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Expert Commentary on Frequently Asked Questions in Ovarian Cancer: Unraveling the Risks and Benefits of Antiangiogenic
Therapy for Ovarian Cancer Patients
Jointly provided by
This activity is supported by an independent educational grant from Genentech.
Activity Information
Release date: June 29, 2015Expiration date: June 28, 2016Educational credits: 0.75 AMA PRA Category 1 Credit(s)TM
Estimated time to complete activity: 45 minutes
TARGET AUDIENCEThis activity is intended for medical, surgical, and gynecological oncologists; oncology nurses; pharmacists; and healthcare professionals managing and treating patients with ovarian cancer.
PURPOSEThe goal of this activity is to close knowledge, competence, and performance gaps by providing clinicians with a solid understanding of the molecular signaling pathways of agents, as well as the most recent evidence-based data for current and emerging agents and their rationale for use for treating patients with ovarian cancer.
ACTIVITY OVERVIEWIn the United States alone, ovarian cancer is estimated to affect 21,290 new patients in 2015 and cause 14,180 deaths. Approximately 75% of patients are diagnosed at an advanced stage, and the majority of ovarian cancer patients often relapse after chemotherapy treatment. This relapse usually occurs more than 6 months after the end of chemotherapy treatment, leaving the cancer sensitive to another chemotherapy treatment and difficult to manage. In light of these obstacles, researchers are exploring the role of targeted therapies as both monotherapy and in combination approaches to expand the treatment armamentarium for recurrent/resistant ovarian cancer. It is therefore imperative that oncologists are educated on newly available evidence-based data regarding these approaches, and their application to clinical practice so they can provide patients with optimal care.
This activity will provide expert commentary on unanswered questions from the CME-certified grand rounds and webinar series entitled, Unraveling the Risks and Benefits of Antiangiogenic Therapy for Ovarian Cancer Patients.
LEARNING OBJECTIVESAt the conclusion of this activity, participants should be able to:
• Analyze controversial data related to first-line treatment approaches for ovarian cancer
• Discuss clinical data incorporating the use of antiangiogenic agents and PARP inhibitors for treating ovarian cancer
• Integrate recent FDA approvals into the treatment armamentarium for ovarian cancer
• Assess emerging novel targets and agents being studied in clinical trials in ovarian cancer
• Apply evidence-based clinical data of newly approved and emerging treatments to the management of recurrent ovarian cancer
FACULTYBradley Monk, MD, FACS, FACOG Professor Division Director, Division of Gynecologic Oncology Vice Chair, Department of Obstetrics and Gynecology University of Arizona Cancer Center Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, a Dignity Health Member Phoenix
Activity Information
PHYSICIAN CONTINUING MEDICAL EDUCATIONAccreditation StatementThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and AXIS Medical Education. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.
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DISCLOSURE OF CONFLICTS OF INTERESTPostgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.
Bradley J. Monk, MD, FACS, FACOG, reported a financial interest/relationship or affiliation in the form of: consulting fee, Boehringer Ingelheim, Genentech - A member of the Roche Group, GlaxoSmithKline, Merck & Co., Inc., and Tesaro, Inc.; speaker’s bureau, Genentech - A member of the Roche Group, and Johnson & Johnson Pharmaceutical Research & Development, LLC; contracted research, Amgen, Inc., Array BioPharma, Inc., Eli Lilly and Company, Genentech - A member of the Roche Group, Janssen Pharmaceuticals, Inc. - a pharmaceutical company of Johnson & Johnson, Novartis Pharmaceuticals Corporation, and Tesaro, Inc.
The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:
The following PIM planners and managers, Judi Smelker-Mitchek, RN, BSN, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, and Jan Schultz, MSN, RN, CHCP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.
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Unraveling the Risks and Benefits of Antiangiogenic Therapy for Ovarian Cancer Patients – 4
Expert Commentary on Frequently Asked Questions in Ovarian CancerUnraveling the Risks and Benefits of Antiangiogenic Therapy for
Ovarian Cancer Patients
Bradley J. Monk, MD, FACS, FACOG
University of Arizona Cancer Center-Phoenix
A CME-certified grand rounds and webinar series
entitled, Unraveling the Risks and Benefits of Antian-
giogenic Therapy for Ovarian Cancer Patients, was
held throughout the United States from October 2014
to April 2015. The questions asked by participants
during these activities were collected, compiled, and
categorized (see Figure 1 below). The questions high-
light several areas of clinical focus in the treatment of
ovarian cancer and will be addressed as part of this
brief analysis.
In our survey, 77% of questions from participants were
treatment related, including questions concerning bev-
acizumab (39%), general treatment (26%), and olaparib
(13%). Other questions focused on predictive mark-
ers (10%), side effects (7%), cost (3%), and screening
(3%). To address these topics, this activity will focus on
questions regarding (1) front-line treatment, (2) recur-
rent disease, (3) antiangiogenic therapy, and (4) poly
(ADP-ribose) polymerase (PARP) inhibitors.
OVARIAN CANCER
Ovarian cancer is the fifth leading cause of death
among women in the United States and the lead-
ing cause of death from a gynecologic malignancy.
