cycles 2–6)

Maintenance (Cycles ≥ 7)

Cytotoxic(Cycles 2–6)


Cytotoxic (Cycles 2–6)


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

aOnset within 30 days of last treatment.bPerforation/fistula/necrosis/leak.Burger et al, 2010.

CP (Arm I)

GOG 218: Investigator-Assessed GOG 218: Investigator-Assessed PFSPFS

+ Bev (Arm II)

+ Bev Bev maintenance (Arm III)

Pro

porti

on P

FS (%

)

Time (Mos Since Randomization)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 12 24 36

Arm I

CP (n = 625)

Patients with event (n; %) 423 (67.7)

Median PFS (mos) 10.3

Stratified analysis HR (95% CI)

One-sided p value (log rank)

Arm III

CP + Bev Bev(n = 623)

360 (57.8)

14.10.717

(0.625–0.824)< .0001a

Arm II

CP + Bev(n = 625)

418 (66.9)

11.20.908

(0.759–1.040).080a

a p = .0116Burger et al, 2010.

GOG 218: Subgroup Analyses of PFSGOG 218: Subgroup Analyses of PFSCP + Bev CP + Bev Bev (Arm III) Vs. CP (Arm I)Bev (Arm III) Vs. CP (Arm I)

HR

Experimental Arm (CP + Bev Bev;

Arm III) BetterControl Arm

(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

Treatment HR

0.33 0.5 0.67 1.0 1.5 2.0 3.0

Burger et al, 2010.

GOG 218: OS Analysis GOG 218: OS Analysis At Time of Final PFS Analysis (January 2010)At Time of Final PFS Analysis (January 2010)

Arm ICP

(n = 625)


Arm IIICP + Bev Bev

(n = 623)

Patients with events (n; %)

156

(25.0)

150

(24.0)

138

(22.2)

Median (mos) 39.3 38.7 39.7

HRa

(95% CI)

1.036(0.827–1.297)

0.915(0.727–1.152)

One-sided p value .361 .252

Pro

porti

on A

live

(%)

Time (Mos Since Randomization)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 12 24 36 48

aStratified analysis.

625/625/623 442/432/437 173/162/171 46/39/40No. at risk

Burger et al, 2010.

ICON7: Study DesignICON7: Study Design

Stratification variables – Stage/surgery– Time since surgery

– GCIG group

aMight vary based on GCIG group.

P 175 mg/m2

C AUC 6a

C AUC 6a

P 175 mg/m2

Arm A

Arm A

ArmArm BB

12 mos12 mos

Front-Line EOC, PP, or FT• Stage I/IIA (grade 3) • Stage IIB/C• Stage III• Stage IV

N = 1,520 (planned)

Bev 7.5 mg/kg

Primary end point: PFS

Secondary end points: OS, RR, QOL, safety, cost-effectiveness,translational

No IRC present

GCIG = Gynecologic Cancer Intergroup; IRC = independent review committee.Kristensen et al, 2011.

Key Differences Between Key Differences Between GOG 218 and ICON7GOG 218 and ICON7

Trial GOG 218 ICON7

Setting/Design

Double-blinded, placebo-controlled 3-arm study Bev for 15 mos Bev dose: 5 mg/kg/wk

Open-label 2-arm study Bev for 12 mos Bev dose: 2.5 mg/kg/wk

Patient Population

Stage III (suboptimal) Stage III (optimal, visual/palpable) Stage IV

Stage I or IIA (grade 3/clear cell histology)

Stages IIB–IV (all)

Additional End Point

OS analysis (formal testing at time of PFS) IRC

Defined final OS analysis (end 2012)

No IRC

Burger et al, 2010; Kristensen et al, 2011.

Stratification Variables Stage and extent of debulking:

I–III debulked ≤ 1 cm Stage I–III debulked > 1 cm Stage IV and inoperable stage III

Timing of intended treatment start≤ 4 vs. > 4 wks after surgery

GCIG group

ICON7 SchemaICON7 Schema

Academic-led, industry-supported trial to investigate use of Bev

and to support licensing

Paclitaxel 175 mg/m2

Carboplatin AUC 5/6

Carboplatin AUC 5/6


18 cycles

N = 1,528a

BEV 7.5 mg/kg q3wks

1:1

aDecember 2006 to February 2009.Kristensen et al, 2011.

