Transcript Strategies for Treatment of Relapsed Ovarian Cancer

Unanswered Questions
in Primary Treatment
of Ovarian Cancer:
Controversial Areas
Deborah K. Armstrong, M.D.
May 29, 2009
Initial Therapy of Ovarian Cancer:
Controversial Areas
• How can we best use targeted biologics with initial
chemotherapy improve outcome?
• Should consolidation therapy be offered to all
ovarian cancer patients?
– Does receiving consolidation therapy alter
response to subsequent chemotherapy?
• Should BRCA-associated cancers be treated
differently?
• Should cost of treatment be an issue in designing
clinical trials?
• Should access/eligibility be broadened to reflect
the “real world”
Initial Therapy of Ovarian Cancer:
Controversial Areas
• How can we best use targeted biologics with initial
chemotherapy improve outcome?
• Should consolidation therapy be offered to all
ovarian cancer patients?
– Does receiving consolidation therapy alter
response to subsequent chemotherapy?
• Should BRCA-associated cancers be treated
differently?
• Should cost of treatment be an issue in designing
clinical trials?
• Should access/eligibility be broadened to reflect
the “real world”
Models for addition of targeted biologic
therapy to initial chemotherapy
Concurrent Chemo & Biologic
Concurrent Chemo & Biologic with Maintenance/Consolidation
Sequential Chemo followed by Biologic (as Maintenance/Consolidation)
Chemotherapy
Biologic Agent
GOG 218
Paclitaxel 175 mg/m2/3h
Carboplatin AUC = 6
OvCa
III/IV
Subopt
R
A
N
D
O
M
I
Z
E
Burger, R. GOG 218
q 21 d x 6
Placebo d1 X 5
begin cycle 2
Placebo
q 21d
X 15 mos
Paclitaxel 175 mg/m2/3h
Carboplatin AUC = 6
Placebo
q 21d
X 15 mos
Paclitaxel 175 mg/m2/3h
Carboplatin AUC = 6
Bev
q 21d
X 15 mos
q 21 d x 6
Bev d1 X 5
begin cycle 2
q 21 d x 6
Bev d1 X 5
begin cycle 2
Bevacizumab 15 mg/kg IV
ICON 7 (Front-line European Trial)
Stages I-IV ovarian
and peritoneal cancer
– Stratified
according to
stage, optimal
status region or
country
Accrual goal: 1,444 patients
Primary endpoint: PFS
Other endpoints: OS (10 mo),
RR, Toxicity
R
A
N
D
O
M
I
Z
E
Carboplatin AUC 6 plus
paclitaxel 175 mg/m2 (3 hr) q 21d x 6
Carboplatin AUC 6 plus
paclitaxel 175 mg/m2 (3 hr) q 21d x 6
plus bevacizumab at 7.5 mg/kg
followed by bevacizumab at 7.5 mg/kg
q 21 d x 12 months
Translational Research
• Tissue and serum markers of angiogenesis
• Genomics
• DCE-MRI
• Quality of life
• Health economics
DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging
ICON = International Collaborative Ovarian Neoplasm Group
OS = overall response
RR = response rate
FIRST LINE MAINTENANCE (EORTC) –
WITH TRANSLATIONAL SUB-STUDY
Stage Ic to IV
epith. ovarian
cancer, having
achieved
CR/PR/SD on
platinum-based
chemo (6-9
courses)
RA
N
D
O
M
I
S
E
Observation
Tarceva 150 mg daily for
up to 2 years or until PD
N = 830
Endpoints: PFS and overall survival
Recruitment completed, study ongoing
Initial Therapy of Ovarian Cancer:
Controversial Areas
• How can we best use targeted biologics with initial
chemotherapy improve outcome?
• Should consolidation therapy be offered to all
ovarian cancer patients?
– Does receiving consolidation therapy alter
response to subsequent chemotherapy?
• Should BRCA-associated cancers be treated
differently?
• Should cost of treatment be an issue in designing
clinical trials?