In 2015, there are estimated to be over 21,290 wom-
en with ovarian cancer and more than 14,180 deaths
(Siegel et al, 2015). The high mortality of women with
ovarian cancer is thought to be due to the advanced
stage of disease at presentation; approximately 75%
of patients have stage III to IV disease at diagnosis. In
the 1990s, platinum/taxane chemotherapy supplanted
cisplatin/cyclophosphamide and became the interna-
tional standard of care for the first-line treatment of
advanced epithelial ovarian cancer (EOC). Despite
initial chemo-sensitivity to platinum/taxane combina-
tions, most patients with advanced EOC experience
disease relapse after first-line therapy. Thus, more ef-
fective therapies are needed to improve response rates
and prolong progression-free survival (PFS), thereby
improving both the quality and length of life following
the diagnosis of advanced EOC (Coleman et al, 2013).
CONTROVERSIES IN FIRST-LINE TREATMENT
Three treatment options have made the first-line
therapy of ovarian cancer increasingly vague and
controversial. These include intraperitoneal (IP)
chemotherapy, dose-dense weekly paclitaxel, and neo-
adjuvant chemotherapy.
Intraperitoneal Chemotherapy
IP chemotherapy enhances the exposure of high
concentrations of cytotoxic agents to tumors in the
peritoneal cavity, the primary site of ovarian cancer.
Three intergroup trials have demonstrated a survival
benefit associated with IP versus intravenous chemo-
therapy in advanced, low-volume ovarian cancer. The
significance of these findings led to a National Cancer
Institute clinical alert recommending IP chemotherapy
in small volume advanced disease (Trimble et al, 2008).
However, the clinical trial reports and National Cancer
Institute clinical alert still did not lead to the pervasive
use of IP treatment.
The hesitancy of clinicians to use IP therapy is likely
attributed to higher toxicity, inconvenience, and cathe-
ter complications. In fact, a significant percent (>50%)
of patients do not complete the proposed treatment
of 6 cycles of IP therapy due to toxicity and other re-
Figure 1:
Frequently Asked Questions (N = 31)
Unraveling the Risks and Benefits of Antiangiogenic Therapy for Ovarian Cancer Patients – 5
lated complications. Thus, the optimal dose, schedule,
and number of cycles of IP chemotherapy necessary
to achieve the maximum benefit are not clear. In addi-
tion, there are no studies that have determined which
patients are more likely to complete the regimen and
benefit from IP therapy, such as those with large vol-
ume versus small volume residual disease (Coleman et
al, 2013; Echarri Gonzalez et al, 2011). However, a recent
publication suggested that the benefits of IP therapy
are sustained over an extended period.
To determine the long-term survival and associat-
ed prognostic factors after IP chemotherapy among
patients with advanced ovarian cancer, data from
Gynecologic Oncology Group (GOG) protocols 114
and 172 were retrospectively analyzed using Cox pro-
portional hazards regression models. In 876 patients,
median follow-up was 10.7 years. Median survival
with IP therapy was 61.8 months (95% CI 55.5-69.5),
compared with 51.4 months (95% CI 46.0-58.2) for
intravenous therapy. IP therapy was associated with
a 23% decreased risk of death (adjusted hazard ratio
[AHR] 0.77; 95% CI 0.65-0.90; P = .002) and improved
overall survival (OS) in those with gross residual
(≤1 cm) disease (AHR 0.75; 95% CI 0.62-0.92; P = .006).
The risk of death decreased by 12% for each cycle of
IP chemotherapy completed (AHR 0.88; 95% CI 0.83-
0.94; P < .001). Factors such as clear/mucinous versus
serous histology (AHR 2.79; 95% CI 1.83-4.24; P < .001),
gross residual versus no visible disease (AHR 1.89; 95%
CI 1.48-2.43; P < .001), and fewer versus more cycles
of IP chemotherapy (AHR 0.88; 95% CI 0.83-0.94;
P < .001) were associated with poorer survival. Younger
patients were more likely to complete the IP regimen,
with a 5% decrease in probability of completion with
each year of age (odds ratio 0.95; 95% CI 0.93-0.96;
P < .001). These data provide provocative evidence
that IP chemotherapy should be considered among
women with small volume residual disease (≤1 cm)
after primary debulking surgery (Tewari et al, 2015).
Dose-Dense Weekly Paclitaxel
Prior studies have shown that a more dose-dense
administration of paclitaxel can enhance its anti-
neoplastic effect by eliciting antiangiogenic and
proapoptotic properties. For example, studies showed
that weekly paclitaxel therapy improved the survival of
patients with early stage or metastatic breast cancer
(Seidman et al, 1998; Norton, 2006). In ovarian cancer,
Japanese investigators found that dose-dense weekly
paclitaxel and carboplatin (ddwT) improved the PFS
and OS compared to conventional every-3-week (q3T)
treatment (Katsumata et al, 2013). In a European study
of weekly paclitaxel combined with weekly carbo-
platin, the Multicenter Italian Trials in Ovarian Cancer
investigators did not find a benefit in weekly therapy
over every-3-week treatment; however, paclitaxel was
not administered in a dose-dense method (Pignata et
al, 2014).
