An Oncology Exchange Activity Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials:

• An Oncology Exchange Activity Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials:

• Pre-activity Survey – Located at the front of your syllabus

• CME Evaluation with Post-activity Survey– Located at the back of your syllabus

• An Oncology Exchange Activity

Disclosures

• The relevant financial relationships reported by faculty that they or their spouse/partner have with commercial interests are located on page 5 of your syllabus

• The relevant financial relationships reported by the steering committee that they or their spouse/partner have with commercial interests are provided on page 5 of your syllabus

• The relevant financial relationships reported by the non-faculty content contributors and/or reviewers that they or their spouse/partner have with commercial interests are located on page 5 of your syllabus

Off-label Discussion Disclosure

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

Learning Objectives

• Review the incorporation of guidelines in clinical decision-making to optimize patient outcomes

• Evaluate the evidence for personalizing therapy based on genetic mutations and resistance markers

• Understand the role of PARP inhibitors and anti-angiogenic agents for platinum-resistant/sensitive recurrent disease

• Discuss the integration of ovarian cancer quality measures to improve patient outcomes

Pre-activity Survey

• Please take out the Pre-activity Survey from your packet• Your answers are important to us and will be used to help

shape future CME activities• It is important that you fill out the information at the top of

the form:– Please select the best answer(s) for the questions below:– Degree: _ MD/DO _ Nursing Professional _ PharmD

_Other:_____________________________ – Specialty: _ Oncology _ Gynecology _ Surgery

_ Internal Medicine _Other:______________________

Pre-activity Survey Question 1

Please rate your level of confidence in personalizing treatment strategies for patients with recurrent ovarian cancer:

1 2 3 4 5

Not confident Expert


Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated benefit in:

1. HER2/neu positive recurrent ovarian cancer2. Platinum-resistant high-grade serous ovarian cancer3. p53 mutant recurrent ovarian cancer 4. Women with ovarian cancer and BRCA germline

mutations


In the AURELIA trial, the addition of bevacizumab to chemotherapy for platinum-resistant recurrent ovarian cancer resulted in which of the following outcomes?

1. A significant improvement in progression-free survival and overall survival by 3.3 months

2. A significant improvement in progression-free survival and response rates, but not in overall survival

3. A significant improvement in overall survival and objective response rate, but not in progression-free survival

4. An increase in objective response rate for the placebo arm

5. A significant increase in median duration of response by 5 months, objective response rate by 21%, and median progression-free survival by 4 months


Which of the following patients with high-grade ovarian cancer should undergo genetic testing for BRCA1/BRCA2?

1. Patients under the age of 602. Patients with a significant family history3. Patients diagnosed at early stage4. All patients

Pre-activity Survey Question 5Following optimal debulking surgery, a 60-year-old woman receives 6 cycles of carboplatin-paclitaxel. Her CA-125 level following adjuvant chemotherapy remains less than 5 for two years. She then develops bloating and ascites associated with carcinomatosis. What is your treatment recommendation at this time?

1. Retreat with a platinum-doublet

2. Non-platinum single agent

3. Delay treatment until bowel obstruction

4. Secondary debulking surgery

Goals of TreatmentRelapsed Ovarian Cancer

• Prolong Survival• Delay Time to Progression• Control Disease-related Symptoms• Minimize Treatment-related Symptoms• Maintain or Improve Quality of Life

Ovarian CancerHow is Relapse Defined?

• Continuous rise in CA-125• CA-125 above 100• Radiographic recurrence• Symptomatic recurrence• Physical examination findings• Combination of above

Issues Impacting Therapy for Recurrent Ovarian Cancer• Treatment-free interval

– Impact of consolidation/maintenance therapy• Number of prior regimens

– Response to prior therapy• Toxicity from prior therapy

– Prior use of growth factors– Transfusion requirements– Neuropathy

• Volume and site(s) of disease– Ascites/GI symptoms– Potential for secondary surgery– Performance status

Effect of Platinum-Free Interval on Response Rate

Non-platinum Therapy

15%

20%

30%

30%

% Response to Second-line Platinum Therapy

Platinum-Free Interval (mos) Markman Gore Blackledge

0-617%

10%

7-12 27% 29%

13-1833% 27%

63%

19-24 94%

>24 59% 57%

Markman M et al. J Clin Oncol. 1991;9:389-393; Gore ME et al. Gynecol Oncol. 1990;36:207-211; Blackledge G et al. Br J Cancer. 1989;59:650-653.

General Approach to Treatment ofRecurrent Disease

• Increasing evidence suggests the duration of the PFI alsoinfluences outcomes of non-platinum chemotherapeuticagents/regimens

Platinumsensitive

PFI >6 mos

Platinumretreatment

Platinum refractory/resistant

PFI <6 mos

Non-platinum treatment

PFI = progression-free interval.

PRI

MARY

TREATMENT

Ovarian Cancer at First Relapse Definition of Sensitivity

Defined as measurable recurrence, not biochemical (CA-125) recurrence

Refractory

Resistant

Sensitive

24 Months

“Very Sensitive”

0 3 6 12 18

Platinum-Sensitive Recurrent Ovarian Cancer

What Do We Know about Secondary Debulking?1. Surgical endpoint: Complete resection or minimal residual disease?

– 8 series >100 patients

• Eisenkop SM, et al. Cancer. 2000;88(1):144-153.

─ Scarabelli C, et al. Gynecol Oncol. 2001;83(3):504-512.

