Prior to the start of the program, please check your syllabus to ensure
An Oncology
you have the following• printed
program Exchange
materials: Activity
• 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 nonfaculty 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 decisionmaking 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
Not confident
2
3
4
5
Expert
Pre-activity Survey Question 2
Poly (ADP-ribose) polymerase (PARP) inhibitors have
demonstrated benefit in:
1. HER2/neu positive recurrent ovarian cancer
2. Platinum-resistant high-grade serous ovarian cancer
3. p53 mutant recurrent ovarian cancer
4. Women with ovarian cancer and BRCA germline
mutations
Pre-activity Survey Question 3
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
Pre-activity Survey Question 4
Which of the following patients with high-grade
ovarian cancer should undergo genetic testing for
BRCA1/BRCA2?
1. Patients under the age of 60
2. Patients with a significant family history
3. Patients diagnosed at early stage
4. All patients
Pre-activity Survey Question 5
Following 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 Treatment
Relapsed Ovarian Cancer
• Prolong Survival
• Delay Time to Progression
• Control Disease-related Symptoms
• Minimize Treatment-related Symptoms
• Maintain or Improve Quality of Life
Ovarian Cancer
How 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
% Response to Second-line
Platinum Therapy
Platinum-Free
Interval (mos)
Markman
0-6
7-12
13-18
19-24
>24
27%
Gore
17%
33%
27%
59%
57%
Non-platinum
Therapy
Blackledge
29%
15%
20%
63%
30%
94%
30%
10%
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 of
Recurrent Disease
Platinum
refractory/resistant
Platinum
sensitive
PFI <6 mos
PFI >6 mos
Non-platinum treatment
Platinum
retreatment
• Increasing evidence suggests the duration of the PFI also
influences outcomes of non-platinum chemotherapeutic
agents/regimens
PFI = progression-free interval.
Ovarian Cancer at First Relapse
Definition of Sensitivity
P 0
3
R
I
M Refractory
A
R
Y
Resistant
T
R
E
A
T
M
E
N
T
6
12
18
Sensitive
“Very Sensitive”
Defined as measurable recurrence, not biochemical (CA-125) recurrence
24
Months
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
1. Surgical endpoint: Complete resection or minimal residual disease?
AGO DESKTOP OVAR I:
Confirming the Surgical Endpoint?
1
0.9
Survival Probability
0.8
No residuals
Median OS 45.2 months
0.7
0.6
0.5
0.4
0.3
Residuals >10 mm
Median OS 19.7 months
0 vs 1-10 mm:
HR: 4.17 (CI 2.42 – 7.16); P<.001
0 vs 10+ mm:
HR: 3.31 (CI 1.86 – 5.88); P<.001
0.2
0.1
Residuals 1 - 10 mm
Median OS 19.6 months
0
0
12
24
Months
CI, confidence interval; HR, hazard ratio; OS, overall survival
Harter P, et al. Ann Surg Oncol. 2006;13(12):1702-1710.
36
48
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.
2. Risks of surgery
AGO-DESKTOP II – Perioperative Morbidity
Study Collective
Patients in intensive care unit
Days intensive care unit [median]
No of patients adm. packed blood cells
No of patients with at least one complication
67 (52%)
2 (range: 1-20)
55 (44%)
42 (33%)
Infections requiring antibiotic treatment
urinary tract
peritonitis
pneumonia
others
31 (24%)
14 (11%)
10 (8%)
4 (3%)
7 (5%)
Relaparotomy
bowel leakage/perforation
abscess/infection
bleeding
fistula
14 (11%)
6 (5%)
3 (2%)
3 (2%)
2 (2%)
Thrombosis / Embolism
Other severe complications
Mortality within 60 days
Harter P, et al. Int J Gynecol Cancer. 2011;21(2):289-295.