The encouraging clinical trial results from dose-dense
paclitaxel and bevacizumab in epithelial ovarian can-
cer and other cancers led to the design of a current
study to determine if dose-dense weekly paclitaxel
combined with carboplatin improves PFS over every-
3-weeks paclitaxel and carboplatin with or without
bevacizumab in primary treatment of ovarian cancer.
GOG protocol 262 randomized (1:1) 692 patients with
newly diagnosed, previously untreated ovarian cancer
to receive either IV paclitaxel 175 mg/m2 every 3 weeks
+ carboplatin (area under the curve [AUC] = 6) for 6
cycles versus paclitaxel 80 mg/m2 weekly + carbopla-
tin (AUC = 6) for 6 cycles. Eighty-four percent opted
to receive bevacizumab. In the intent-to-treat analy-
sis; ddwT did not improve PFS over q3T (14.8 vs 14.3
mo; HR 0.97; 95% CI 0.79-1.18). Of those who did not
receive bevacizumab (n = 112), ddwT was associated
with a 4-month improvement in PFS over q3T (14 vs 10
mo; HR 0.60; 95% CI 0.37-0.96). However, in those who
received bevacizumab, ddwT did not prolong PFS over
q3T (15 mo for both arms; HR 1.06; 95% CI 0.86-1.31). A
test for homogeneity of treatment effect across strata
was significant (P = .047). Compared to q3T, ddwT had
more grade 3 or worse anemia (40.8% vs 15.7%), more
grade 2 or worse sensory neuropathy (25.9% vs 17.8%),
but less grade 3 or worse neutropenia (72% vs 83.1%).
This study concluded that ddwT does not prolong
PFS over q3T in ovarian cancer. However, in patients
who do not receive bevacizumab, ddwT increased the
duration of PFS (Chan et al, 2013). The results of this
trial suggest that ddwT without bevacizumab pro-
vides comparable PFS of q3T with bevacizumab and
requires confirmation but is hypothesis generating. It
is unclear if these results will affect current treatment
decisions in clinical practice.
Unraveling the Risks and Benefits of Antiangiogenic Therapy for Ovarian Cancer Patients – 6
Neoadjuvant Chemotherapy
Although the standard therapeutic strategy for ad-
vanced ovarian cancer is maximum primary debulking
surgery followed by chemotherapy, a European Or-
ganization for Research and Treatment of Cancer
(EORTC) prospective randomized trial of 632 patients
reported by Vergote and colleagues demonstrated
that neoadjuvant chemotherapy followed by interval
debulking surgery was not inferior to the standard
procedure (Vegote et al, 2010). The HR for death in
the group assigned to neoadjuvant chemotherapy
followed by interval debulking, as compared with the
group assigned to primary debulking surgery followed
by chemotherapy, was 0.98 (90% CI 0.84-1.13; P = .01
for noninferiority), and the HR for PFS was 1.01 (90%
CI 0.89-1.15). Although postoperative rates of adverse
effects and mortality tended to be higher after prima-
ry debulking than after interval debulking, this study
raised several controversies, particularly regarding the
quality of debulking surgery. Importantly, complete
resection of all macroscopic disease (at primary or in-
terval surgery) was the strongest independent variable
in predicting OS. However, only 41.6% of patients were
rendered optimally debulked to 1 cm or less of residual
tumor after primary cytoreduction, as compared with
80.6% of patients after interval cytoreduction (Vergote
et al, 2010). Based on these results, neoadjuvant che-
motherapy may be a reasonable option for significantly
malnourished patients and other nonoptimal surgical
candidates, but with the significantly lower optimal
debulking rates, these data do not demonstrate nonin-
feriority of neoadjuvant chemotherapy in terms of PFS
and OS among all women with newly diagnosed ad-
vanced ovarian cancer.
Results from the European randomized chemotherapy
or upfront surgery noninferiority trial (CHORUS) were
presented at the 2013 Annual Meeting of the Ameri-
can Society of Clinical Oncology in the Gynecologic
Oncology Track (Kehoe et al, 2013). Eligibility criteria
included imaging consistent with FIGO stage 3 to 4
disease, serum cancer antigen 125:carcinoembryonic
antigen (CA-125:CEA) >25, anticipated use of carbopla-
tin-based chemotherapy, and acceptable performance
status. The primary endpoint was OS. Patients (N =
552) from 76 centers were randomized between 2004
and 2010. No significant differences in either OS or
PFS were identified, and the authors concluded that
neoadjuvant chemotherapy was noninferior to primary
cytoreduction. Within the primary surgery cohort, 16%
of subjects were left with no residual disease, and 25%
with ≤1 cm residual. In the neoadjuvant cohort, 40%
were left with microscopic residual disease and 35%
had ≤1 cm gross residual following interval cytoreduc-
tion (Kehoe et al, 2013). Similar to the EORTC study,
the results of the CHORUS study should also be inter-
preted with caution given the low microscopic residual
disease rate in the primary surgery arm, and identical
median surgical times in both arms of 120 minutes.