─ Zang RY, et al. Cancer. 2004;100(6):1152-1161.

─ Harter P, et al. Ann Surg Oncol. 2006;13(12):1702-1710.

─ Chi DS, et al. Cancer. 2006;106(9):1933-1939.

─ Oksefjell H, et al. Ann Oncol. 2009;20(2):286-293.

─ Tian WJ, et al. J Surg Oncol. 2010;101(3):244-250.

─ Sehouli J, et al. J Surg Oncol. 2010;102(6):656-662.

2. Risks of surgery

3. Identification of surgical candidates

CI, confidence interval; HR, hazard ratio; OS, overall survivalHarter P, et al. Ann Surg Oncol. 2006;13(12):1702-1710.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 12 24 36 48

Surv

ival

Pro

babi

lity

Months

No residualsMedian OS 45.2 months

Residuals >10 mm

Residuals 1 - 10 mm

0 vs 1-10 mm:HR: 4.17 (CI 2.42 – 7.16); P<.0010 vs 10+ mm:HR: 3.31 (CI 1.86 – 5.88); P<.001

Median OS 19.7 months

Median OS 19.6 months

1. Surgical endpoint: Complete resection or minimal residual disease?

AGO DESKTOP OVAR I:Confirming the Surgical Endpoint?

1. Surgical endpoint: Complete resection or minimal residual disease? What Is the Role of Cytoreductive Surgery for Recurrent Ovarian Cancer?• Surgery may be appropriate in selected patients • As yet there is no level I evidence that demonstrates a

survival advantage associated with surgical cytoreduction for women with recurrent ovarian cancer

• Randomized phase III trials evaluating the role of surgery in recurrent ovarian cancer are a priority

• Cytoreductive surgery for women with recurrent ovarian cancer may be beneficial if it results in optimal cytoreduction

Friedlander M et al. Int J Gyn Cancer. 2011;21:771-775.

Study Collective

Patients in intensive care unit 67 (52%)Days intensive care unit [median] 2 (range: 1-20)No of patients adm. packed blood cells 55 (44%) No of patients with at least one complication 42 (33%)

Infections requiring antibiotic treatment 31 (24%) urinary tract 14 (11%) peritonitis 10 (8%) pneumonia 4 (3%) others 7 (5%)

Relaparotomy 14 (11%) bowel leakage/perforation 6 (5%) abscess/infection 3 (2%) bleeding 3 (2%) fistula 2 (2%)

Thrombosis / Embolism 3 (2%) / 4 (3%)

Other severe complications 12 (9%)

Mortality within 60 days 1 (0.8%)

Harter P, et al. Int J Gynecol Cancer. 2011;21(2):289-295.

2. Risks of surgery

AGO-DESKTOP II – Perioperative Morbidity

Primary Surgery Year Patients, n Mortality, %

Aletti 2006 194 1.5

Chi 2010 141 1.4

Harter 2011 187 2.3

Sehouli 2011 332 3.1

Gerestein 2009 Pop. based 3.7

Surgery for Relapse

DESKTOP II 2011 129 0.8

Chi 2006 153 0

Tian 2010 123 0

Sehouli 2010 240 3.8

Oksefjell 2010 217 Not reported

2. Risks of surgery

Perioperative Mortality at First Diagnosis and Relapse

Frequency of complete resection in AGO-Score positive patients

Harter P, et al. Int J Gynecol Cancer. 2011;21(2):289-295.

DESKTOP HypothesisP<.05


AGO-DESKTOP II: An International Multicenter GCIG Trial Prospective Validation of a Predictive Score for Resectability in Platinum-Sensitive ROC

• DESKTOP II = positive

• Positive AGO score predicts complete resection in more than 2 out of 3 pts


Selected Patients – DESKTOP II

08/06 - 03/08: Screening of 516 patients with platinum-sensitive 1st or 2nd relapse in 46 centers

51% (261 patients) AGO score positive

49% (255 patients)AGO score negative

29% (148) surgery 15% (80) surgery

44% (228) surgery

Nearby half of patients in dedicated centers undergo surgery for relapse.


A Frequently Asked Question After DESKTOP II

• What was the rate of complete resection in score negative patients?

• 63% in a multicenter study– Further selection criteria for surgery by the

centers– Underreporting of score negative patients without

surgery (~ 30% of score negative pts with surgery)?

Number at risk

Early 265 23 16 14 11 11 10 10 9

Delayed 264 177 116 91 69 56 49 42 33

0.0

00.2

50.5

00.7

51.0

0

Pro

port

ion

Alive N

ot

Sta

rted

S

econ

d-L

ine C

hem

oth

era

py

0 3 6 9 12 15 18 21 24

Months Since Randomization


Candidates for Surgery: Time From Randomization to Second-Line Chemotherapy

• Rarely relapse diagnosed by symptoms

Rustin GJ, et al. Lancet. 2010;376(9747):1155-1163.

MedianEarly 0.8 monthsDelayed 5.6 months

HR = 0.29 (95% CI 0.24, 0.35) P<.00001

CA-125 elevation 5 months before clinical relapse!


In Patients Treated Mainly Without Surgery*…

0.0

00.2

50.5

00.7

51.0

0

Pro

port

ion

Su

rviv

ing

0 6 12 18 24 30 36 42 48 54 60Months Since Randomization

HR = 1.00 (95%CI 0.82-1.22) P = .98

EarlyDelayed

Abs diff at 2 years = 0.1% (95% CI diff = -6.8, 6.3%)

Rustin GJ, et al. Lancet. 2010;376(9747):1155-1163.