R

ICON7 PFS: UpdatedICON7 PFS: Updated

17.419.8

ControlResearch

Kristensen et al, 2011.

PFS: “High Risk” Subgroup (Ad Hoc Analysis)PFS: “High Risk” Subgroup (Ad Hoc Analysis)

Number At RiskControl 234 205 98 36 14 2Research 231 213 159 56 10 1

1.00

0.75

0.50

0.25

0

Prop

ortio

n A

live

With

out P

rogr

essi

on (%

)

Time (mos) 0 3 6 9 12 15 18 21 24 27 30

Control(n = 234)

Research (n = 231)

Events, n (%) 173 (74) 158 (68)Median (mos) 10.5 15.9Log-rank test p < .001HR (95% CI) 0.68 (0.55–0.85)Restricted mean 13.3 16.5

10.5 15.9

ControlResearch


High Risk: Stage IIIC Suboptimal/Stage IV

Interim Analysis of Overall Survival Interim Analysis of Overall Survival


Case Study 2Case Study 2Optimally Managing Recurrent Optimally Managing Recurrent

Ovarian CancerOvarian Cancer

Case Study 2 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?

Recurrence After First-Line Chemotherapy

PlatinumPlatinumSensitiveSensitive

> 6 Mos> 6 Mos

ChemotherapyChemotherapyDoubletDoublet

Platinum Platinum Refractory/ResistantRefractory/Resistant

< 6 Mos< 6 Mos

Non-PlatinumNon-PlatinumSingle AgentSingle Agent

The Traditional Treatment Paradigm The Traditional Treatment Paradigm

Ushijima, 2010.

Recurrent Ovarian Cancer:Recurrent Ovarian Cancer:Definition of Disease SensitivityDefinition of Disease Sensitivity

0 3 6 12 18 24

Refractory

PREVIOUS

TREATMENT

Resistant

Sensitive

Time to Recurrence (mos)

Highly Sensitive

Our Patient

Ushijima, 2010.

Major Trials in Major Trials in Recurrent Ovarian CancerRecurrent 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.

FDA-Approved Drugs inFDA-Approved Drugs inOvarian CancerOvarian Cancer

1978

Cisp

latin

Carb

opla

tin

Altre

tam

ine

Pacli

taxe

lTo

pote

can

PLD

(acc

eler

ated

)Li

poso

mal

dox

orub

icin

(full)

Gem

citab

ine

(with

car

bopl

atin

)

2006

1989

1990

1992

1996

1999

2005

2009

Trab

ecte

din;

EU

only

(with

PLD

)

1964

Mel

phal

anDo

xoru

bicin

1974

NCCN, 2011; Shah et al, 2009.

Recurrence RegimensRecurrence RegimensNCCN Preferred AgentsNCCN Preferred Agents

aPlatinum-based combination therapy should be considered for platinum sensitive recurrences. NCCN = National Comprehensive Cancer Network.NCCN, 2011.

Phase III Study (Doublets): CALYPSOPhase III Study (Doublets): CALYPSO

RANDOMIZE

Relapse


Carboplatin AUC 5q3wks

PLD 30 mg/m2

Carboplatin AUC 5q4wks

Ovarian Cancer – First relapse– Platinum-sensitive

Pujade-Lauraine et al, 2010.

Opened: 4/2005Closed: 10/2007

N = 976

PFS: ITTPFS: ITTCD 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.

Intermediate Sensitive: 6–12 mosIntermediate Sensitive: 6–12 mosCD 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

Pujade-Lauraine et al, 2010.

Months from Randomization

PFS: Highly Platinum-Sensitive PFS: Highly Platinum-Sensitive (PFI > 24 mos)(PFI > 24 mos)

C-PLD C-P HR pPFS 12.0

mos12.3 mos

1.05 (0.79–1.40)

.73

RR 42% 38% .46

PFI = progression-free interval.Mahner et al, 2011.

CALPYSO: OS AnalysisCALPYSO: OS Analysis

Marth et al, 2011.

Bevacizumab: The First Active Bevacizumab: The First Active Targeted Agent in Ovarian CancerTargeted 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

CG + PLA

OCEANS: Study SchemaOCEANS: Study Schema

CG for 6 (up to 10) cycles

Stratification VariablesPlatinum-free interval

(6–12 vs. > 12 mos)Cytoreductive surgery for

recurrent disease (yes vs. no)

Platinum-Sensitive ROCa Measurable disease ECOG 0/1 No prior chemotherapy for ROC No prior BEV

(N = 484)

aEOC, PP, or FT cancer.ROC = recurrent ovarian cancer; ECOG = Eastern Cooperative Oncology Group.Aghajanian et al, 2011.