Nevertheless, neoadjuvant chemotherapy is becoming
increasingly popular for the infirm and when complete
resection (R0) is not deemed feasible.
APPROACH TO RECURRENT DISEASE
As discussed above, although nearly 75% of patients
with advanced disease will respond to platinum- and
taxane-based combination therapy and enter into re-
mission, most will unfortunately experience disease
relapse during the first 3 years of follow-up (Ledermann
et al, 2013). Treatment of these patients is typically
based on the perceived tumor sensitivity to platinum
agents and may include retreatment with platinum-
based combination therapy or completely different
agents. Some patients may undergo secondary cyto-
reduction, depending on the clinical scenario. Unlike
patients commencing primary therapy for whom the
goal is to cure the cancer, and for whom parameters
such as toxicity and convenience of chemotherapy
schedule are of secondary importance, in the patient
population characterized by disease relapse the goals
are to control the disease whenever possible.
Importantly, among those with recurrent disease, qual-
ity of life as described by tolerability of therapy and
ease of administration (eg, oral versus parenteral route,
every 21 days versus every 28 days schedule) becomes
a primary focus (Ledermann et al, 2013).
The sensitivity of disease to platinum agents may be
categorized as platinum sensitive, partially platinum
sensitive, platinum resistant, and platinum refrac-
tory (Ledermann et al, 2013; Figure 2). It is important
to recognize that the 6-month disease-free interval,
which separates platinum-resistant disease from the
Unraveling the Risks and Benefits of Antiangiogenic Therapy for Ovarian Cancer Patients – 7
partially platinum-sensitive disease, and the 12-month
disease-free demarcation, which separates partially
platinum-sensitive disease from platinum-sensitive
disease, are both arbitrary clinical break points that
are not underlined by any known molecular or biologic
mechanisms. In addition, it has become increasingly
clear that platinum sensitivity is not only an important
clinical prognostic factor in this disease, but also a clin-
ical phenomenon that casts a wide net and may be
interchangeable with chemotherapy sensitivity.
Women with disease that enters remission following
primary therapy and relapses within 6 months are
considered to have platinum-resistant disease and
represent a group for whom conventional therapies
are probably ineffective or, at most, offer short-term
benefit. These patients should also strongly consider
participating in clinical trials. In the absence of a new
therapeutic study, most patients with platinum-resis-
tant disease are treated with single agents such as
pegylated liposomal doxorubicin (PLD) or topotecan
and other agents (Coleman et al, 2013). The new ap-
proval of combining bevacizumab in this setting is
discussed below. (Figure 3)
Women who experience recurrence between 6 and 12
months following platinum-based first-line chemother-
apy are classified as having partially platinum-sensitive
disease and can benefit from platinum-based reinduc-
tion chemotherapy. However, the therapeutic effect
is lower than that in women with platinum-sensitive
disease (see discussion below). Patients described as
having partially platinum-sensitive disease may also be
considered for participation in clinical trials evaluating
new agents and combinations for platinum-sensitive re-
currences (Coleman et al, 2013). The combination of PLD
and trabectedin is the first non-platinum chemotherapy
doublet and has been approved by the European Can-
cer Commission for treatment of platinum-sensitive
recurrent ovarian cancer (Monk et al, 2012). The pivotal
OVA-301 phase 3 randomized trial that led to regula-
tory approval of this new combination demonstrated
improved PFS and overall response rate with the com-
bination of PLD and trabectedin over PLD alone with
acceptable tolerance in the second-line treatment of re-
current ovarian cancer (Monk et al, 2010).
Patients who experience disease relapse >12 months
following primary platinum-based therapy have plati-
num-sensitive disease. The therapeutic landscape for
these patients is dominated by re-induction of plati-
num-based chemotherapy (Coleman et al, 2013). The
addition of a second compound to platinum performed
favorably against single-agent platinum in the Inter-
national Collaborative Ovarian Neoplasm 4 (ICON4)
randomized trial (Parmar et al, 2003). Carboplatin
combined with paclitaxel, gemcitabine, or PLD have
emerged as the principle platinum-based chemother-
apy doublets (Coleman et al, 2013). Importantly, the
replacement of paclitaxel with PLD in the CALYPSO
trial proved the noninferiority of the regimen over car-
boplatin plus paclitaxel (Pujade-Lauraine et al, 2010);
interestingly, carboplatin plus PLD was associated with
improved PFS and enhanced therapeutic ratio.
Figure 2:
Categories of Disease Sensitivity to
Platinum Agents
Courtesy of Dr. Bradley J. Monk, MD, FACS, FACOG.
End of front-line therapy (month 0) 6 months 12 months
Primary treatment
Refractory Chemo-resistant Chemo-sensitive
“Intermediate-sensitive”
“High-sensitive”
Figure 3:
Current Chemotherapy Algorithm Based on
Platinum Free-Interval
PFI, platinum-free interval.Courtesy of Dr. Bradley J. Monk, MD, FACS, FACOG.