Number at risk

Early 265 247 211 165 131 94 72 51 38 31 22

Delayed 264 236 203 167 129 103 69 53 38 31 19

* only ~ 6% with surgery for recurrent disease

Indication for second-line chemo are symptoms and not lab values


Hypothesis: Management of Relapse Depends on Time and Diagnostic Tools

PET-CT positiveMRI/CT positive

Ultrasound positive

Surgery + chemo

MRI/CT negative

Ultrasound negative

„Invis

ibl

e“

Chemo only

Earlier treatment by improved diagnostic tools and surgical skills?

Tum

or

Bu

rden

Time, monthsCA125 ↑

↑

Symptoms

↑

Diagnosis of 1st relapse by symptoms + ascites→ chemotherapy

Diagnosis of 1st relapse by CA125+ PET-CT→ Surgery + Chemo

2nd relapse


Real Benefit by Earlier Diagnosis and Surgery?


Aim of Cytoreductive Surgery• Cure - early and “mid” advanced ovarian cancer

– Unlikely in surgery for relapse

• Palliation of symptoms - eg, ileus, pain– Rarely in selected “ideal” candidates

• Prolongation of PFS (only)– Con: hospitalization, complications, surgical risks

• Prolongation of OS– Yes, but only if clinically significant– OS after surgery suggests superiority but this may be

confounded by earlier start of treatment (and counting days) and by selection of favorable biology

Galaal K, Naik R, Bristow RE, Patel A, Bryant A, Dickenson HO

AUTHORS’ CONCLUSIONS

Implications for practice

We found no current evidence from RCTs to guide clinical practice, however the results of an ongoing RCT AGO-OVAR OP.4 are awaited to determine the efficacy of secondary surgical cytoreduction with chemotherapy compared to chemotherapy alone for women with recurrent epithelial ovarian cancer.


Cytoreductive Surgery Plus Chemotherapy Versus Chemotherapy Alone for Recurrent EOC

A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive and AGO score–positive recurrent ovarian cancer

Strata:

Platinum-free-interval

6-12 mos vs > 12 mos

First-line platinum-

based chx: yes vs no

Cytoreductivesurgery

Platinum-basedchemotherapy*recommended

* Recommended platinum-based chemotherapy regimen: - Carboplatin/paclitaxel- Carboplatin/gemcitabine +/- bevacizumab- Carboplatin/pegliposomal doxorubicin - Or other platinum combinations in prospective trials

No surgery

Rn=408


AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)

Bevacizumab 15 mg/kg q3w to PD

Open: December 6, 2007Closed: OngoingTarget accrual: 660


GOG-0213: Secondary Cytoreduction + Bevacizumab

Coleman, et al. 2008

• Primary endpoint: OS• Stratification: Time to

recurrence

Yes

R

NoR

Paclitaxel 175 mg/m2 q3w

CarboplatinAUC5 q3w

Bevacizumab 15 mg/kg

Paclitaxel 175 mg/m2 q3w

CarboplatinAUC5 q3w

Surgery

No surger

y

Pretreated platinum-sensitive,

EOC, PP or FTC (n = 660)

Surgical candidat

e

Newly Diagnosed Advanced Ovarian Cancer

Case 1: Platinum-Sensitive“Chemical” Recurrence• Alice, a 60-year-old college professor, underwent TAH and

BSO plus omentectomy for stage IIIB epithelial ovarian carcinoma 2 years ago.

• Following optimal debulking surgery, she received 6 cycles of IV carboplatin-paclitaxel and tolerated it well. Her Ca-125 level following adjuvant chemotherapy was <5.

• She was followed every 3 months with examinations and Ca-125 levels, which were always <5.

Case 1 Treatment Decisions

• Six months ago her Ca-125 was slightly higher at 9. Three months later it was 21. Repeat physical examination at this time remains normal, imaging is normal, and this woman is asymptomatic. However, her Ca-125 is now up to 31.

1. What treatment plan would you recommend for Alice at this time?

2. What evidence would you cite as the basis for your plan?

A PET/CT shows no measurable disease and 6 weeks later the CA125 is now 79.

3. How would your treatment change if she had three 4-6 cm masses. One in the pelvis and another two in the “residual omentum”?

Case 1 Question 1

Would you recommend secondary debulking surgery?

1. Yes

2. No

Aim of Cytoreductive Surgery

• Cure - early and “mid” advanced ovarian cancer– Unlikely in surgery for relapse

• Palliation of symptoms - eg, ileus, pain– Rarely in selected “ideal” candidates

• Prolongation of PFS (only)– Con: hospitalization, complications, surgical risks

• Prolongation of OS– Yes, but only if clinically significant– OS after surgery suggests superiority but this may be confounded by earlier

start of treatment (and counting days) and by selection of favorable biology

Case 1 Question 2

Which chemotherapy would you recommend?