3 (2%) / 4 (3%)
12 (9%)
1 (0.8%)
2. Risks of surgery
Perioperative Mortality at First
Diagnosis and Relapse
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
DESKTOP II
2011
129
0.8
Chi
2006
153
0
Tian
2010
123
0
Sehouli
2010
240
3.8
Oksefjell
2010
217
Not reported
Surgery for Relapse
3. Identification of surgical candidates
AGO-DESKTOP II: An International Multicenter GCIG
Trial Prospective Validation of a Predictive Score for
Resectability in Platinum-Sensitive ROC
Frequency of complete resection in AGO-Score positive patients
P<.05
DESKTOP Hypothesis
• DESKTOP II = positive
• Positive AGO score predicts complete resection in more than 2 out of 3 pts
Harter P, et al. Int J Gynecol Cancer. 2011;21(2):289-295.
3. Identification of surgical candidates
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
29% (148) surgery
49% (255 patients)
AGO score negative
15% (80) surgery
44% (228) surgery
Nearby half of patients in dedicated centers undergo surgery
for relapse.
3. Identification of surgical candidates
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)?
3. Identification of surgical candidates
Candidates for Surgery: Time From Randomization to
Second-Line Chemotherapy
0.00 0.25 0.50 0.75 1.00
Proportion Alive Not Started
Second-Line Chemotherapy
• Rarely relapse diagnosed by symptoms
Early
Delayed
P<.00001
0
3
6
9
Median
0.8 months
5.6 months
HR = 0.29 (95% CI 0.24, 0.35)
12
15
18
21
24
Months Since
Randomization
Number at risk
Early
265
23
16
14
11
11
10
10
9
Delayed
264
177
116
91
69
56
49
42
33
CA-125 elevation 5 months before clinical relapse!
Rustin GJ, et al. Lancet. 2010;376(9747):1155-1163.
3. Identification of surgical candidates
1.00
HR = 1.00 (95%CI 0.82-1.22) P = .98
0.25
0.50
0.75
Abs diff at 2 years = 0.1%
(95% CI diff = -6.8, 6.3%)
Early
Delayed
0.00
Proportion Surviving
In Patients Treated Mainly Without Surgery*…
0
6
12
18
24
30
36
42
48
Months Since Randomization
Early
265
247
211
165
131
94
72
51
Delayed
264
236
203
167
129
103
69
53
54
60
38
31
22
38
31
19
Number at risk
Indication for second-line chemo are symptoms and not lab values
* only ~ 6% with surgery for recurrent disease
Rustin GJ, et al. Lancet. 2010;376(9747):1155-1163.
3. Identification of surgical candidates
Chemo only
Surgery + chemo
„Invisible“
Tumor Burden
Hypothesis: Management of Relapse
Depends on Time and Diagnostic Tools
Ultrasound negative
MRI/CT negative MRI/CT positive
PET-CT positive
↑
CA125 ↑
Ultrasound positive
↑
Time, months
Symptoms
Earlier treatment by improved diagnostic tools and surgical skills?
3. Identification of surgical candidates
Real Benefit by Earlier Diagnosis and
Surgery?
Diagnosis of 1st relapse
by CA125+ PET-CT
→ Surgery + Chemo
Diagnosis of 1st relapse
by symptoms + ascites
→ chemotherapy
2nd
relapse
3. Identification of surgical candidates
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
3. Identification of surgical candidates
Cytoreductive Surgery Plus Chemotherapy Versus
Chemotherapy Alone for Recurrent EOC
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.