Platinum Refractory/Resistant
PFI < 6 Months
Non-Platinum Single Agent +/- Bevacizumab
Platinum Sensitive
PFI > 6 Months
Chemotherapy Doublet +/- Bevacizumab
Unraveling the Risks and Benefits of Antiangiogenic Therapy for Ovarian Cancer Patients – 8
ANTIANGIOGENIC THERAPY
Angiogenesis plays a fundamental role in normal
ovarian physiology as well as in the pathogenesis of
ovarian cancer, promoting tumor growth and progres-
sion through ascites formation and metastatic spread.
Vascular endothelial growth factor (VEGF) and VEGF
receptor (VEGFR) are expressed on ovarian cancer
cells, and increased VEGF expression has been associ-
ated with the development of malignant ascites and
tumor progression (Monk et al, 2012). Bevacizumab,
a humanized anti-VEGF monoclonal antibody, is the
most widely studied antiangiogenesis agent both
across tumor types and specifically in EOC, receiv-
ing approval by the US Food and Drug Administration
(FDA) on November 14, 2014 in combination with pa-
clitaxel, pegylated liposomal doxorubicin, or topotecan
for the treatment of patients with platinum-resistant,
recurrent epithelial ovarian, fallopian tube, or primary
peritoneal cancer (Monk et al, 2012; FDA News Release,
2014a). Preclinical data suggest that prolonged admin-
istration of bevacizumab as maintenance therapy after
cisplatin-based chemotherapy prolongs survival by
inhibiting or delaying disease recurrence in a murine
ovarian cancer model (Mabuchi et al, 2008).
In March of 2005, single agent bevacizumab at 15 mg/
kg (IV) every 3 weeks was first reported to be active in a
case of recurrent high-grade serous ovarian cancer after
failing 11th-line cytotoxic chemotherapy and radiation.
An objective durable response lasting at least 5 months
was documented (Monk et al, 2005). Since then, many
case series and phase 2 trials have confirmed these
results. For example, the GOG protocol 170-D prospec-
tively studied single agent bevacizumab at this dose and
schedule (15 mg/kg IV every 21 days) among 62 women
with recurrent ovarian cancer. Thirteen patients (21.0%)
had documented responses (2 complete, 11 partial; me-
dian response duration, 10 months), and 25 (40.3%) had
PFS for at least 6 months. Median PFS and OS were
4.7 and 17 months, respectively. Prior platinum sensitiv-
ity, age, number of prior chemotherapeutic regimens, or
performance status were not predictive of clinical activ-
ity (Burger et al, 2007).
Most recently, 4 randomized phase 3 trials have been
performed adding bevacizumab to either front-line
chemotherapy (GOG 218 [Burger et al, 2011] or ICON7
[Perren et al, 2011]) or to chemotherapy in platinum-
resistant (AURELIA Trial [Pujade-Lauraine et al, 2012])
or platinum-sensitive (OCEANS Trial [Aghajanian et
al, 2012]) recurrent EOC. Although all 4 studies met
their primary endpoints of prolonging PFS (Table 1),
only 2 suggested an improvement in OS among unique
subsets of patients. In ICON7, among patients at high
risk for progression, the benefit of adding bevaci-
zumab was greatest. The estimated median PFS was
10.5 months with standard therapy, as compared with
15.9 months with bevacizumab (HR for progression or
death in the bevacizumab group, 0.68; 95% CI 0.55-
0.85; P ≤ .001). Similarly, there were 188 deaths in this
group of women with FIGO stage IV disease or FIGO
stage III disease and >1.0 cm of residual disease after
debulking surgery (109 in the standard-therapy group
and 79 in the bevacizumab group) and the median OS
was increased from 28.8 months in the standard ther-
apy group to 36.6 months in the bevacizumab group
(HR for death in the bevacizumab group, 0.64; 95% CI
0.48-0.85; P = .002) (Perren et al, 2011). In GOG 218, the
median OS for FIGO stage IV subjects was increased
from 32.8 months in arm 1 (placebo-containing arm)
to 40.6 months in arm 3 with the addition of bevaci-
zumab plus maintenance (HR 0.72, 95% CI 0.53-0.97)
(Randall et al, 2013).
Unfortunately, there has been concern about toxicity
especially bowel perforation (Han et al, 2007), renal
dysfunction, and hypertension (Hayman et al, 2012). In
addition, the expense and cost effectiveness of beva-
cizumab has created much controversy (Cohn et al,
2011). Biomarkers and imaging have not consistently
been predictive of response (Han et al, 2010; Chase
et al, 2012; Gourley et al, 2014) and patient-reported
outcomes have not shown improvements in quality
of life with the addition of bevacizumab (Monk et al,
2013). Importantly, both AUERLIA and ICON7 were
not placebo-controlled trials, creating a potential bias
in evaluating both patient-reported outcome and PFS.
OCEANS had no patient-reported outcomes at all.
