expert commentary on frequently asked questions in ovarian...

Expert Commentary on Frequently Asked Questions in Ovarian Cancer: Unraveling the Risks and Benefits of Antiangiogenic

Therapy for Ovarian Cancer Patients

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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

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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.

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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)


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.


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


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


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


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


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-


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-


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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