managedcareoncology.com | 23

pipelinereport

by Howard “Skip” Burris, M.D., CMO and executive director, drug development, Sarah Cannon Research Institute

On the positive side, more effective

therapies are in development and

the early results are encouraging. The

American Cancer Society estimates

that in 2013, over 22,000 women in

the United States will receive a new

ovarian cancer diagnosis and more

than 14,000 women will die from the

disease. Among women, ovarian cancer

is the ninth most common cancer

and it ranks fifth in cancer deaths.

Unfortunately, approximately

60 percent of patients are diagnosed

with distant disease and five-year

survival is only 27 percent for these

stage IV patients.

One class of promising new

therapies in development for ovarian

cancer is the poly(ADP-ribose)

polymerase (PARP) inhibitors.

AstraZeneca’s olaparib has

been accepted for review

by the European Medicines

Agency, setting up a possible

approval in the near future.

Hopefully a U.S. review

would follow in short order.

Olaparib is among the first

drugs in the new PARP

inhibitor class to come

through development and is being

investigated for maintenance treatment

of patients with BRCA-mutated

platinum-sensitive relapsed serous

ovarian cancer. PARP inhibitors are

designed to treat cancer by blocking the

repair of DNA in tumor cells. There has

been great excitement around some of

the clinical results, particularly in the

BRCA-mutated patients, although some

early candidates were withdrawn from

development for a variety of factors.

AstraZeneca reported phase 2 trial

(Study 19) results with olaparib in 2011

in a more generalized group of ovarian

cancer patients that did not achieve

its primary end point. A reanalysis of

the data in the BRCA-positive patients,

coupled with a reformulation of the

drug, has led to renewed enthusiasm

about its potential role in this disease.

Study 19 compared maintenance

treatment with olaparib to placebo

in platinum-sensitive relapsed

serous ovarian cancer patients who

had all received previous treatment

with at least two platinum regimens

and were in a maintained partial or

complete response. Olaparib was

found to be superior to placebo on the

primary outcome of progression-free

survival (PFS), as well as a number of

additional efficacy measures.

In women with an inherited

(germline) BRCA mutation, the PFS

was 11.2 months for women treated

with olaparib versus 4.1 months for

women who received the placebo plus

best supportive care. Additionally,

there was evidence of a quality-of-life

benefit as measured with standard

tools. Phase 3 confirmatory trials are

planned. Women whose tumors had a

BRCA mutation (a somatic mutation)

also had a higher response to treatment

with olaparib than women with no

germline or somatic BRCA mutation. A

regulatory approval would likely make

olaparib the first PARP inhibitor to

reach the market. Additional phase 3

ovarian cancer continues to be a devastating disease for which far too many women are diagnosed at an advanced stage and die too soon from its effects.

NEw DRUGS IN THE TREATMENT OF

Ovarian Cancer

24 | managedcareoncology Quarter 4 2013

trials in patients with BRCA 1/2

mutations are under way in multiple

disease settings. Several other PARP

inhibitors are also in development.

Tesaro’s niraparib, a former Merck

compound, is in phase 3 trials, while

Clovis Oncology’s rucaparib, a former

Pfizer agent, AbbVie’s veliparib and

BioMarin’s BMN 673 are in earlier-

phase clinical studies.

The area of angiogenesis inhibition

remains promising in the treatment

of ovarian cancer. Results with

bevacizumab in the first-line and

maintenance settings have consistently

shown PFS benefits, although overall

survival (OS) improvements remain

elusive. Among other agents, a

phase 3 study of pazopanib, an oral

angiogenesis inhibitor approved

in renal cell cancer and soft tissue

sarcoma, showed an improvement in

PFS of 5.6 months in a study of almost

1,000 women with ovarian cancer

(17.9 months PFS compared to

12.3 months for the placebo arm)

when used as maintenance therapy

after front-line platinum-based therapy.

Phase 3 trial results showed that the

addition of cediranib AZ2171, a potent

oral inhibitor of vascular endothelial

growth factor (VEGF) receptor tyrosine

kinases 1, 2 and 3, to chemotherapy

increased progression-free survival

by about three months in women

with recurrent platinum-sensitive

ovarian cancer. Additional benefit was

obtained when cediranib was used as

maintenance therapy, increasing overall

and progression-free survival over

chemotherapy alone.

Cediranib had previously

demonstrated single-agent activity in

ovarian cancer, leading investigators to

test whether the addition of cediranib

could improve the results achieved

with chemotherapy and whether

maintenance therapy could be used to

further improve outcomes in patients

with platinum-sensitive ovarian cancer

in first relapse.

ICON6 was an international,

randomized, three-arm, double-blind,

placebo-controlled, phase 3 trial that

enrolled 456 patients from 63 centers

who were randomized 2:3:3 to one

of three cohorts: platinum-based che-

motherapy with placebo maintenance

(reference), concurrent cediranib at

20 mg/day during chemotherapy fol-

lowed by placebo for up to 18 months

(concurrent) or cediranib 20 mg/day

followed by maintenance cediranib

(concurrent + maintenance). Chemo-

therapy consisted of up to six cycles of

platinum/paclitaxel, platinum alone,

or platinum/gemcitabine. The primary

end point was PFS in the reference arm

as compared to the concurrent + main-

tenance arms. Secondary end points

were OS, toxicity and quality of life.

The patients’ median age was

62 years, and their Eastern Cooperative

Oncology Group (ECOG) performance

status was 0/1. The interval from

previous treatment was more than

12 months in 67 percent of patients

and baseline characteristics were

balanced among the arms.

Patient benefit was demonstrated

in the cediranib maintenance arm,

with time to progression, OS and

PFS all extended by several months.

Similarly, OS increased by 2.7 months,

from 17.6 to 20.3, in the concurrent +

maintenance cediranib arm over the

reference arm, respectively.

The authors commented that

this was the first time an overall

survival benefit has been seen with

a VEGF receptor tyrosine kinase

inhibitor in recurrent ovarian cancer.

Cediranib given concurrently with

platinum-based chemotherapy

improved progression-free survival

and significantly improved both

progression-free and overall survival

when continued as maintenance in

women with recurrent ovarian cancer.

Another antiangiogenesis strategy

is to inhibit binding of angiopoietin

managedcareoncology.com | 25

1/2 to the Tie2 receptor. Trebananib

(Amgen) is an antiangiogenesis

peptibody that inhibits the binding

of angiopoietin 1/2 to the Tie2

receptor, thus interfering with the

additional blood supply that supports

oncogenesis. TRINOVA-1 was a phase 3

randomized, double-blind trial that

compared paclitaxel plus trebananib

to paclitaxel and placebo. The trial

enrolled 919 women with recurrent

epithelial ovarian cancer who were

stratified according to their platinum-

free interval (PFI). Patients were to

receive paclitaxel 80 mg/m2 IV weekly

on a three weeks on/one week off basis,

plus either placebo or trebananib at

15 mg/kg weekly.

Patients were required to have

received one prior front-line platinum-

based regimen and up to two

additional cytotoxic regimens. Patients

withaPFI>12monthsorwhowere

platinum-refractory were excluded.

Treatment arms were similar with

regard to age, race, primary tumor

site and grade, and number of prior

regimens. The primary end point

was PFS and OS was a secondary end

point. Results showed a statistically

significant difference in PFS, which

was prolonged by 52 percent

with trebananib; median PFS was

7.2 months in the trebananib arm

versus 5.4 months in the control arm

(HR 0.66; p < 0.001). Final OS data

are expected in 2014; however, at an

interim analysis preplanned at

313 deaths, a trend toward improved

OS of median 19.0 versus

17.3 months (HR 0.86; p = 0.19)

favoring trebananib was observed.

Several other novel classes of

therapy have shown interesting results.

A phase 2 study of vintafolide (Merck/

Endocyte, EC145) plus pegylated

liposomal doxorubicin in women

with platinum-resistant ovarian cancer

showed some benefit. Vintafolide is a

vinca derivative that targets cells that

overexpress folate receptors, which

include most epithelial ovarian cancer

cells. Phase 3 trials are under way.

A phase 2 trial of volasertib, a

polo-like kinase inhibitor (BI 6727,

Boerhinger), versus chemotherapy in

patients with platinum-refractory/

-resistant ovarian cancer showed that

volasertib did not improve disease

control rate (31 versus 43 percent for

the chemotherapy arm) or PFS (13.1

versus 20.6 weeks). However, single-

agent volasertib showed antitumor

activity similar to chemotherapy. A

potential predictive biomarker for

volasertib is being explored.

A number of antibody-drug conju-

gates (ADCs) are currently being evalu-

ated in ovarian cancer. The sensitivity

of the cancer to chemotherapy, coupled

with several viable receptor targets and

the lack of advances in biologic therapy

for the disease, make ADCs an attrac-

tive option.

The requirements for an ADC

consist of: 1) a highly selective

monoclonal antibody for a tumor-

associated antigen that has restricted

expression on normal cells; 2) a potent

cytotoxic designed to induce target cell

death when internalized in the cell and

released; and 3) a linker that is stable

in circulation but releases the cytotoxic

agent in cancer cells.

ADCs targeting MUC16

(DMUC5754A, Roche/Genentech),

NaPi2b (Anti-NaPi2b-vc-E, Roche/

Genentech), folate receptor alpha

(IMGN 853, ImmunoGen) and

mesothelin (BAY 94-9343, Bayer) are

completing phase 1 trials with activity

demonstrated against ovarian cancer.

It is likely that each of these agents

will enter later-stage clinical trials in

selected populations.

MUC16 is a large transmembrane

protein belonging to the mucin family

that is highly expressed in 80 percent

of ovarian cancer patients. CA-125,

26 | managedcareoncology Quarter 4 2013

the well-established biomarker, is the

extracellular portion of MUC16, which

is cleaved and released into circulation.

Thus, following CA-125 for tumor

response becomes unreliable with

this targeted agent. The cytotoxic with

this ADC is monomethyl auristatin E

(MMAE), an extremely potent tubulin

inhibitor.

At a recommended dose of

2.4 mg/kg administered every three

weeks, the primary toxicities were

grade 3 neutropenia and grade 2

peripheral neuropathy (10 percent).

In very heavily pretreated patients,

five of 22 patients with IHC 2+ or

3+ overexpression for the target had

objective responses.

The Bayer antimesothelin ADC (BAY

94-9343) utilizes the maytansinoid

DM4 tubulin polymerizing agent as its

cytotoxic. Over 80 percent of ovarian

cancers overexpress mesothelin and

are thus suitable candidates. The side

effects have included grade 2 peripheral

neuropathy and some reversible

corneal toxicity. Encouraging evidence

of preliminary antitumor activity has

been seen.

The ImmunoGen ADC (IMGN

853) also utilizes DM4 as a payload

with the folate receptor alpha as its

target and binding site. The linker is

unique, as it is engineered to counter

multidrug resistance. More than

70 percent of serous and 50 percent of

endometrioid carcinomas overexpress

the target receptor. Objective responses

and reductions in CA-125 have been

documented in platinum-resistant

patients.

Exploiting the novel NaPi2b

receptor is the ADC known as

DNIB0600A with an MMAE/auristatin

cytotoxic. This unique target controls

transcellular absorption of inorganic

phosphate and is overexpressed in

almost 90 percent of nonmucinous

ovarian cancer. In the phase 1

study, nearly half of the 20+ heavily

pretreated ovarian cancer patients

had objective responses. Modest

grade 2 peripheral neuropathy and

neutropenia have been documented.

Plans for phase 2 trials in platinum-

refractory ovarian cancer are in

progress.

In conclusion, novel biologics such

as the PARP inhibitors, proven biologics

such as the angiogenesis inhibitors and

targeted biologics with chemotherapy,

such as the ADCs, are making strides

in the fight against ovarian cancer.

Continued efforts at identifying better

biomarkers and determining which

subsets of patients are likely to benefit

will be important research strategies.

Improving the outcomes for BRCA

patients with the PARP inhibitors

appears very promising, and the

benefit/risk ratio with the ADCs in

delivering effective chemotherapy will

be a welcome addition to the treatment

of ovarian cancer.