Newer antiangiogenics as well as agents like vascular
disrupting agents (VDAs) that target existing blood
vessels are in development. Angiopoietin-1 (Ang1)
and -2 (Ang2) interact with the Tie2 receptor, which
is expressed on endothelial cells, to mediate vascu-
lar remodeling in a signaling pathway that is distinct
Unraveling the Risks and Benefits of Antiangiogenic Therapy for Ovarian Cancer Patients – 9
from the VEGF axis. Ang1 promotes vessel stabiliza-
tion by increasing endothelial junctions and pericyte
coverage; Ang2 blocks Ang1’s blood vessel stabiliz-
ing action, increasing angiogenesis and vascularity
in tumors (Augustin et al, 2009; Falcon et al, 2009;
Scharpfenecker et al, 2005). Trebananib (formerly
known as AMG 386) is a peptide-Fc fusion protein (or
peptibody) that acts by binding both Ang 1 and Ang2,
thus preventing their interaction with the Tie2 receptor.
Trebananib has shown antiangiogenesis activity in pre-
clinical models of ovarian cancer, single-agent activity
in relapsed ovarian cancer in a phase 1 study, as well as
prolongation of PFS in randomized phase 2 and 3 trials
in recurrent EOC (Herbst et al, 2009; Karlan et al, 2012;
Monk et al, 2014). In contrast to anti-VEGF agents, tre-
bananib has not been associated with an increase in
typical class-related anti-VEGF toxicities (Burger et al,
2011). Its most significant toxicity has been reported to
be edema (Monk et al, 2014). The results of Trebananib
in Ovarian Cancer -1 (TRINOVA-1), a 919 subject ran-
domized placebo-controlled phase 3 trial investigating
the addition of trebananib to single-agent weekly pa-
clitaxel in relapsed EOC, showed a PFS improvement
of 52% (Cox model HR 0.66; 95% CI 0.56-0.76; P < .001)
from a median of 5.4 (95% CI 4.3-5.5) to 7.2 months
(95% CI 5.8-7.4) (Monk et al, 2014).
VDAs are distinct from typical antiangiogenics and
are ideal candidates to combine with antiangiogenic
agents such as bevacizumab. In contrast to antiangio-
genesis agents that target VEGF and angiopoetins,
VDAs target existing tumor vascular rather than pre-
venting neovascularization. Tumor vessels can be
selectively targeted by VDAs because the newly
formed endothelial cells associated with cancer pro-
gression lack smooth muscle and pericyte coverage
thereby relying more on intracellular tubulin to main-
tain their flat tube-like shape in vessel walls. VDAs that
inhibit cancer-associated endothelial cell tubulin cause
the affected endothelial cells to “round up” thereby ob-
structing tumor-associated blood vessel lumens. This
causes vessel collapse and obstruction. Finally, non–
tumor-associated blood vessels are relatively resistant
to VDAs not only because of increased amounts of
endothelial cell smooth muscle, but also because of in-
creased endothelial pericyte coverage, allowing them
to maintain their shape when exposed to VDAs (Spear
et al, 2011; Mita et al, 2013).
Trial Treatment Arms PFS (mo)
GOG 218First-line EOC
Carboplatin/paclitaxel + placebo, placebo maintenance 10.6
Carboplatin/paclitaxel + bevacizumab, placebo maintenance
11.6(HR 0.89; P = .0437)
Carboplatin/paclitaxel + bevacizumab, bevacizumab maintenance
14.7(HR 0.70; P < .0001)
ICON7First-line EOC
Carboplatin/paclitaxel 17.3
Carboplatin/paclitaxel + bevacizumab 19.0(HR 0.81; P = .0041)
AURELIAPlatinum-resistant recurrent EOC
Single-agent chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan)
3.4
Single-agent chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan) + bevacizumab
6.7(HR 0.48; P < .001)
OCEANSPlatinum-sensitive recurrent EOC
Carboplatin/gemcitabine + placebo 8.4
Carboplatin/gemcitabine + bevacizumab 12.4(HR 0.48; P < .0001)
Table 1:
PFS Improvement With Addition of Bevacizumab in Phase 3 Trials of Advanced Epithelial Ovarian Cancer
Unraveling the Risks and Benefits of Antiangiogenic Therapy for Ovarian Cancer Patients – 10
Interestingly, cells on the periphery of solid tumors
are also relatively insensitive to VDA-induced vascular
shutdown. This resistant peripheral rim of tumor cells
contributes to tumor regeneration, metastasis, and on-
going progression after VDA exposure. Conceptually,
combining VDAs with antiangiogenesis compounds
such as bevacizumab might overcome this “regrowth”
phenomenon (Spear et al, 2011; Mita et al, 2013).
Combretastatin A4 (CA4) is a VDA originally iso-
lated from the African bush willow (Combretum
caffrum). Fosbretabulin is a water-soluble prodrug
of cis-combretastatin A4 (cis-CA4) otherwise known
as combretastatin A4 mono tris phosphate (abbre-
viated in the literature as CA4P). Fosbretabulin is a
small molecule that acts as a potent and reversible
tubulin depolymerizing agent (Gridelli et al, 2009).