Gemcitabine 1,000 mg/m2

Days 1, 8

Carboplatin AUC 4

PLA q3wks Until Progression

Carbopaltin AUC 4

BEV 15 mg/kg q3wks Until Progression

Gemcitabine 1,000 mg/m2

Days 1, 8CG + BEV

OCEANS: Patient CharacteristicsOCEANS: Patient CharacteristicsCharacteristic

CG + PLA (n = 242)

CG + BEV (n = 242)

Median age (yrs) (range)

61(28−86)

60(38–87)

Age ≥ 65 yrs (%) 38 35Race (%) White Other

928

9010

ECOG PS 0 (%) 76 75Histologic subtype (%) Serous Mucinous/clear cell Other

843 14

785

17Platinum-free interval (%) 6–12 mos > 12 mos

4258

4159

Cytoreductive surgery for recurrent disease (%) 10 12

Aghajanian et al, 2011.

242 177 45 11 3 0CG + PL

OCEANS: Primary Analysis of PFSOCEANS: Primary Analysis of PFSCG + PLA(n = 242)

CG + BEV(n = 242)

Events, n (%) 187 (77) 151 (62)Median PFS (mos) (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)

< .0001

Time (mos)Number At Risk

242 203 92 33 11 0CG + BV

1.0

0.8

0.6

0.4

0.2

0

Prop

ortio

n PF

S (%

)

0 6 12 18 24 30

ORRGC: 57.4%GC+B: 78.5% p < .0001


Median PFS (mos)

Baseline risk factor No. of patients CG + PLA

(n = 242)CG + BEV (n = 242) HR (95% CI)

CG + BEV

betterCG + PLA

betterAll patients 484 8.4 12.4 0.49 (0.40–

0.61)Platinum-free interval (mos)

6–12 202 8.0 11.9 0.41 (0.29–0.58)

> 12 282 9.7 12.4 0.55 (0.41–0.73)

Cytoreductive surgery for recurrent disease

Yes 54 7.5 16.7 0.50 (0.24–1.01)

No 430 8.4 12.3 0.49 (0.39–0.62)

Age (yrs) < 65 306 8.5 12.5 0.47 (0.36–0.62)

≥ 65 178 8.4 12.3 0.50 (0.34–0.72)

Baseline ECOG PS 0 367 8.6 12.5 0.47 (0.36–0.60)

1 116 8.3 10.6 0.61 (0.39–0.95)

OCEANS: PFS Subgroup AnalysesOCEANS: PFS Subgroup Analyses

HR0.2 0.5 1 2 5


OCEANS: Interim OSOCEANS: Interim OS1.0

0.8

0.6

0.4

0.2

0

Prop

ortio

n A

live

(%)

0Time (mos)

6 12 30 36 42

Number At Risk

18 24

242 235 195 26 8 0CG + PL 131 77242 238 200 42 8 0CG + BV 146 82

CG + PLA(n = 242)

CG + BEV(n = 242)

Events, n (%) 78 (32) 63 (26)Median OS (mos) (95% CI)

29.9(26.4–NE)

35.5(30.0–NE)

Stratified analysis HR (95% CI)Log-rank p value

0.751(0.537–1.052)

.094a

ap value does not cross pre-specified boundary of .001NE = not estimable.Aghajanian et al, 2011.

OCEANS: AEs of Special InterestOCEANS: AEs of Special Interest Patients (%)

CG + PLA(n = 233)

CG + BEV(n = 247)

ATE, all grades 1 3VTE, grade ≥ 3 3 4CNS bleeding, all grades < 1 1Non-CNS bleeding, grades ≥ 3 1 6CHF, grades ≥ 3 1 1Neutropenia, grade ≥ 3 56 58Febrile neutropenia, grade ≥ 3 2 2HTN, grade ≥ 3 < 1 17Fistula/abscess, all grades < 1 2GI perforation, all grades 0 0a

Proteinuria, grade ≥ 3 1 9RPLS, all grade 0 1Wound-healing complication, grades ≥ 3 0 1

aTwo GI perforations occurred 69 days after last BEV dose.ATE = arterial thromboembolic event; VTE = venous thromboembolic event. Aghajanian et al, 2011.