Galaal K, Naik R, Bristow RE, Patel A, Bryant A, Dickenson HO
3. Identification of surgical candidates
AGO-OVAR DESKTOP III (Protocol AGO - OVAR OP.4)
A randomized trial evaluating cytoreductive surgery in patients with
platinum-sensitive and AGO score–positive recurrent ovarian cancer
Cytoreductive
surgery
Strata:
Platinum-free-interval
Platinum-based
chemotherapy*
recommended
R
n=408
6-12 mos vs > 12 mos
First-line platinum-
No surgery
based chx: yes vs no
* Recommended platinum-based chemotherapy regimen:
- Carboplatin/paclitaxel
- Carboplatin/gemcitabine +/- bevacizumab
- Carboplatin/pegliposomal doxorubicin
- Or other platinum combinations in prospective trials
3. Identification of surgical candidates
GOG-0213: Secondary Cytoreduction +
Bevacizumab
Pretreated
platinum-sensitive, EOC,
PP or FTC (n = 660)
Surgical
candidate
No
CarboplatinAUC5 q3w
Paclitaxel 175 mg/m2
q3w
R
CarboplatinAUC5 q3w
Paclitaxel 175 mg/m2
q3w
Yes
R
Surgery
Bevacizumab
15 mg/kg q3w
to PD
Bevacizumab 15 mg/kg
No
surgery
•
Primary endpoint: OS
•
Stratification: Time to recurrence
Open:
Closed:
Target accrual:
Coleman, et al. 2008
December 6, 2007
Ongoing
660
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 Ca125 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
GCIG CALYPSO Trial
Accrual 864 patients
PFS primary endpoint
Ovarian Cancer
Platinum Sens.
Stratify:
≤ 0.5 cm
> 0.5-2 cm
R
A
N
D
O
M
I
Z
E
PLD 30 mg/m2
Carboplatin AUC = 5
q 28 days x 6
Paclitaxel 175 mg/m2
Carboplatin AUC = 5
q 21 days x 6
GCIG = Gynecologic Cancer Intergroup
PFS = progression-free survival
PLD = pegylated liposomal doxorubicin
Pujade-Lauraine E et al. J Clin Oncol. 2010; 28(20): 3323-3329.
CALYPSO
Pujade-Lauraine E et al. J Clin Oncol. 2010; 28(20): 3323-3329.
Selected Non-Hematologic Grade 2
Toxicities 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
OCEANS: Study Schema
Platinum-sensitive
recurrent OCa
C AUC 4
CG + PL
G 1000 mg/m2, d1 & 8
• Measurable disease
• ECOG 0/1
• No prior chemo for
recurrent OC
• No prior BV
PL q3w until progression
C AUC 4
(n=484)
G 1000 mg/m2, d1 & 8
CG + BV
Stratification variables:
• Platinum-free interval
(6–12 vs >12 months)
BV 15 mg/kg q3w until progression
CG for 6 (up to 10) cycles
• Cytoreductive surgery for recurrent
disease (yes vs no)
BV = bevacizumab; PL = placebo
aEpithelial ovarian, primary peritoneal, or fallopian tube cancer
Aghajanian C et al. J Clinc Oncol 2012; 30(17): 2039-2045.
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)
Proportion progression free
1.0
0.8
Stratified analysis HR
(95% CI)
Log-rank P-value
0.6
0.484
(0.388–0.605)
<0.0001
0.4
0.2
0
0
No. at risk
CG + PL
CG + BV
6
12
18
24
30
11
33
3
11
0
0
Months
242
242
177
203
45
92
Aghajanian C et al. J Clinc Oncol 2012; 30(17): 2039-2045.
OCEANS: Third Interim OS Analysisa
Proportion surviving
Aghajanian et al. ESMO 2012
GC + PL
(n=242)
GC + BV
(n=242)
Events, n (%)
142 (58.7)
144 (59.5)
1.0
Median OS, months
(95% CI)
33.7
(29.3‒38.7)
33.4
(30.3‒35.8)
0.8
HR (95% CI)
Log-rank P value
0.960 (0.760–1.214)
P=0.7360
0.6
0.4
0.2
0.0
0
Number at risk:
GC + PL
GC + BV
aData
6
12
18
24
30
36
42
48
54
60
77
78
44
48
23
27
7
7
0
0
Months
242
242
235
239
221
226
190
201
159
171
117
127
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)
OCEANS: Select Adverse Events
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
0
Proteinuria, grade ≥ 3
1
9
RPLS, all grade
0
1
Wound-healing complication, grades ≥ 3
0
1
Patients (%)
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.