1. Carboplatin + paclitaxel

2. Carboplatin + gemcitabine

3. Carboplatin + PLD

4. Carboplatin + paclitaxel + bevacizumab

5. Carboplatin + gemcitabine + bevacizumab

6. Carboplatin + PLD + bevacizumab

Randomized Trials in Platinum Sensitive Disease

Platinum Sensitive Disease: Comparison of Combination vs Single Agent

Benefit

Regimen Author PFS OS

Carboplatin vs epirubicin + carboplatin du Bois et al. 2001 No No

Carboplatin vs paclitaxel + carboplatin Parmar et al. 2003 Yes Yes

Carboplatin vs paclitaxel + carboplatin Gonzales-Martin et al. 2005 Yes Yes

Carboplatin vs gemcitabine + carboplatin Pfisterer et al. 2005 Yes No

Carboplatin vs PLD + carboplatin Pujade-Lauraine et al. 2010 No Yes

Ovarian CancerPlatinum Sens.Stratify:≤ 0.5 cm> 0.5-2 cm

GCIG CALYPSO Trial

Pujade-Lauraine E et al. J Clin Oncol. 2010; 28(20): 3323-3329.

PLD 30 mg/m2

Carboplatin AUC = 5q 28 days x 6

Paclitaxel 175 mg/m2

Carboplatin AUC = 5q 21 days x 6

GCIG = Gynecologic Cancer IntergroupPFS = progression-free survivalPLD = pegylated liposomal doxorubicin

Accrual 864 patientsPFS primary endpoint

RANDOMIZE

CALYPSO

Pujade-Lauraine E et al. J Clin Oncol. 2010; 28(20): 3323-3329.

Selected Non-Hematologic Grade 2Toxicities During Treatment

Carboplatin + PLD (n=466)

Carboplatin + Paclitaxel (n=501)

Alopecia* 7% 84%

Neuropathy (sensory)* 5% 27%

Allergic reaction* 6% 19%

Arthralgia/myalgia* 4% 19%

*P < 0.001

CG + PL

OCEANS: Study Schema

CG for 6 (up to 10) cycles

Stratification variables:• Platinum-free interval

(6–12 vs >12 months)• Cytoreductive surgery for recurrent

disease (yes vs no)

Platinum-sensitive recurrent OCa

• Measurable disease• ECOG 0/1• No prior chemo for

recurrent OC• No prior BV

(n=484)

BV = bevacizumab; PL = placeboaEpithelial ovarian, primary peritoneal, or fallopian tube cancer

G 1000 mg/m2, d1 & 8

C AUC 4

PL q3w until progression

C AUC 4

BV 15 mg/kg q3w until progression

G 1000 mg/m2, d1 & 8CG + BV

Aghajanian C et al. J Clinc Oncol 2012; 30(17): 2039-2045.

242 177 45 11 3 0CG + PL

OCEANS: Primary analysis of PFS

CG + PL(n=242)

CG + BV(n=242)

Events, n (%) 187 (77) 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

MonthsNo. at risk

242 203 92 33 11 0CG + BV

1.0

0.8

0.6

0.4

0.2

0Prop

ortio

n pr

ogre

ssio

n fr

ee

0 6 12 18 24 30

Aghajanian C et al. J Clinc Oncol 2012; 30(17): 2039-2045.

OCEANS: Third Interim OS Analysisa

GC + PL(n=242)

GC + BV(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

1.0

0.8

0.6

0.4

0.2

0.0

0 6 12 18 24 30 36 42 48 54 60

242 235 221 190 159 117 77 44 23 7 0242 239 226 201 171 127 78 48 27 7 0

Number at risk: GC + PLGC + BV

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)

Prop

ortio

n su

rviv

ing

Months

Aghajanian et al. ESMO 2012

OCEANS: Select Adverse Events

Patients (%)

CG + PLA(n = 233)

CG + BEV(n = 247)

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

aTwo GI perforations occurred 69 days after last BEV dose.ATE = arterial thromboembolic event; VTE = venous thromboembolic event. Aghajanian C et al. J Clinc Oncol 2012; 30(17): 2039-2045.

• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer• Recurrence (CT or MRI verified), >6 m from prior platinum• GCIG (AGO, ANZGOG, GEICO, GINECO, NCIC, NSGO)

ICON6: Carboplatin +/- Cediranib

Open: DEC-2007Closed: DEC-2011Target Accrual: 2000 pts (Actual 486)

Ledermann J. Presented at: European Cancer Congress, 2013. Abstract 10.

In SEP-2011, primary endpoint changed to PFS, with primary analysis limited between Arms I vs III, and a reduction in overall sample size

x 6II

x 6I Platinum-based therapyOral Placebo daily, q 21d

Placebo(18 m total)

Placebo(18 m total)

Cediranib(18 m total)

x 6III

Platinum-based therapyOral Cediranib daily, q 21d

Platinum-based therapyOral Cediranib daily, q 21d

2

3

3

R

Adverse events include increased hypertension, diarrhea, hypothyroidism, hemorrhage, proteinuria, and fatigue.

ICON6: Overall SurvivalCarboplatin +/- Cediranib

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30Months On-study

Prop

ortio

n Su

rviv

ing

CediranibCediranib (Maintenance)

PlaceboPlacebo (Chemotherapy)

PP CC

OS events, n (%) 63/118 75/164

Median, months 20.3 26.3

Log-rank test P=0.042

HR (95% CI) 0.70 (0.51 – 0.99)

Test for non-proportionality P=0.0042

Restricted means, months 17.6 20.3


ICON6: Progression-Free Survival Carboplatin +/- Cediranib

0.00

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18 21 24

Months On-study

Prop

ortio

n Pr

ogre

ssio

n-fre

e

PlaceboPlacebo

CediranibCediranib

CediranibPlacebo

PP CP CC

Events/N 112/118 152/174 139/164

Median PFS, m 8.7 10.1 11.1

HR (95% CI) 0.67 (0.53–0.87)

0.57(0.44–0.74)