OCEANS: Preliminary ConclusionsOCEANS: 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


Novel Therapies andNovel Therapies and Future Directions Future Directions

PARP InhibitorsPARP InhibitorsSuggested Mechanism of ActionSuggested Mechanism of Action

PARP1

PARP1

PARP1

CELL DEATHCELL SURVIVAL

BRCA1BRCA2

Replication fork collapse

Double strand DNA break

Disables DNA

base-excision repair

Inhibition of PARP1

Base-excision repair of DNA damage

PARP1 Upregulation

Chemotherapy inflicts DNA damage via adducts and

DNA cross-linking

PARP Inhibitor

PARP = poly (ADP-ribose) polymerase; DNA = deoxyribonucleic acid. O’Shaughnessy et al, 2009.

Phase II Study of Olaparib of Patients With Phase II Study of Olaparib of Patients With BRCA1 BRCA1 or or BRCA2BRCA2 Mutation Mutation

Two dosages tested in sequential cohorts of patients with recurrent, measurable disease

Primary end point: RR

AEs: Nausea, fatigue, anemiaBRCA = breast cancer gene; BID = twice daily; ORR = overall response rate.Audeh et al, 2010.

400 mg BIDn = 33ORR = 33%

100 mg BIDn = 24ORR = 13%

Study 19: Aim and DesignStudy 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

OLA 400 mg po BID

Randomized 1:1

PLApo BID

Patient EligibilityPlatinum-sensitive high grade serous ovarian cancer 2 previous platinum regimens Last chemotherapy: Platinum-based with a

maintained responseStable CA125 at trial entryRandomization stratification factors

– Time to PD on penultimate platinum therapy– Objective response to last platinum therapy – Ethnic descent

Treatment until PD

po = oral; PD = progressive disease.Ledermann et al, 2011.

Patient CharacteristicsPatient CharacteristicsOlaparib

400 mg bid(n = 136)

Placebo(n = 129)

Median age, yrs (range) 58 (21–89) 59 (33–84)

Ethnicity, n (%)Jewish descent 20 (15) 17 (13)

ECOG status, n0 / 1 / 2 / unknown 110 / 23 / 1 / 2 95 / 30 / 2 / 2

BRCA mutation status, n (%)a

BRCA1BRCA2BRCA1 and BRCA2Known negativeUnknown

25 (18)6 (4)

018 (13)87 (64)

20 (16)7 (5)1 (1)

20 (16)81 (63)

aBRCA mutation status was not a requirement.Ledermann et al, 2011.

Progression-Free SurvivalProgression-Free Survival

0

Time from randomization (mos)

136 104 51 23 6 0 0129 72 23 7 1 0 0

At risk (n)OlaparibPlacebo

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

No. of events: Total patients (%)

Median PFS (mos)

Olaparib60:136 (44.1)

8.4

Placebo93:129 (72.1)

4.8

HR 0.35 (95% CI, 0.25–0.49)p < .00001

Olaparib 400 mg bidPlacebo

Randomized TreatmentProp

ortio

n of

PFS

(%)

Ledermann et al, 2011.

Preplanned Subgroup Analysis of PFSPreplanned Subgroup Analysis of PFS

Global interaction test showed no evidence of inconsistency across the subgroups (p = .282)

HR (OLA: PLA) and 95% CI0.0 0.2 0.4 0.6 0.8 1.00.1 0.3 0.5 0.7 0.9

OverallBRCA mutationBRCA status known

Age < 50Age ≤ 50 to < 65Age ≥ 65Race, whiteNon-Jewish descentCR at baselinePR at baselineTTP penultimate platinum regimen 6–12 mosTTP penultimate platinum regimen > 12 mos

BRCA unknown

Favors OLA

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.

Pharmacogenomics

Molecular Biology

Companion Diagnostics

Bioinformatics Translational Genomics

Pharmacometabonomics

Personalized Medicine

Confluence of Multiple AdvancesConfluence of Multiple Advances

Targets

AngiogenesisVEGF/VEGFR

MoAb

EGFR

FR

Repackaging Traditional Agents

PARP

mTOR/Akt/PI3K

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.

ER

CA125

Src

PDGFR HSP90PKC

Future Strategies in Ovarian CancerFuture Strategies in Ovarian Cancer

Transforming Treatment in Ovarian Cancer

Health & Medicine

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