• Should access/eligibility be broadened to reflect
the “real world”
GOG #178
SWOG #9701
Ovarian cancer
Stage III or IV
5-6 cycles
platinum and
Paclitaxel, in
Clinical CR
R
A
N
D
O
M
I
Z
E
Paclitaxel
135 mg/m2/3h
Q 28 days x 3
Paclitaxel
135 mg/m2/3h
Q 28 days x 12
GOG #178
SWOG #9701
# pts at risk
12 months
110
3 months
112
# relapsed
20
34
28 months
21 months
Median PFS
P=.0023
SWOG 9701/GOG 178:
Overall Survival
Overall Survival
100%
80%
60%
40%
20%
At Risk
Paclitaxel 12 courses
Paclitaxel 3 courses
0%
0
24
Median
Deaths in Months
150
146
66
80
53
46
48
Months After Registration
Markman M, et al. J Clin Oncol. 2006;24(18S):Abstract 5005.
72
96
Initial Therapy of Ovarian Cancer:
Controversial Areas
• How can we best use targeted biologics with initial
chemotherapy improve outcome?
• Should consolidation therapy be offered to all
ovarian cancer patients?
– Does receiving consolidation therapy alter
response to subsequent chemotherapy?
• Should BRCA-associated cancers be treated
differently?
• Should cost of treatment be an issue in designing
clinical trials?
• Should access/eligibility be broadened to reflect
the “real world”
Initial Therapy of Ovarian Cancer:
Controversial Areas
• How can we best use targeted biologics with initial
chemotherapy improve outcome?
• Should consolidation therapy be offered to all
ovarian cancer patients?
– Does receiving consolidation therapy alter
response to subsequent chemotherapy?
• Should BRCA-associated cancers be treated
differently?
• Should cost of treatment be an issue in designing
clinical trials?
• Should access/eligibility be broadened to reflect
the “real world”
In response to DNA
damage the Fanconi
Anemia (FA) complex is
activated, translocated and
binds with chromatin
containing the BRCA1
protein and BRCA2
proteins. This complex
promotes DNA repair.
In the presence of mutated,
nonfunctional or absent
BRCA1 or BRCA2 proteins,
DNA repair is
compromised increasing
sensitivity to
chemotherapeutic agents,
particularly the platinum
salts.
Olopade and Wei, Cell 2003
Ovarian Cancer Relapse:
Effect of BRCA Mutations
Boyd et.el. JAMA 2000
Ovarian Cancer Survival:
Effect of BRCA Mutations
Cass et.al. Cancer May 2003
BRCA1 and BRCA2 Mutated
Ovarian Carcinomas
• BRCA1 and BRCA2 are critical proteins in DNA
repair via homologous recombination
• BRCA-associated cancers develop after a deletion
or mutation of the wildtype allele
• Normal non-malignant cells retain the wildtype
allele and intact BRCA function
• Cells defective in BRCA1 or BRCA2 are more
sensitive to ionizing radiation and platinum
compounds
• BRCA-deficient cells are dependent on an
alternate, PARP-dependent DNA repair pathway
Questions about the use of
PARP inhibitors in ovarian cancer
• Is there a role for PARP inhibitors in ovarian
cancer patients without a BRCA mutation?
– Other defects in the homologous
recombination pathway
– BRCA promoter methylation to silence BRCA
genes
• Will resistance develop to PARP inhibitors?
– Documentation of second BRCA mutations
that revert to wild type function
• Are platinum resistant patients likely to be
PARP inhibition resistant?
Initial Therapy of Ovarian Cancer:
Controversial Areas
• How can we best use targeted biologics with initial
chemotherapy improve outcome?
• Should consolidation therapy be offered to all
ovarian cancer patients?
– Does receiving consolidation therapy alter
response to subsequent chemotherapy?
• Should BRCA-associated cancers be treated
differently?
• Should cost of treatment be an issue in designing
clinical trials?
• Should access/eligibility be broadened to reflect
the “real world”
Comparative Effectiveness
• $1.1 Billion of ARRA funds slated for comparative
effectiveness research (CER)
• No agreement on definition of CER
– Efficacy is determined within specific populations
under controlled conditions
– Effectiveness is closer to what actually happens
in the real world
• “Cooperative groups, being publicly funded, may be
best positioned to conduct such studies”
• The CER agenda may conflict with the mission to
advance science
The Cancer Letter, May 22, 2009
From Edmonson, Gynecologic Oncology , 2000