Randomized, Open-label, Phase II Study in Patients with Platinum-sensitive, Advanced Serous Ovarian Cancer

Platinum-sensitiveadvanced 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

Olaparib 400 mg bid continuously

No further study treatment

Completion of 4–6 x 21-day cycles

of chemotherapy

Arm B

Arm A

n=81

n=81

n=66

n=55

Multinational study; 43 sites in 12 countries* Capsule formulation

Patients with:

Patients with:

Maintenance Phase

Maintenance Phase

Oza A. Presented at: 2012 Annual Meetings of the American Society of Clinical Oncology. Chicago, IL.. Abstract 5001

Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) in Platinum-sensitive Recurrent Ovarian Cancer: PFS

Time from randomization (months)0

Prop

ortio

n of

pat

ient

s pr

ogre

ssio

n fr

ee

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

2 4 6 8 10 12 16 20

Number of patients at risk

Olaparib + P + C (AUC4)P + C (AUC6)

14 18

81 80 76 71 55 37 34 3 020 081 68 65 57 40 18 15 2 08 1

O/P/CP/C

Oza A. Presented at: 2012 Annual Meetings of the American Society of Clinical Oncology. Chicago, IL.. Abstract 5001.

O/P/C P/C

Events: Total patients (%) 47:81 (58.0) 55:81 (67.9)Median (months) 12.2 9.6

Hazard ratio = 0.51 95% CI (0.34, 0.77)

P=0.0012

Platinum-Sensitive Recurrence

• Secondary surgical debulking can be considered for patients with late recurrence and low volume disease

• Platinum retreatment is standard• Treatment with a platinum-based doublet improves response

rate, progression-free survival, and possibly overall survival– Taxane Carboplatin: Paclitaxel, Docetaxel

• Weekly paclitaxel ?

– Gemcitabine Carboplatin +/- Bevacizumab– PLD Carboplatin

• The role of targeted agents yet to be determined

Platinum-Resistant Recurrent Ovarian Cancer

Case 2: Platinum-Resistant Recurrent Ovarian Cancer• Kathy, a 60-year-old therapist, is referred by her gynecologist after a

routine annual exam demonstrated a palpable adnexal mass. She has undergone TAH and BSO with findings of a stage IIIC high-grade serous adenocarcinoma with involvement of both ovaries, fallopian tubes, and the peritoneal cavity.

• Debulking surgery was considered suboptimal with several residual nodules greater than 1 cm, and her Ca-125 several weeks post-op was mildly elevated at 30.

• She completed 6 cycles of carboplatin-paclitaxel 5 months ago. At her most recent follow-up, she complained of anorexia and abdominal pain. CT scan reveals diffuse intraperitoneal disease.

• Kathy has a medical history that includes diverticular disease treated with antibiotics 2 years ago, mild hypertension, and a DVT following an appendectomy 20 years ago

Case 2 Questions

1. What chemotherapy plan would you recommend for Kathy at this time?

2. What evidence would you cite as the basis for your plan?

3. How does her past medical history (HTN, diverticulitis, DVT) influence your decision?

Case 2 Question 1

Would you recommend secondary debulking surgery?

1. Yes

2. No

Case 2 Question 2

Which chemotherapy would you recommend?

1. Paclitaxel (weekly)

2. Topotecan

3. PLD

4. Paclitaxel (weekly) + bevacizumab

5. Topotecan + bevacizumab

6. PLD + bevacizumab

Randomized Trials in Platinum-Resistant Disease

Resistant Disease: Comparison of Combination vs Single Agent

Regimen Author BenefitPFS / OS

Paclitaxel vs epirubicin + paclitaxel Bolis et al 1999 No

Paclitaxel vs doxorubicin + paclitaxel Torri et al. 2000 No

Paclitaxel vs epirubicin + paclitaxel Buda et al. 2004 No

Topotecan vs topotecan + etoposide or gemcitabine Sehouli et al. 2008 No

PLD vs PLD + trabectedin Monk et al. 2010 No

Wkly paclitaxel vs weekly paclitaxel + carboplatin or weekly topotecan Gladieff et al. 2009 No

FDA approvedTopotecan Paclitaxel

Bevacizumab Pegylated liposomal doxorubicin

Not FDA approved, compendium listedEtoposide Gemcitabine DocetaxelEtoposide Nab-PaclitaxelPemetrexed ThioTEPA Vinorelbine

Not FDA approved, not compendium listedAromatase inhibitors Tamoxifen

Active Agents in Platinum-resistant Ovarian Cancer

Platinum-Resistant Ovarian Cancer Cytotoxic Therapy

STUDY* AGENT N RESPONSE RATE

126-J Docetaxel 58 22%

126-N Weekly Paclitaxel 48 21%

126-M Ixabepilone 50 14%

126-Q Pemetrexed 48 21%

126-R nab-Paxlitaxel 47 23%

Thresholds: 10%, 25%

Randomized phase II, NKTR-102*

145 mg/m2 q14 d 33 21%

145 mg/m2 q21 d 31 23%

Vergote IB et al. J Clin Oncol. 2010;28:15s (suppl; abstr 5013).

*Median of 3 prior lines

*1 prior line

AURELIA: A Randomized Phase III Trial Evaluating Bevacizumab (BEV) plus Chemotherapy (CT) for Platinum (PT) Resistant Recurrent Ovarian Cancer (OC)

Recurrent EOC• platinum resistant• ≤ 2 prior therapies• no clinical or radiologic

evidence of bowel involvement

Non-Platinum Chemotherapy

RANDOMIZE

Non-Platinum Chemotherapy +

Bevacizumab 15 mg/kg

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

Stratifiedchemotherapy

PFI (<3 vs 3-6 mo)prior anti-angiogenesis

Treat to progression

Treat to progression

n = 361

Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002.