Preclinical models have shown that fosbretabulin
results in massive acute vascular collapse as early as
2 hours after administration with recovery as soon as
24 hours providing further rationale for combining with
bevacizumab. In a phase 1 study of the combination
of fosbretabulin plus bevacizumab, the dose-limit-
ing toxicity appeared to be hypertension with the
maximum tolerated dose of fosbretabulin being
63 mg/m2 every other week. Importantly, this study
showed dynamic contrast enhanced diffusion weighted
MRI evidence of profound vascular changes associated
with fosbretabulin administration that were only sus-
tained following bevacizumab (Nathan et al, 2012). In a
recent randomized phase 2 study in recurrent ovarian
cancer, the combination of bevacizumab + fosbretab-
ulin improved PFS compared to bevacizumab alone
(HR 0.685; 90% 2-sided CI 0.47-1.00). The proportion
responding to bevacizumab was 28.2% (90% CI 16.7-
42.3) among 39 patients with measurable disease and
35.7% (90% CI 23.5-49.5) among 42 patients treated
with the combination (Monk et al, 2014). Phase 3 trials
of this novel non-cytotoxic chemotherapy combina-
tion are indicated.
PARP INHIBITORS
The most common histologic subtype of EOC is high-
grade serous and is characterized by genetic instability
and almost universal p53 dysfunction. This phenotype
frequently arises as a consequence of defects in the
repair of damaged DNA, rendering cancer cells sus-
ceptible to DNA-damaging platinum compounds and
targeted therapies affecting homologous recombina-
tion repair (Ahmed et al, 2010). PARP is a family of
proteins involved in the repair of signal single-strand
DNA breaks. When cells already deficient in homol-
ogous recombination repair are exposed to PARP
inhibitors, apoptosis occurs by way of synthetic lethal-
ity (Curtin et al, 2013).
Recently, Kaufman et al studied olaparib (400 mg twice
daily) in a spectrum of BRCA1/2-associated cancers.
Enrollment was restricted to patients with germline
BRCA1/2-positive, platinum-resistant recurrent ovarian
cancer, breast cancer following 3 or more chemothera-
py regimens, pancreatic cancer with prior gemcitabine
treatment, or prostate cancer with progression on
hormonal therapy and 1 systemic therapy. In the entire
cohort of 298 evaluable patients, the overall response
rate was 26.2% overall. The highest responses were
reported in patients with prostate (50.0%, 4/8) and
ovarian cancer (31.1%, 60/193; 95% CI 24.6-38.1). Only 8
(12.9%; 95% CI 5.7-23.9) of the 62 women with breast
cancer experienced objective tumor response by RE-
CIST criteria. Grade 3 or higher adverse events were
reported for 54% of patients, with anemia (17%) being
most common (Kaufman et al, 2015).
On June 25, 2014, the FDA’s Oncology Drugs Advi-
sory Committee panel members voted 11 to 2 against
regulatory approval of olaparib as maintenance ther-
apy for ovarian cancer based on Study 19 (described
below) (FDA News Release, 2014b; Ledermann et al,
2012). Additional data from the single arm, open-label
phase 2 trial by Kaufman and colleagues was submit-
ted, emphasizing the 31.1% response rate observed in
the BRCA-deficient ovarian cancer cohort (Kaufman
et al, 2015). These data prompted the FDA to extend
the original October 3, 2014 Prescription Drug User
Fee Act action date to January 3, 2015. On Decem-
ber 19, 2014, the FDA granted accelerated approval to
olaparib as fourth-line therapy for women with BR-
CA-deficient (germline only) ovarian carcinoma (FDA
News Release, 2014c). The ongoing phase 3 random-
ized study, SOLO 2 (NCT01874353), and its successor
SOLO 3 (NCT02282020), are integral to the phase
4 commitment following accelerated approval. FDA
approval was done in conjunction with regulatory
approval of a companion diagnostic genetic test (BRA-
Unraveling the Risks and Benefits of Antiangiogenic Therapy for Ovarian Cancer Patients – 11
CAnalysis CDx) that will screen blood from patients
with ovarian cancer for mutations in the BRCA genes
(gBRCAm). Interestingly, 1 day before regulatory ap-
proval in the United States, on December 18, 2014, the
European Commission granted marketing authoriza-
tion for olaparib as a first-line maintenance therapy for
adult patients with platinum-sensitive, relapsed BRCA-
mutated (germline and/or somatic) high-grade serous
epithelial ovarian, tubal, or peritoneal carcinoma (as
reported in Study 19) (Ledermann et al, 2012; Astra-
Zeneca News Release, 2014).
In the randomized, double-blind, placebo-controlled,
phase 2 Study 19, 265 patients with platinum-sensitive,
relapsed, high-grade serous ovarian cancer who had
received 2 or more platinum-based regimens and had
had a partial or complete response to their most re-
cent platinum-based regimen were randomized 1:1 to
receive either olaparib, at a dose of 400 mg twice dai-
ly (n = 136), or placebo (n = 129). In March 2012, data
from this interim analysis were published in The New
England Journal of Medicine showing an improvement
in median PFS of 8.4 months with olaparib compared
with 4.8 months with placebo (HR 0.35; 95% CI 0.25-
.049; P < .001) but no significant difference for OS
(Ledermann et al, 2012). In a retrospective, preplanned
analysis by BRCA mutation status, median PFS was
significantly longer in the olaparib group than in the
placebo group (11.2 months [95% CI 8.3-not calcula-
ble] vs 4.3 months [95% CI 3.0-5.4]; HR 0.18 [0.10-0.31];
P < .0001) for patients with a BRCA mutation. BRCA
status was known for 131 (96%) patients in the olaparib
group versus 123 (95%) in the placebo group, of whom
74 (56%) versus 62 (50%) had a deleterious or sus-
pected deleterious germline or tumor BRCA mutation.