a
ICON6: Carboplatin +/- Cediranib
• Epithelial Ovarian, Fallopian, or Primary Peritoneal Cancer
• Recurrence (CT or MRI verified), >6 m from prior platinum
• GCIG (AGO, ANZGOG, GEICO, GINECO, NCIC, NSGO)
2
R
3
3
Open: DEC-2007
Closed: DEC-2011
Target Accrual: 2000 pts
(Actual 486)
Platinum-based therapy
Oral Placebo daily, q 21d
x6
Placebo
(18 m total)
II Oral Cediranib daily, q 21d
x6
Placebo
(18 m total)
Platinum-based therapy
Oral Cediranib daily, q 21d
x6
Cediranib
(18 m total)
I
Platinum-based therapy
III
In SEP-2011, primary endpoint changed to PFS, with primary analysis
limited between Arms I vs III, and a reduction in overall sample size
Adverse events include increased hypertension, diarrhea, hypothyroidism, hemorrhage,
proteinuria, and fatigue.
Ledermann J. Presented at: European Cancer Congress, 2013. Abstract 10.
ICON6: Overall Survival
Carboplatin +/- Cediranib
Proportion Surviving
1.00
CediranibCediranib (Maintenance)
PlaceboPlacebo
(Chemotherapy)
0.75
0.50
0.25
PP
CC
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
0.00
0
6
17.6
20.3
12
18
Months On-study
Ledermann J. Presented at: European Cancer Congress, 2013. Abstract 10.
24
30
ICON6: Progression-Free Survival
Carboplatin +/- Cediranib
1.00
CediranibCediranib
Proportion Progression-free
Events/N
0.75
PP
CP
CC
112/118
152/174
139/164
8.7
10.1
11.1
Median PFS, m
PlaceboPlacebo
0.50
0.67
0.57
(0.53–0.87) (0.44–0.74)
HR (95% CI)
CediranibPlacebo
0.25
0.00
0
3
6
9
12
Months On-study
Ledermann J. Presented at: European Cancer Congress, 2013. Abstract 10.
15
18
21
24
Randomized, Open-label, Phase II Study in
Patients with Platinum-sensitive, Advanced
Serous Ovarian Cancer
Patients with:
Platinum-sensitive
advanced ovarian cancer
n=81
• 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)
Randomization
(1:1)
n=81
Paclitaxel 175 mg/m2
(iv, d1)
+ carboplatin AUC6
(iv d1)
Maintenance Phase
Olaparib 400 mg bid
continuously
Patients with:
Multinational study; 43 sites in 12 countries
* Capsule formulation
n=66
Completion of
4–6 x 21-day cycles
of chemotherapy
Maintenance Phase
n=55
No further study
treatment
Arm A
Arm B
Oza A. Presented at: 2012 Annual Meetings of the American Society of Clinical Oncology. Chicago, IL.. Abstract 5001
All patients
followed for
objective
radiologic
progression
and survival
Proportion of patients progression free
Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib
(O/P/C) in Platinum-sensitive Recurrent Ovarian
Cancer: PFS
1.0
Events: Total patients (%)
0.9
Median (months)
0.8
O/P/C
P/C
47:81 (58.0)
55:81 (67.9)
12.2
9.6
Hazard ratio = 0.51
95% CI (0.34, 0.77)
P=0.0012
0.7
0.6
0.5
0.4
0.3
0.2
Olaparib + P + C (AUC4)
P + C (AUC6)
0.1
0
0
Number of
patients at risk
O/P/C
81
P/C
81
2
4
6
8
10
12
14
16
18
20
3
2
0
1
0
0
Time from randomization (months)
80
68
76
65
71
57
55
40
37
18
34
15
20
8
Oza A. Presented at: 2012 Annual Meetings of the American Society of Clinical Oncology. Chicago, IL.. Abstract 5001.
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
Benefit
PFS / OS
Regimen
Author
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
Active Agents in Platinum-resistant
Ovarian Cancer
FDA approved
Topotecan
Paclitaxel
Bevacizumab
Pegylated liposomal doxorubicin
Not FDA approved, compendium listed
Etoposide
Gemcitabine
Etoposide
Nab-Paclitaxel
Pemetrexed
ThioTEPA
Docetaxel
Vinorelbine
Not FDA approved, not compendium listed
Aromatase inhibitors
Tamoxifen
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%
*1 prior line
Randomized
phase II, NKTR102*
Thresholds: 10%, 25%
145 mg/m2 q14 d
33
21%
145 mg/m2 q21 d
31
23%
*Median of 3 prior lines
Vergote IB et al. J Clin Oncol. 2010;28:15s (suppl; abstr 5013).
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
R
A
N
D
O
M
I
Z
E
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
Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002.
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
AURELIA
Progression-Free Survival
Estimated Probability
1.0
Events, n (%)
Median PFS, mths
(95% CI)
HR (unadjusted)
(95% CI)
Log-rnakP-value
(2-sided, unadjusted)
0.8
0.6
0.4
CT
BEV + CT
(n = 182)
(n = 179)
166 (91%) 135 (75%)
3.4
6.7
(2.2-3.7)
(5.7-7.9)
0.48
(0.38-0.60)
< 0.001
0.2
3.4
0.0
0
6.7
6
12
24
Time (months)
Number at risk
CT
BEV + CT
18
182
179
93
140
37
88
20
49
8
18
Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002.
1
4
1
1
0
1
0
30
Response Rates for Chemotherapy Alone
(CT: weekly paclitaxel, pegylated liposomal doxorubicin or
topotecan) or with bevacizumab (BEV + CT)
50
45
Patients (%)
40
CT
P<0.001a
35
BEV + CT
P=0.001a
P<0.001a
31.8
30.9
30
27.3
25
20
15
12.6
11.8
11.6
10
5
0
Responders
(RECIST and/or CA-125) (n=350)
RECIST responders (n=287)
CA-125 responders (n=297)
• aTwo-sided chi-square test with Schouten correction
Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002.
AURELIA
Overall Survival
Proportion Surviving
1.00
Events, n (%)
Median OS,
months (95% CI)
CT
(n=182)
BEV + CT
(n=179)
136 (75)
13.3
(11.9-16.4)
128 (72)
16.6
(13.7-19.0)
HR (unadjusted)
(95% CI)
0.75
0.85
(0.66‒1.08)
P=0.174a
0.50
Overall, 40% of patients assigned to chemotherapy
received bevacizumab post-progression
0.25
0
0
6
12
18
24
Time (months)
Witteveen P et al. Presented at: European Cancer Congress, 2013.
European Society for Medical Oncology. Amsterdam, Netherlands.
30
36
42
AURELIA
OS by Regimen
PEG-Lipo-Dox (n = 126)
HR 0.91 (0.62-1.36)
Paclitaxel qw (n = 115)
HR 0.65 (0.42-1.02)
Witteveen P et al. Presented at: European Cancer Congress, 2013.
European Society for Medical Oncology. Amsterdam, Netherlands.
Topotecan (n = 120)
HR 1.09 (0.72-1.67)
Exploratory analysis of overall
survival according to selected
chemotherapy regimen
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 = 2
Range 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
RESPONSE
RATE
n
2 mg/kg
3.8%
Aflibercept
(VEGF-TRAP)1
VEGF
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
40
5% at 36 weeks
vs placebo
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.
4 mg/kg
215
7.3%
Recurrent Ovarian Cancer
Randomized Phase II Studies
Ovarian, primary
peritoneal, or
fallopian tube
cancer
n=161
1-3 prior lines
R
A
N
D
O
M
I
Z
E
Weekly Paclitaxel
AMG-386 10 mg/kg IV weekly
n=53
Weekly Paclitaxel
AMG-386 3 mg/kg IV weekly
n=53
Weekly Paclitaxel
Placebo
n=55
PD
AMG-386
10 mg/kg IV
weekly
Paclitaxel 80 mg/m2 IV weekly,
3 weeks on/1 week off
10 mg/kg
3 mg/kg
Placebo
7.2
5.7
4.6
*Median PFS, months
*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)
Karlan BY et al. J Clin Oncol. 2010;28:15s (suppl; abstr 5000).
37%
19%
27%
Recurrent Ovarian Cancer
Randomized Phase II Studies
STUDY*
AGENTS
186-G
Bevacizumab-Everolimus vs
Bevacizumab-Placebo
186-I
Bevacizumab-Fosbretabulin vs
Bevacizumab
Improvement in PFS, 7.6 vs.
6.1 mos, P=0.139
186-J
Weekly Paclitaxel-Pazopanib vs
Weekly Paclitaxel-Placebo
Completed Accrual
186-K
Weekly Paclitaxel vs
Cabozantinib
Completed Accrual
*1-3 prior lines
Primary endpoint = PFS
NS
PARP Inhibitors
in Ovarian Cancer
Single-arm, Open-label, Phase II Study of Olaparib
Monotherapy in Patients with Germline BRCAmutated Advanced 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
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
Kaufman et al. J Clin Oncol. 2015;33:244-250.
Olaparib
400 mg po bid
Treatment until
disease
progression
Tumor Response Rates in Ovarian Cancer
Response
Ovarian
(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 DOR
Objective Response Rate (95% CI)
Patients with germline BRCA-mutated advanced ovarian
cancer who have received ≥ 3 prior lines of
chemotherapy (N=137)
34% (26, 42)
CR
2%
PR
32%
Median DOR in months (95% CI)
Kaufman et al. J Clin Oncol. 2015;33:244-250.
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.
Kaufman et al. J Clin Oncol. 2015;33:244-250.
GOG 280 Phase II Schema
Recurrent EOC, FT, PPT
BRCA1/2 deficient
1-3 prior regimens
Measureable disease
PS 0-2
Opened: 4-09-2012
• First stage closed: 7-23-12
• Second stage open: 10-15-12
Veliparib 400 mg po BID
1 cycle = 28 days
Treat until progression,
toxicity, voluntary
withdrawal
Closed: 11-15-12
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
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
Coleman R et al. Presented at: 2013 Society of Gynecologic Oncology. Abstract LBA5.
ClinicalTrials.gov identifier: NCT01540565.
Phase 2 Veliparib: Results
Fisher’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
Proportion Surviving/Progression-Free
1.0
Endpoint
0.8
Total
Event
Median
1: PFS
50
38
8.1
2: OS
50
16
19.7
0.6
0.4
0.2
0.0
0
6
12
18
24
Months on Study
• 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.
Coleman R et al. 2014. Society of Gynecologic Oncology. Abstract 136.
PARPi in Phase III Development as Maintenance
Therapy in Platinum-Sensitive Recurrence
1.
AZD 2281 (KU-0059436) = Olaparib
–
2.
MK-4827 = Niraparib
–
3.
SOLO-2 [NCT01874353] = Platinum-sensitive HGS
maintenance in BRCAmut
NOVA [NCT01847274] = Platinum-sensitive HGS
maintenance in BRCAmut and BRCAwt
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 CA125. 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
Not confident
2
3
4
5
Expert
Post-activity Survey Question 2
Poly (ADP-ribose) polymerase (PARP) inhibitors have
demonstrated benefit in:
1. HER2/neu positive recurrent ovarian cancer
2. Platinum-resistant high-grade serous ovarian cancer
3. p53 mutant recurrent ovarian cancer
4. Women with ovarian cancer and BRCA germline
mutations
Post-activity Survey Question 3
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
Post-activity Survey Question 4
Which of the following patients with high-grade
ovarian cancer should undergo genetic testing for
BRCA1/BRCA2?
1. Patients under the age of 60
2. Patients with a significant family history
3. Patients diagnosed at early stage
4. All patients
Post-activity Survey Question 5
Following 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
Thank you for joining us today!
• An Oncology Exchange Activity
Please remember to turn in your
evaluation form.
Your participation will help shape future
CME activities.