AURELIA Progression-Free Survival

1.0

0.8

0.6

0.4

0.2

0.06 12

Time (months)

Estim

ated

Pro

babi

lity

18 3024

182 93 37 8 1 1 0 020179 140 88 18 4 1 149

0

BEV + CTC T

Number at risk

Events, n (%)Median PFS, mths(95% CI)

166 (91%)3.4

(2.2-3.7)

135 (75%)

CT(n = 182)

BEV + CT(n = 179)

6.7(5.7-7.9)

HR (unadjusted)(95% CI)Log-rnakP-value(2-sided, unadjusted)

0.48(0.38-0.60)

< 0.001

3.4 6.7


Response Rates for Chemotherapy Alone (CT: weekly paclitaxel, pegylated liposomal doxorubicin or topotecan) or with bevacizumab (BEV + CT)

Responders(RECIST and/or CA-125)

(n=350)

RECIST responders (n=287) CA-125 responders (n=297)0

5

10

15

20

25

30

35

40

45

50

12.6 11.8 11.6

30.927.3

31.8

CT BEV + CT

• aTwo-sided chi-square test with Schouten correction

P=0.001aP<0.001a P<0.001a

Patie

nts

(%)


AURELIA Overall Survival

Prop

ortio

n Su

rvivi

ng

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=0.174a

0 6 12 18 24 30 36 42

Time (months)

1.00

0.75

0.50

0.25

0

Overall, 40% of patients assigned to chemotherapy received bevacizumab post-progression

Witteveen P et al. Presented at: European Cancer Congress, 2013. European Society for Medical Oncology. Amsterdam, Netherlands.

AURELIA OS by Regimen

Exploratory analysis of overall survival according to selected

chemotherapy regimen

Paclitaxel qw (n = 115)HR 0.65 (0.42-1.02)

PEG-Lipo-Dox (n = 126)HR 0.91 (0.62-1.36)

Topotecan (n = 120)HR 1.09 (0.72-1.67)

Witteveen P et al. Presented at: European Cancer Congress, 2013. European Society for Medical Oncology. Amsterdam, Netherlands.

Other Targeted Agents in Recurrent Ovarian Cancer

Bevacizumab in Relapsed Ovarian Cancer

GOG 170-D*(n = 62)

NCI 5789**(n = 70)

Phase II Study***(n = 44)

Study Treatment

Single agent BV 15 mg/kg q 3 wk

BV 10 mg/kg q 2 wks + low dose oral

cyclophos.

Single agent BV 15 mg/kg

q 3 wk

Prior Regimens

1 – 21/62 (34%) 2 - 41/62 (62%)

Median = 2Range 1-3

2 - 23/44 (52%)3 - 21/44 (48%)

Platinum Resistant 42% 40% 100%

Efficacy ORR 6-mo PFS

21%39%

24%56%

16%27%

GIP or fistula 0 4 (6%) 5 (11%)

* 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.

Recurrent Ovarian Cancer: Targeted Therapy

AGENT Target n RESPONSE RATE

Aflibercept(VEGF-TRAP)1 VEGF

2 mg/kg215

3.8%

4 mg/kg 7.3%

Sunitinib2 VEGF/PDGF 30 3.3%

Cediranib3 VEGF/c-kit 46 17%

Cabozantinib4 VEGFR2/c-met 70 24%

Pazopanib5 VEGFR/PDGFR/c-kit 36 18%

Nintedanib6 VEGFR/PDGFR/FGFR 43 16.3% at 36 weeks

vs placebo 40 5% at 36 weeks

1Tew WP et al. J Clin Oncol. 2007; 25: (suppl; abstr 5508).2Biagi JJ et al. Ann Oncol. 2011; 22(2): 335-340.3Matulonis UA et al. J Clin Oncol. 2009; 27(33): 5601-5606.4Buckanovich RJ et al. J Clin Oncol. 2011; 29: (suppl; abstr 5008).5Friedlander M et al. Gynecol Oncol. 2010; 119(1): 32-37.6Ledermann JA et al. J Clin Oncol. 2011; 29(28): 3798-3804.

Recurrent Ovarian Cancer Randomized Phase II Studies

Ovarian, primary peritoneal, or fallopian tube

cancern=161

1-3 prior lines

Weekly PaclitaxelAMG-386 10 mg/kg IV weekly

n=53

Weekly PaclitaxelAMG-386 3 mg/kg IV weekly

n=53

RANDOMIZE

Karlan BY et al. J Clin Oncol. 2010;28:15s (suppl; abstr 5000).