The most common grade 3 or worse adverse events in
the olaparib group were fatigue (7% vs 3%) and ane-
mia (5% vs <1%) (Ledermann et al, 2014).
The clinical implications of approving a drug for
fourth-line therapy need to be framed in the context
of toxicity assessment. This is particularly important in
the setting of recurrent disease where quality of life/
disease control is the goal. BRCA-deficient patients
who were initially platinum sensitive and have become
candidates for olaparib therapy are likely to have re-
ceived 2 lines of platinum-based therapy and a third
line of therapy consisting of either one of the AURE-
LIA regimens or monotherapy with PLD or topotecan.
Olaparib can then be weighed against what they did
not receive in third line. Alternatively, in designing a
fourth-line chemotherapy regimen, one must consider
that the patient will have been treated with platinum-
based therapy in the first line, one of the AURELIA
regimens in the second line, and either PLD or topo-
tecan (with or without bevacizumab) in the third line.
In both examples, toxicity assessment can guide drug
selection. As can clearly be seen, olaparib appears to
have a more favorable safety profile compared to con-
ventional chemotherapy used in the recurrent setting.
The combination of olaparib (400 mg twice daily) plus
bevacizumab (10 mg/kg every 2 weeks) was well toler-
ated with no dose-limiting toxicities in a phase 1 study
involving 12 heavily pretreated patients with solid tu-
mors (Dean et al, 2012). Finally, in a randomized phase 2
study of 90 women with either measureable platinum-
sensitive, recurrent, high-grade serous or endometrioid
ovarian carcinoma or those with deleterious germline
BRCA1/2 mutations were randomized to olaparib 400
mg twice daily or 200 mg twice daily plus the antian-
giogenesis orally administered drug, cediranib 30 mg
daily. The combination was associated with significant-
ly improved PFS (17.7 vs 9.0 months; HR 0.42; 95% CI
0.23-0.76; P = .005). Grade 3 and 4 fatigue, diarrhea,
and hypertension were more common with combina-
tion therapy (Liu et al, 2014). This represents another
chemotherapy-free alternative for select patients with
recurrent disease.
CONCLUSIONS AND LOOKING TOWARD
THE FUTURE
With 2 new FDA approvals of targeted agents for EOC
in 2014, the future is bright. Angiogenesis and PARP
inhibitors are valid targets for the treatment of EOC.
Other angiogenesis agents such as those that target
Ang1/Ang2 as well as VDAs and novel combinations
are in development. Importantly, biosimilars open new
opportunities for less expensive medicines.
The next frontier, like many other solid tumors, is immu-
notherapy. It is now commonly believed that ovarian
cancers are immunogenic tumors. A large stepping-
stone in the advancement of anti-tumor immune
responses in ovarian carcinomas has been the char-
Unraveling the Risks and Benefits of Antiangiogenic Therapy for Ovarian Cancer Patients – 12
acterization of tumor infiltrating lymphocytes (TILs).
Correlation between the presence of TILs and pro-
longed PFS and OS has been demonstrated in patients
with advanced stage ovarian carcinoma. Specifically,
the presence of CD8+ TILs has been demonstrated
to correlate with increased survival. Conversely, the
presence of immunosuppressive regulatory T cells,
classified as CD4+/CD25+/FoxP3+ T cells, have been
associated with decreased survival. Finally, ovarian
cancers express tumor antigens, and patients have
demonstrated spontaneous anti-tumor responses,
which are specific to these antigens. Antibody-based
therapies, immune checkpoint blockade, cancer vac-
cines, and chimeric antigen receptor-modified T cells
have all demonstrated preclinical success and entered
clinical testing (Mantia-Smaldone et al, 2012).
Given the cost, potential for toxicity, and finding that
only a subset of patients will benefit from these drugs,
identification of predictive biomarkers is critical. In
addition, there are challenges regarding the optimal
drug combination, schedule, timing, and dose of che-
motherapeutic agents in ovarian cancer. It is also clear
that a substantial number of cases of ovarian cancer
will develop resistance to antiangiogenesis and PARP
inhibitor therapy. This has led to the urgent investiga-
tion of stem cells and mechanisms of drug resistance.
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GLOSSARY OF PHARMACEUTICAL AGENTS
Generic Name Trade Name
bevacizumab Avastin®
carboplatin Paraplatin®
cediranib Recentin™
cisplatin Platinol®
cyclophosphamide Cytoxan® Neosar®
fosbretabulin (CA4P) Zybrestat®
gemcitabine Gemzar®
olaparib Lynparza™
paclitaxel Taxol®
pegylated liposomal doxorubicin Doxil® Evacet™ Lipo-Dox® Caelyx® Doxilen™
topotecan Hycamtin®
trabectedin Yondelis®
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