Paclitaxel 80 mg/m2 IV weekly, 3 weeks on/1 week off

PDWeekly Paclitaxel

Placebon=55

AMG-38610 mg/kg IV

weekly

10 mg/kg 3 mg/kg Placebo

*Median PFS, months 7.2 5.7 4.6*HR (Arm A+B vs placebo) = 0.76 (80% CI, 0.59, 0.98), P=0.17, Trend test, P=0.037

ORR (CR+PR) 37% 19% 27%

Recurrent Ovarian Cancer Randomized Phase II Studies

STUDY* AGENTS

186-G Bevacizumab-Everolimus vsBevacizumab-Placebo

NS

186-I Bevacizumab-Fosbretabulin vsBevacizumab

Improvement in PFS, 7.6 vs. 6.1 mos, P=0.139

186-J Weekly Paclitaxel-Pazopanib vsWeekly Paclitaxel-Placebo

Completed Accrual

186-K Weekly Paclitaxel vsCabozantinib

Completed Accrual

Primary endpoint = PFS*1-3 prior lines

PARP Inhibitors in Ovarian Cancer

• Study Aim: To assess the efficacy of oral olaparib as monotherapy in a spectrum of BRCA 1/2- associated cancers (ovarian, breast, pancreatic, and prostate cancers)

• Prospective, multicenter, non-randomized Phase II study

Olaparib 400 mg po bid

Patient eligibility:• Individuals with a confirmed germline loss-of-function

BRCA1 or BRCA2 mutation deemed deleterious or suspected deleterious and advanced solide tumor

• One of the following: platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancer; breast, pancreatic, prostate or other tumor types with progression beyond ≥ 1 line of therapy in the metastatic setting

Treatment until disease

progression

Single-arm, Open-label, Phase II Study of Olaparib Monotherapy in Patients with Germline BRCA-mutated Advanced Cancer

Kaufman et al. J Clin Oncol. 2015;33:244-250.

Tumor Response Rates in Ovarian Cancer

ResponseOvarian (N=193)N (%)

Tumor Response rate 60 (31.1)

95% CI 24.6-38.1

CR 6 (3)

PR 54 (28)

Stable disease ≥ 8 weeks 79 (40)

95% CI 33.4-47.7

Progressive disease 41 (21)

Not evaluable 14 (7)


Response Rate and DORPatients with germline BRCA-mutated advanced ovarian

cancer who have received ≥ 3 prior lines of chemotherapy (N=137)

Objective Response Rate (95% CI) 34% (26, 42)

CR 2%

PR 32%

Median DOR in months (95% CI) 7.9 (5.6, 9.6)

Progression-free Survival and Overall Survival

The proportion of patients alive at 12 months was 64.4%, 44.7%, 40.9%, and 50.0%, in the ovarian, breast, pancreatic, and prostate cancer groups, respectively.


GOG 280 Phase II Schema

1 cycle = 28 daysTreat until progression,

toxicity, voluntary withdrawal

Recurrent EOC, FT, PPTBRCA1/2 deficient1-3 prior regimensMeasureable diseasePS 0-2

Veliparib 400 mg po BID

Primary End Points: RR (RESIST v1.1), Tolerability (CTCAE v.4)

Secondary End Points:PFS, OS, PFS@6 months

Translational End Points: Explore associations between single nucleotide polymorphisms (SNPs) in DNA repair genes and clinical characteristics, response, and patient outcomes

Opened: 4-09-2012• First stage closed: 7-23-12• Second stage open: 10-15-12

Closed: 11-15-12

ClinicalTrials.gov identifier: NCT01540565.Coleman R et al. Presented at: 2013 Society of Gynecologic Oncology. Abstract LBA5.

CTCAE=common terminology criteria for adverse events; EOC=epithelial ovarian carcinoma; FT=fallopian tube; PFS=progression free survival; OS=overall survival; PPT=primary peritoneal cancer; RR=response rate

Phase 2 Veliparib: ResultsFisher’s Exact P = 0.33

Fisher’s Exact P = 1.0

Coleman R et al. 2014. Society of Gynecologic Oncology. Abstract 136.

GOG 280: PFS & OS

Coleman R et al. 2014. Society of Gynecologic Oncology. Abstract 136.

• Grade 4 toxicity: thrombocytopenia in one patient.• Grade 3 adverse events included fatigue, nausea, leukopenia, neutropenia, dehydration, and elevated

alanine transaminase level.• Grade 2 adverse events in >10% of patients included: nausea, fatigue, vomiting, and anemia.

1.0

0.8

0.6

0.4

0.2

0.06 12

Months on Study

Prop

ortio

n Su

rvivi

ng/P

rogr

essio

n-Fr

ee

18 240

Endpoint Total Event Median

1: PFS 50 38 8.1

2: OS 50 16 19.7

PARPi in Phase III Development as Maintenance Therapy in Platinum-Sensitive Recurrence1. AZD 2281 (KU-0059436) = Olaparib

– SOLO-2 [NCT01874353] = Platinum-sensitive HGS maintenance in BRCAmut

2. MK-4827 = Niraparib

– NOVA [NCT01847274] = Platinum-sensitive HGS maintenance in BRCAmut and BRCAwt

3. CO-338 (AG014699, PF-01367338) = Rucaparib

– ARIEL-3 [NCT01968213] = Platinum-sensitive HGS and endometrioid maintenance in BRCAmut and BRCAwt

HGS = High grade serous

Other Phase III Recurrent Ovarian Cancer Clinical Trials

Agent NCT Number/Trial Name Primary/Study Completion

Status as of Sept 2014

Trebananib NCT01281254; TRINOVA-2 March 2011 / May 2019 Active, not recruiting

Trebananib NCT01204749; TRINOVA-1 June 2013 / April 2017 Active, not recruiting

Bevacizumab NCT01802749; MITO16MANGO2b

February 2015 / July 2015 Recruiting

Bevacizumab NCT00565851; GOG-0213 December 2015 / Unknown Recruiting

Pertuzumab NCT01684878 April 2016 / April 2016 Recruiting

Debulking vs Chemotherapy

NCT01166737; DESKTOP III July 2016 / December 2016 Recruiting

Platinum-Resistant Recurrence

• Multiple active chemotherapeutic agents:

– PLD, topotecan, weekly paclitaxel, gemcitabine, oral etoposide

• Single-agent chemotherapy used sequentially rather than in combination

• Multiple targeted biologics with some demonstrated activity

• Multiple trials of chemotherapy plus a targeted agent showing increased ORR or PFS, but none to-date with OS advantage

Screening and Diagnosis

• CA-125: most commonly measured tumor marker

• USPSTF, ACOG, & SGO do not recommend screening asymptomatic women as the clinical utility has not been confirmed

• Current screening modalities allow detection of only 30%-45% of women with early-stage disease

• Several biomarkers under evaluation for higher sensitivity and specificity to detect early-stage disease

• FDA approval obtained for HE4 assay to monitor disease recurrence or progression of epithelial ovarian cancer

• Tools:

– Risk of Ovarian Malignancy Algorithm (ROMA): uses HE4, CA-125, and menopausal status. Sensitivity 94.3%, Specificity 75%.

– Risk of Ovarian Cancer Algorithm (ROCA): uses age and longitudinal changes in CA-125. Specificity 99.9%.

Huhtinen et al. Br J Cancer. 2009; 100: 1315-1319.

Personalizing Therapy: Genetic Mutations and Resistance Markers

• BRCA: Existing and emerging data on PARP inhibition and BRCA1/BRCA2 mutation show promise in the treatment of ovarian cancer

• NCCN guidelines recommend germline testing for all patients with epithelial ovarian cancer, fallopian tube cancer and peritoneal cancer

• Secondary mutations in 53CP1 or PTIP restrain DNA repair and may cause BRCA1/BRCA2 mutations to stop responding to PARP inhibitors

• In the PRECEDENT trial, patients with platinum-resistant disease likely to benefit from the combination of vintafolide and PLD was enhanced by the FR-targeted imaging agent etarfolide (Naumann et al, J Clin Oncol, 2013).

Quality Measures – ASCO Quality Oncology Practice Initiative (QOPI)• Complete staging for women with invasive stage I-IIIB ovarian, fallopian tube, or

peritoneal cancer

• Intraperitoneal chemotherapy offered and administered within 42 days of optimal cytoreduction to women with invasive stage III ovarian, fallopian tube, or peritoneal cancer

• Platinum or taxane administered within 42 days following cytoreduction to women with invasive stage 1 (grade 3), IC-IV ovarian, fallopian tube, or peritoneal cancer

• VTE prophylaxis administered within 23 hours of cytoreduction to women with invasive ovarian, fallopian tube, or peritoneal cancer (NQF endorsed #0218)

• Order for prophylactic parenteral antibiotic administration within 1-2 hours before cytoreduction for women with invasive ovarian, fallopian tube, or peritoneal cancer (NQF endorsed #0527)

• Order for prophylactic parenteral antibiotic discontinuation within 24 hours after cytoreduction for women with invasive ovarian, fallopian tube, or peritoneal cancer (NQF endorsed #0529)

Patient Information Brochures from Ovarian Cancer National Alliance

• A copy has been provided with your syllabus

• Excellent tool to provide patients• Can be shipped to your office

(minimal charge for postage)• Available online with additional

resources at:– http://www.ovariancancer.org/

Participant CME Evaluation

• Please take out the Participant CME Post-survey and Evaluation from the back of your packet

• If you are not seeking credit, we ask that you fill out the information pertaining to your degree and specialty, as well as the few questions we will read through now measuring the knowledge and competence you have garnered from this program. The post-survey is located on page 1 of the evaluation form.

Post-activity Survey Question 1

After participating in this activity, how confident are you in personalizing treatment strategies for patients with recurrent ovarian cancer?

1 2 3 4 5

Not confident Expert


Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated benefit in:

1. HER2/neu positive recurrent ovarian cancer2. Platinum-resistant high-grade serous ovarian cancer3. p53 mutant recurrent ovarian cancer 4. Women with ovarian cancer and BRCA germline

mutations


In the AURELIA trial, the addition of bevacizumab to chemotherapy for platinum-resistant recurrent ovarian cancer resulted in which of the following outcomes?

1. A significant improvement in progression-free survival and overall survival by 3.3 months

2. A significant improvement in progression-free survival and response rates, but not in overall survival

3. A significant improvement in overall survival and objective response rate, but not in progression-free survival

4. An increase in objective response rate for the placebo arm

5. A significant increase in median duration of response by 5 months, objective response rate by 21%, and median progression-free survival by 4 months


Which of the following patients with high-grade ovarian cancer should undergo genetic testing for BRCA1/BRCA2?

1. Patients under the age of 602. Patients with a significant family history3. Patients diagnosed at early stage4. All patients

Post-activity Survey Question 5Following optimal debulking surgery, a 60-year-old woman receives 6 cycles of carboplatin-paclitaxel. Her CA-125 level following adjuvant chemotherapy remains less than 5 for two years. She then develops bloating and ascites associated with carcinomatosis. What is your treatment recommendation at this time?

1. Retreat with a platinum-doublet

2. Non-platinum single agent

3. Delay treatment until bowel obstruction

4. Secondary debulking surgery

• An Oncology Exchange Activity Thank you for joining us today!

Please remember to turn in your evaluation form.

Your participation will help shape future CME activities.

Documents

An Oncology Exchange Activity Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials: