First-Line Management of Advanced High-Grade Serous Ovarian Cancer

Abstract

Purpose of review:
Epithelial ovarian cancer is a disease that encompasses a number of histologically and molecularly distinct entities; the most prevalent subtype being high-grade serous (HGS) carcinoma. Standard first-line treatment of advanced HGS carcinoma includes cytoreductive surgery plus intravenous paclitaxel/platinum-based chemotherapy. Despite excellent responses to initial treatment, the majority of patients develop recurrent disease within 3 years. The introduction of the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, and poly(ADP-ribose) polymerase (PARP) inhibitors into first-line management has changed the outlook for this lethal disease. In this review, we summarise the most recent clinical trials that determine current primary therapy of advanced HGS carcinoma and the ongoing trials that aim to change management in the future.

Recent findings:
Recent phase III clinical trials have shown that delayed primary surgery after completing neo-adjuvant chemotherapy is non-inferior to immediate primary surgery, but could provide a survival benefit in FIGO (International Federation of Gynecology and Obstetrics) stage IV disease. The use of weekly intravenous chemotherapy regimens has not been proven to be more effective than standard 3-weekly regimens in Western patient populations, and the use of intraperitoneal chemotherapy remains controversial in the first-line setting. In contrast, newer systemic anti-cancer therapies targeting angiogenesis and/or HR-deficient tumours have been successfully incorporated into front-line therapeutic regimens to treat HGS carcinoma. Recent results from randomised trials investigating the use of PARP inhibitors as monotherapy and in combination with the anti-angiogenic agent, bevacizumab, have demonstrated highly impressive efficacy when combined with traditional first-line multi-modality therapy. Management of HGS carcinoma is evolving, but further work is still required to optimise and integrate tumour and plasma biomarkers to exploit the potential of these highly efficacious targeted agents.

Full text

Current Oncology Reports (2020) 22: 64
GYNECOLOGIC CANCERS (NS REED, SECTION EDITOR)
First-Line Management of Advanced High-Grade Serous
Ovarian Cancer
Reem D. Mahmood
1
&Robert D. Morgan
1,2
&Richard J. Edmondson
2,3
&Andrew R. Clamp
1
&Gordon C. Jayson
1,2
#The Author(s) 2020
Abstract
Purpose of Review Epithelial ovarian cancer is a disease that encompasses a number of histologically and molecularly distinct
entities; the most prevalent subtype being high-grade serous (HGS) carcinoma. Standard first-line treatment of advanced HGS
carcinoma includes cytoreductive surgery plus intravenous paclitaxel/platinum-based chemotherapy. Despite excellent responses
to initial treatment, the majority of patients develop recurrent disease within 3 years. The introduction of the vascular endothelial
growth factor (VEGF) inhibitor, bevacizumab, and poly(ADP-ribose) polymerase (PARP) inhibitors into first-line management
has changed the outlook for this lethal disease. In this review, we summarise the most recent clinical trials that determine current
primary therapy of advanced HGS carcinoma and the ongoing trials that aim to change management in the future.
Recent Findings Recent phase III clinical trials have shown that delayed primary surgery after completing neo-adjuvant chemo-
therapy is non-inferior to immediate primary surgery, but could provide a survival benefit in FIGO (International Federation of
Gynecology and Obstetrics) stage IV disease. The use of weekly intravenous chemotherapy regimens has not been proven to be
more effective than standard 3-weekly regimens in Western patient populations, and the use of intraperitoneal chemotherapy
remains controversial in the first-line setting. In contrast, newer systemic anti-cancer therapies targeting angiogenesis and/or HR-
deficient tumours have been successfully incorporated into front-line therapeutic regimens to treat HGS carcinoma. Recent
results from randomised trials investigating the use of PARP inhibitors as monotherapy and in combination with the anti-
angiogenic agent, bevacizumab, have demonstrated highly impressive efficacy when combined with traditional first-line
multi-modality therapy.
Summary Management of HGS carcinoma is evolving, but further work is still required to optimise and integrate tumour and
plasma biomarkers to exploit the potential of these highly efficacious targeted agents.
Keywords Ovarian cancer .Bevacizumab .PARP inhibitors .Cytoreductive surgery .Intra-peritoneal chemotherapy
Introduction
Ovarian cancer is the 8th commonest cancer diagnosed in
women and the 8th commonest cause of female cancer-
related death worldwide [1]. Approximately 300,000 women
were diagnosed with ovarian cancer in 2018 [1]; the majority
being diagnosed with FIGO (International Federation of
Gynecology and Obstetrics) stage III/IV disease [2,3].
Ovarian cancer originates from the epithelial cells (ovarian
surface/distal fallopian tube epithelium) in around 90% of
cases, with the histological subtype high-grade serous (HGS)
accounting for 70% of cases [4]. Standard first-line treatment
of advanced HGS carcinoma involves cytoreductive
(debulking) surgery with paclitaxel/platinum-based chemo-
therapy [5,6]. Despite excellent initial treatment responses
in around 70% of women, the majority of patients develop
recurrent disease within 3 years of their primary therapy [7].
First-line treatment for advanced stage HGS carcinoma
provides the only realistic opportunity for cure, with a 5-year
survival of 27% in patients with FIGO stage III disease [8]. In
This article is part of the Topical Collection on Gynecologic Cancers
*Gordon C. Jayson
Gordon.Jayson@christie.nhs.uk
1
Department of Medical Oncology, Christie NHS Foundation Trust,
Wilmslow Road, Withington, Manchester M20 4BX, UK
2
Faculty of Biology, Medicine and Health, University of Manchester,
Manchester, UK
3
Department of Gynaecological Oncology Surgery, Saint Mary’s
Hospital, Manchester University NHS Foundation Trust, Oxford
Road, Manchester, UK
https://doi.org/10.1007/s11912-020-00933-8
Publishe d online: 4 J une 2020
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

women whose disease is not cured, first-line treatment often
leads to the longest disease-free interval (DFI), allowing for
the greatest time period to regain quality of life during the
disease. For these reasons, research has focused on therapeutic
strategies that optimise outcomes of primary therapy. This
review summarises the key clinical trial data that have led to
the current status of first-line treatment of advanced HGS
carcinoma.
Primary Cytoreductive Surgery
Primary cytoreductive surgery allows for accurate FIGO stag-
ing and should be directed towards achieving complete
debulking (i.e., no residual disease [RD]) [9,10].
Traditionally, immediate primary surgery (IPS) was
performed followed by adjuvant platinum-based chemothera-
py. However, a proportion of women diagnosed with ad-
vanced stage disease are unable to undergo IPS due to con-
tra-indications, including comorbidities and/or disease-related
factors e.g. tumour burden [11]. For these patients, delayed
primary surgery (DPS) after completing 3–4cyclesof
platinum-based neoadjuvant chemotherapy (NACT) was
demonstrated as a non-inferior therapeutic option in two
randomised phase III trials by comparison of the primary out-
come of overall survival (OS) [12,13]. In the EORTC 55791
trial, 632 women diagnosed with FIGO stage IIIC-IV epithe-
lial ovarian cancer (EOC) (61.8% serous adenocarcinoma)
were randomised to undergo either IPS followed by at least
6 cycles of adjuvant platinum-based chemotherapy versus
3 cycles of platinum-based NACT followed by DPS and a
further 3 (or more) cycles of adjuvant chemotherapy [12]. In
the CHORUS trial, 550 women diagnosed with FIGO stage
IIIA-IV EOC (70.5% HGS) were randomised to undergo IPS
followed by 6 cycles of adjuvant platinum-based chemother-
apy or 3 cycles of platinum-based NACT followed by DPS
and a subsequent 3 cycles of chemotherapy [13]. There was no
difference in overall survival (OS) between groups in either
trial (EORTC 55791: HR 0.98, 95% CI 0.84–1.13; CHORUS:
HR 0.87 95% CI 0.72–1.05). However, in a subsequent meta-
analysis including individual patient data from both trials,
patients diagnosed with FIGO 1988 stage IV disease had sig-
nificantly improved OS (24.3 versus 21.2 months, HR 0.76,
95% CI 0.58–1.00, p= 0.048) if they were treated with NACT
followed by DPS [14•]. Both EORTC 55791 and CHORUS
demonstrated that peri- and post-operative morbidity/
mortality occurred less frequently in those women undergoing
NACT-DPS [12,13].
EORTC55971andCHORUShavebeencriticiseddueto
the low number of patients in whom surgery achieved com-
plete cytoreduction at IPS; debulking to less than 1 cm of
residual disease was achieved in 42.3% of patients in
EORTC 55971 and 41.6% of patients in CHORUS [12,13].
As a result, TRUST (NCT02828618) was initiated, which is
an ongoing randomised phase III trial recruiting women diag-
nosed with FIGO stage IIIB-IVB EOC within quality-assured
gynaecological oncology centres that fulfil certain criteria in-
cluding that they carry out more than 36 debulking surgeries a
year, achieve complete cytoreduction in ≥50% of cases and
are willing to undergo audits from the TRUST committee to
verify these numbers [15]. Nevertheless, EORTC 55971 and
CHORUS led to the paradigm shift in clinical practice, in
which DPS is now routinely considered in patients unlikely
to achieve no RD/complete cytoreduction with IPS and those
with comorbidities indicating high peri-operative morbidity/
mortality risk [5,6]. Factors which impact on the ability to
achieve complete cytoreduction include extra-abdominal me-
tastases, extensive bowel involvement or complex blood ves-
sel involvement [16,17].
During primary cytoreductive surgery, the removal of
bulky or suspicious lymph nodes is part of complete
cytoreduction. However, complete pelvic lymph node resec-
tion at time of surgery is not currently recommended [6].
Retrospective analysis had suggested an OS benefit with com-
plete systematic pelvic and para-aortic lymphadenectomy [18,
19]. A phase III trial then showed that systematic resection of
pelvic and para-aortic lymph nodes compared to resection of
bulky lymph nodes only did not provide a survival benefit.
But this trial was criticised due to the inclusion of patients with
complete resection and residual disease up to 1 cm after sur-
gery [20]. The phase III LION trial was set up to determine if
systematic lymph node dissection prolongs OS with a more
homogeneous group of patients [21•]. Women (n=647)were
recruited with diagnosed FIGO stage IIB-IV EOC and were
randomly allocated intraoperatively to proceed to complete
lymphadenectomy or not if they met the following criteria:
achieved complete macroscopic resection, intraoperatively
remained in good condition and had no clinically positive
lymph nodes. The study showed that systematic lymphade-
nectomy increased detection of sub-clinical retroperitoneal
metastases in 56% of patients but was not associated with
improved OS (69.2 versus 65.5 months, HR 1.06, 95% CI
0.83–1.34). Systematic lymphadenectomy did increase post-
operative morbidity and mortality [21•]. The results from the
LION trial confirm guidelines from the European Society of
Medical Oncology (ESMO) that lymph node resection at pri-
mary surgery should focus only on nodes that are suspected to
harbour metastatic disease [6].
Dose-Dense First-Line Chemotherapy
Standard first-line chemotherapy for EOC includes 3-weekly
platinum and 3-weekly paclitaxel chemotherapy [5,6]. In the
United Kingdom (UK), guidance from the National Institute
for Health and Care Excellence (NICE) also currently
Curr Oncol Rep (2020) 22: 64
64 Page 2 of 14
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recommends to offer single-agent platinum-based chemother-
apy as an alternative to combination regimens [22]. Dose-
dense regimens involve weekly administration of chemother-
apy. Indeed, preclinical data showed that metronomic sched-
uling of docetaxel or paclitaxel was effective [23], and early
phase trial data supported the evaluation of dose-dense
taxanes within randomised phase III trials [24–27]. Four
randomised phase III trials have been reported investigating
dose-dense first-line therapies (Table 1)[28–31].
In JGOG 03016, 631 women diagnosed with FIGO stage
II–IV EOC (55.7% serous adenocarcinoma) were recruited
from 85 centres in Japan. Women were randomised to 3-
weekly carboplatin (AUC6) and weekly paclitaxel (80 mg/
m
2
) versus 3-weekly carboplatin (AUC6) plus 3-weekly pac-
litaxel (180 mg/m
2
)[28]. JGOG 03016 reported a significant
improvement in PFS (28.0 versus 17.2 months, HR 0.71, 95%
CI 0.58–0.88) and OS (100.5 versus 62.2 months, HR 0.79,
95% CI 0.63–0.99, p= 0.39) in the dose-dense weekly pacli-
taxel arm [28,32]. Similar toxicity profiles were reported in
each treatment arm, although the prevalence of
myelosuppression was greater in the dose-dense arm and neg-
atively impacted on the ability to complete the target 6 cycles
of chemotherapy (Table 2)[28]. The results from this trial
were encouraging, although additional data was required to
determine if the trends were reproducible within different eth-
nic populations.
Three randomised phase III trials have since been reported
investigating dose-dense therapy in European (MITO-7,
ICON8) and North American (GOG 262) populations
[29–31] (Table 1). In MITO-7, 822 women, from Italy or
France, diagnosed with FIGO stage IC-IV EOC (69.6% se-
rous adenocarcinoma) were randomly allocated to receive ei-
ther 3-weekly carboplatin (AUC6) plus 3-weekly paclitaxel
(175 mg/m
2
) or weekly carboplatin (AUC2) plus weekly pac-
litaxel (60 mg/m
2
)[29]. In ICON8, 1566 women, from the
UK, Ireland, Australia, New Zealand, Mexico or South Korea,
diagnosed with FIGO stage IC-IV EOC (68.5% HGS) were
randomised to receive either 3-weekly carboplatin (AUC5/6)
plus 3-weekly paclitaxel (175 mg/m
2
) or one of two experi-
mental arms: 3-weekly carboplatin (AUC5/6) plus weekly
paclitaxel (80 mg/m
2
) or weekly carboplatin (AUC2) plus
weekly paclitaxel (80 mg/m
2
)[30••]. Neither MITO-7 nor
ICON8 showed an improvement in PFS in the dose-dense
experimental arms [29,30](Table1).
In GOG 262, 692 North American women diagnosed with
FIGO III-IV incompletely resected at IPS or FIGO II–III with
residual lesions ≤1 cm after IPS EOC (88% serous adenocar-
cinoma) were randomised to receive 3-weekly carboplatin
(AUC6) with either 3-weekly paclitaxel (175 mg/m
2
)orweek-
ly paclitaxel (80 mg/m
2
)[31]. In addition, all patients were
given the option of incorporating the anti-angiogenic agent,
bevacizumab (15 mg/kg; 3-weekly from cycle 2 until disease
progression or intolerable adverse event). In total, 84% of
patients recruited to the trial chose to receive bevacizumab.
In keeping with MITO-7 and ICON8, GOG 262 showed no
significant difference in PFS between arms (14.7 versus
14.0 months, HR 0.89, 95% CI 0.74–1.06) [31].
Tolerability of weekly dose-dense chemotherapy differed
between MITO-7, ICON8 and GOG 262 (Table 2) in that
fewer patients who received weekly treatment had grade 3 or
more neutropenia in MITO-7 and GOG 262, whereas the op-
posite was reported in ICON8. Moreover, the prevalence of
grade 2 or more neuropathy was lower in patients receiving
weekly treatment in MITO-7, higher in GOG 262, but not
different in ICON8. The dose-dense MITO-7 regimen, which
incorporated a lower dose of weekly paclitaxel to the other
studies (60 mg/m
2
versus 80 mg/m
2
), was tolerated better by
patients, and patients reported significantly better quality of
life scores than those on 3-weekly treatment. This could jus-
tify the use of this regimen in patients with advanced stage
disease and poorer performance status (i.e. 3 to 4). Weekly
carboplatin (AUC2) plus paclitaxel (60 mg/m
2
) is recom-
mended by the National Comprehensive Cancer Network
(NCCN) for patients with a poorer ECOG (Eastern
Cooperative Oncology Group) performance status or for use
in patients > 70 years old and/or those with comorbidities (e.g.
renal disease) [5]. However, all trials limited inclusion criteria
to those with an ECOG performance status of 2 or less, so
tolerability of weekly regimens may not be translated clinical-
ly to other subgroups of patients [33].
Table 1 PFS outcomes from first-line, phase III dose-dense
chemotherapy trials [28–31]
Trial PFS (months)
3-weekly
carboplatin and 3-
weekly paclitaxel
3-weekly
carboplatin and
weekly paclitaxel
Wee k ly
carboplatin and
weekly
paclitaxel
JGOG3016 17.5 28.2
(HR 0.76, 95%
CI 0.62–0.91,
p= 0.0037)
N/A
MITO-7 17.3 N/A 18.3
(HR 0.96, 95%
CI 0.80–1.16,
p=0.66)
ICON 8 17.7 20.8
(p=0.35)
21.0
(p=0.51)
GOG 262
+ 3-weekly
bevacizu-
mab
14.0 14.7
(HR 0.89, 95%
CI 0.74–1.06,
p=0.18)
N/A
The initial JGOG trial showed an advantage to dose dense chemotherapy
but this was not confirmed in subsequent randomised trials (MITO-7,
ICON8 and GOG 262). In addition, currently ongoing is the ICON 8B
trial which is comparing weekly chemotherapy regimens with 3-weekly
regimens, with concurrent bevacizumab (7.5 mg/kg) 3-weekly for a max-
imum of 22 cycles. The primary outcomes of ICON8B are PFS and OS
Curr Oncol Rep (2020) 22: 64 Page 3 of 14 64
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Although the reason for differences in efficacy between
trials recruiting East Asian or European/North American
women is unknown, it may be explained through
pharmacogenetics [34,35]. In addition, the interaction be-
tween bevacizumab and dose-dense regimens remains unclear
and will be addressed in the ongoing ICON8B trial. Due to the
variation in trial results, at present, the use of dose-dense che-
motherapy is not considered standard of care management for
the first-line treatment of advanced HGS cancer in Western
populations.
Intraperitoneal and Hyperthermic
Intraperitoneal Chemotherapy
Intraperitoneal (IP) chemotherapy delivers greater concentra-
tions of cytotoxic agents to the peritoneal cavity compared to
intravenous (IV) chemotherapy [36]. The NCCN guidelines
suggest IP chemotherapy as a potential option for FIGO stage
II–III EOC following optimal debulking (< 1 cm RD) [5]. This
guidance was based on improved survival outcomes reported
in the randomised phase III trial, GOG 172 [37]. ESMO
guidelines recognise this trial but still regard IP chemotherapy
as experimental and difficult to administer [6].
In GOG 172, women (n= 429 women) that were optimally
debulked at IPS (< 1 cm RD), with FIGO stage III EOC (79%
serous adenocarcinoma), were randomised to receive 6 cycles
of 3-weekly IV paclitaxel (135 mg/m
2
on day 1) plus IV
cisplatin (75 mg/m
2
on day 2) or 6 cycles of 3-weekly IV
paclitaxel (135 mg/m
2
on day 1) plus IP cisplatin (100 mg/
m
2
on day 2) and IP paclitaxel (60 mg/m
2
on day 8). GOG 172
demonstrated that patients receiving IPchemotherapy had sig-
nificantly improved PFS (23.8 versus 18.3 months, HR 0.80,
95% CI 0.64–1.00, p= 0.05) and OS (65.6 versus
49.7 months; HR 0.75, 95% CI 0.58–0.97, p= 0.03) [37].
Nevertheless, grade 3 and 4 adverse effects (e.g. increased
pain, myelosuppression and gastrointestinal and neurological
toxicity) occurred more frequently in patients treated with IP
chemotherapy. In addition, the IP regimen was more frequent-
ly curtailed before completion of primary therapy, with only
42% of women receiving all 6 cycles [37]. The primary rea-
sons for discontinuation were catheter-related e.g. infection
and blockage [38]. Furthermore, post-publication discussion
raised the question of the tolerability of the control arm, as
only 83% of patients received all 6 cycles of IV chemotherapy,
which were fewer patients than would be expected through
treatment with carboplatin and paclitaxel. Aiming to address
these criticisms and with the incorporation of maintenance
therapies, GOG 252 was carried out.
In the randomised phase III trial, GOG 252, IP chemother-
apy was delivered with concurrent IV bevacizumab [39•].
Here, women (n= 1560) diagnosed with FIGO stage II–IV
EOC (72.2% HGS), who had undergone maximal
cytoreduction at IPS, were randomised to receive IV weekly
paclitaxel (80 mg/m
2
) plus one of three regimens: 3-weekly
IV carboplatin (AUC6 on day 1); 3-weekly IP carboplatin
(AUC6 on day 1) or 3-weekly IP cisplatin (75 mg/m
2
on
day 2) and 3-weekly IP paclitaxel (60 mg/m
2
on day 8). All
arms were given with the addition of 3-weekly bevacizumab
(15 mg/kg on day 1 from cycle 2 for a maximum of 22cycles).
This trial did not report a significant difference in progression-
free survival between arms (24.9 versus 27.4 versus
Table 2 Toxicities reported in dose-dense chemotherapy trials [28–31]
Trial JGOG3016 MITO-7 ICON8 GOG 262
3-weekly
carboplatin
and 3-
weekly
paclitaxel
3-weekly
carboplatin
and weekly
paclitaxel
3-weekly
carboplatin
and 3-
weekly
paclitaxel
Wee k ly
carboplatin
and weekly
paclitaxel
3-weekly
carboplatin
and 3-
weekly
paclitaxel
3-weekly
carboplatin
and weekly
paclitaxel
Wee k ly
carboplatin
and weekly
paclitaxel
3-weekly
carboplatin and
3-weekly
paclitaxel ± 3-
weekly
bevacizumab
3-weekly
carboplatin and
weekly
paclitaxel ± 3-
weekly
bevacizumab
Tox ici ty
Grade 3–4
anaemia
44% 69%* 8% 6% 5% 13%* 5% 16% 36%*
Grade 3–4
neutropenia
88% 92% 50% 42%* 15% 35% 30% 83% 72%*
Grade 3–4
thrombocyto-
penia
38% 44% 7% 1%* 3% 8% 2% 16% 20%
Grade 2 or
higher
neuropathy
6% 7% 17% 6%* 27% 24% 22% 18% 26%*
*A statistically significant difference (p<0.05)
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64 Page 4 of 14
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26.2 months, respectively) [39•]. The conflicting outcomes
from these clinical trials have meant that IP chemotherapy
has yet to be universally accepted as a routine first-line thera-
py. This is likely also due to the perceived complexity of
delivery, reported increased toxicity, and development of
newer first-line maintenance therapies [36].
Hyperthermic intraperitoneal chemotherapy (HIPEC) in-
volves a single intra-operative administration of heated cyto-
toxic chemotherapy into the abdomino-pelvic cavity follow-
ing surgery. The high temperature leads to increased drug
penetration and tumour cell sensitivity to cytotoxic chemo-
therapy and induces apoptosis [40,41]. First-line HIPEC has
been investigated in two clinical trials [42,43]. In the
randomised phase III trial, OVIHIPEC-1, 245 patients diag-
nosed with FIGO stage III EOC (89.4% HGS) were referred
for NACT if IPS was not feasible or would likely have left
residual disease of > 1 cm [42•]. Patients were treated with
neoadjuvant 3-weekly carboplatin (AUC5/6) and 3-weekly
paclitaxel (175 mg/m
2
) for 3 cycles and then randomised in-
traoperatively to receive HIPEC with IP cisplatin (100 mg/m
2
)
or nothing. The cisplatin was administered at the end of
cytoreductive surgery after the abdominal cavity had been
heated to 40 °C using heated saline. In this trial, HIPEC was
associated with a significant improvement in PFS (14.2 versus
10.7 months, HR 0.66, 95% CI 0.50–0.87) and OS (45.7 ver-
sus 33.9 months, HR 0.67, 95% CI 0.48–0.94) [42•].
However, the results from OVIHIPEC-1 were inconsistent
with those reported in a randomised phase II undertaken in
Korea [43]. In this trial, 184 women diagnosed with FIGO
stage III–IV EOC were randomised intra-operatively during
IPS or DPS, after optimal cytoreduction (RD < 1 cm), to re-
ceive HIPEC with IP cisplatin (75 mg/m
2
)ornothing.The
abstract reports that there was no difference in PFS or OS
between groups (PFS: 20 versus 19 months and OS: 54 versus
51 months), but peer-reviewed publication of this trial is still
awaited.
The reason for the inconsistency between studies remains
unclear, but the slow recruitment in both trials (9 years in
OVIHIPEC-1; 6 years in the Korean study) suggests that
HIPEC can only be delivered to a relatively small and select
group of patients [44]. In addition, OVIHIPEC-1 was also
criticised as the results were not stratified based on prognostic
factors such as BRCA status and/or histological subtype.
These factors could have skewed the data in favour of the
HIPEC group, which contained fewer patients with a histo-
logical diagnosis associated with a worse prognosis (i.e., mu-
cinous, clear cell or carcinosarcoma). Moreover, the results
were also very different between sites, with sites that recruited
the most patients reporting worse outcomes in the HIPEC
group. The OVIHIPEC-2 trial (NCT03772028) has been
designed to address many of the issues that arose in previous
trials and to determine if surgery with HIPEC can prolong OS
with acceptable morbidity in the context of modern
maintenance treatment. Patients that will be recruited are those
with FIGO stage III EOC and they will be randomised to
receive primary cytoreductive surgery with or without
HIPEC with cisplatin.
At present, HIPEC is not widely used as standard first-line
treatment and further investigation in randomised phase III
trials is necessary [45]. Unfortunately, defining the position
of HIPEC and IP chemotherapy in the current era is becoming
harder as more effective maintenance therapies and greater
understanding of BRCA/HRD start to impact first-line treat-
ment regimens.
Bevacizumab Maintenance First-Line Therapy
Angiogenesis, the formation of new blood vessels, is a hall-
mark of cancer [46,47]. The sensitivity of EOC to vascular
endothelial growth factor (VEGF) inhibition is most likely
related to the fundamental role that VEGF plays in the phys-
iology of the normal ovary [48]. Indeed, the clinical utility of
VEGF inhibition, using the humanised monoclonal anti-
VEGF antibody bevacizumab, within first-line treatment of
EOC, has been demonstrated in two randomised phase III
trials [49,50].
In ICON7, 1528 women diagnosed with FIGO stage IIB-
IV EOC (69% serous adenocarcinoma) were randomised to
receive 3-weekly carboplatin (AUC5/6) plus 3-weekly pacli-
taxel (175 mg/m
2
) with or without 3-weekly bevacizumab
(7.5 mg/kg). Bevacizumab was administered concurrently
with chemotherapy and continued thereafter for a maximum
of 18 cycles in total. The addition of bevacizumab significant-
ly improved median PFS (19.0 versus 17.3 months, HR 0.81,
95% CI 0.70–0.94) [49], but an improvement in median OS
was only demonstrated in women considered at “high-risk”of
developing relapsed disease (39.7 versus 30.2 months, HR
0.78, 95% CI 0.63–0.97) [51]. High-risk disease included
FIGO stage III with > 1 cm of RD following cytoreductive
surgery, FIGO stage IV disease and/or inoperable disease [51].
In GOG 218, 1837 patients diagnosed with incompletely
resected FIGO stage III or FIGO stage IV EOC (83.6% serous
adenocarcinoma) were randomised to receive 3-weekly
carboplatin (AUC6) plus 3-weekly paclitaxel (175 mg/m
2
)
with or without 3-weekly bevacizumab (15 mg/kg).
Bevacizumab was administered concurrently with chemother-
apy only (cycles 2–6) or alongside chemotherapy and as main-
tenance (cycle 2–22) for a maximum of 21 cycles in total. The
group of patients that continued bevacizumab as maintenance
achieved a significantly improved PFS compared to those that
had chemotherapy alone (14.1 versus 10.3 months, HR 0.717,
95% CI 0.0625–0.824) [50]. In keeping with ICON7, GOG
218 also demonstrated that patients with FIGO stage IV dis-
ease achieved significantly longer OS (42.8 versus
Curr Oncol Rep (2020) 22: 64 Page 5 of 14 64
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32.6 months, HR 0.75, 95% CI 0.59–0.95) with bevacizumab
[52••].
Following the results of ICON7 and GOG 218,
bevacizumab was recommended for use in the first-line man-
agement of patients with advanced stage EOC, to be used
alongside chemotherapy and continued for 15 (12 in the
UK) months as maintenance therapy [5,6]. It remains unclear
if additional cycles of bevacizumab can extend PFS further,
and so the results of the BOOST trial (NCT01462890) are
eagerly awaited; comparing 15 versus 30 cycle in the first-
line setting.
Other anti-angiogenic agents, including nintedanib [53]
and pazopanib [54] also showed improved PFS in the first-
line setting as maintenance therapies, although these orally
administered small molecule tyrosine kinase inhibitors dem-
onstrated an increased incidence of diarrhoea and
haematological toxicities.
There has been a global search for biomarkers that could be
used to optimise the use of VEGF inhibitors. We have shown
that a reduction and subsequent increase in plasma Tie2, in
patients with ovarian or colorectal cancer treated with
bevacizumab, reflect vascular response and then vascular pro-
gression, respectively [55,56]. Taken in conjunction with
similar pharmacodynamic changes in plasma Tie2, induced
by cediranib in patients diagnosed with glioma [57], these
findings together suggest that plasma Tie2 is the first tumour
vascular response biomarker for VEGF inhibitors [58].
Further prospective validation of Tie2 utility is underway in
the VALTIVE-1 study.
Poly(ADP-Ribose) Polymerase Inhibitors
Recently, poly(ADP-ribose) polymerase (PARP) inhibitors
have changed the outlook for some women with FIGO stage
III/IV HGS carcinoma. Small molecule inhibitors of PARP1
and PARP2 act in BRCA-mutant and Homologous
recombination-deficient (HRD) tumours, probably through
the mechanistic framework of synthetic lethality, although
there are several theories for the exact mechanism of action
[59]. Approximately 20% of HGS tumours have a germline or
somatic BRCA1/2 mutation and in total up to 50% are HRD
[60,61]; both mechanisms playing important roles in DNA
repair and error-free repair of double-strand breaks (DSBs),
respectively. In HRD tumour cells, alternative “error-prone”
DSB repair pathways (e.g. non-homologous end joining
[NHEJ]) are more heavily relied upon, thereby leading to ge-
nomic instability [62]. One theory is that PARP inhibitors can
exploit this unique molecular feature of HGS carcinoma by
inhibiting DNA single-strand break (SSB) repair [63,64].
Indeed, unrepaired SSBs may form lethal DSB during the
G2/S-phase of the cell cycle. Subsequently, HRD tumours that
are unable to repair DSBs are more likely to die after exposure
to PARP inhibitors. PARP inhibitors prevent repair of SSBs
by inhibiting catalytic formation of polymers of ADP-ribose
forming and trapping PARP1 on DNA [65,66]. The NHEJ
pathway also appears to play a key role in the way PARP
inhibitors work in HRD cells and studies have shown cells
with already defective NHEJ may in fact be resistant PARP
inhibitors [67,68].
A number of randomised phase III trials have recently re-
ported the efficacy of PARP inhibitors as first-line mainte-
nance monotherapy [69–71] (Table 3). SOLO-1 reported a
70% reduction in the risk of progression or death in patients
with FIGO stage III/IV BRCA-mutant (germline or somatic)
platinum-sensitive HGS or high-grade endometrioid carcino-
ma following 24 months of olaparib (300 mg twice daily)
compared to placebo (HR 0.30, 95% CI 0.23–0.41) [69••]
(Table 3). In the PRIMA trial, 733 patients with FIGO stage
III–IV HGS carcinoma were randomised following a
complete/partial response to cytoreductive surgery plus
platinum-based chemotherapy to receive either niraparib
(300 mg once daily, 28-day cycles) or placebo for a maximum
of 36 months [70••]. The trial reported an improvement in PFS
in all patients with niraparib compared to placebo (13.8 versus
8.2 months, HR 0.62, 95% CI 0.05–0.76). The greatest bene-
fits in PFS were demonstrated in BRCA-mutant and/or HRD
tumours (Table 3).
In the VELIA trial, 1140 women with FIGO stage III–IV
HGSC were randomised prior to receiving first-line multi-mo-
dality therapy to one of 3 arms: (A) chemotherapy with con-
current and maintenance veliparib (150 mg twice-daily) or (B)
chemotherapy with concurrent veliparib and placebo mainte-
nance therapy or (C) placebo throughout chemotherapy and as
maintenance [71••]. For patients randomised to take veliparib
with and following chemotherapy, a PFS advantage was dem-
onstrated, again with the greatest benefits reported in patients
with BRCA-mutant and HRD tumours (Table 3). There was no
significant difference in PFS between the group that took
veliparibwithchemotherapyonlyincomparisonwiththepla-
cebo group. Interestingly, unlike olaparib or niraparib,
veliparib was administered concurrently with platinum thera-
py, whereas previous trials had shown that combining PARP
inhibitors and platinum caused intolerable myelotoxicity [72].
The most common adverse effects of PARP inhibitors re-
ported in trials were myelosuppression, nausea and fatigue
(Table 4). The olaparib trial reported fewer incidences of grade
3 or above anaemia or neutropenia than niraparib and
veliparib. More rare, but clinically significant, adverse effects
such as pneumonitis, myelodysplastic syndrome and acute
myeloid leukaemia were reported infrequently in the trials
but more commonly with olaparib (Table 4)[69–71].
In PRIMA and VELIA, HRD tumours were identified
through the myChoice® companion diagnostic (CDx) test
(Myriad Genetics, Inc., Salt Lake City, UT, USA). This assay
determines an HRD “score”using three algorithms calculating
Curr Oncol Rep (2020) 22: 64
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genetic aberrations in single nucleotide polymorphisms
(SNPs). These algorithms assess genetic characteristics of tu-
mour DNA, including loss of heterozygosity (LOH),
telomeric allelic imbalance (TAI) and large-scale transitions
(LST), all surrogate markers of genomic instability [73–75].
The assay provides an HRD “score”that is calculated based
on the accumulative score of each algorithm (LOH, TAI and
LST). A tumour is considered HRD according to a set score
e.g. in PRIMA HRD tumours had a HRD score ≥42, whereas
in VELIA, the threshold was set at 33 [70,71]. In both trials,
women with HRD tumours who received the PARP inhibitor
had significantly longer PFS compared to those who received
placebo. The difference in the HRD score may impact upon
the choice of PARP inhibitor used in front-line therapy.
Table 3 PFS outcomes in PARP inhibitor trials based on genetic stratification [69–71]
PFS (months) SOLO1 PRIMA VELIA PAOLA-1
Control
arm
Placebo
Experimental
arm
Oral olaparib
300 mg BD
maintenance
after
chemotherapy
Control
arm
Placebo
Experimental
arm
Oral niraparib
300 mg OD
maintenance
after
chemotherapy
Control
arm
Placebo
Experimental arm
Oral veliparib
150 mg BD
throughout
chemotherapy and
continued as
maintenance
Control arm
Placebo +
bevacizumab
15 mg/kg
Experimental arm
Oral olaparib 300 mg
BD maintenance
after
chemotherapy +
bevacizumab
15 mg/kg
Intention-to-treat
population
N/A N/A 8.2 13.8
(HR 0.62, 95%
CI
0.50–0.76)
17.3 23.5
(HR 0.68, 95% CI
0.56–0.83)
16.6 22.1
(HR 0.59, 95% CI
0.49–0.72)
All HRD positive
(includes BRCA1/2
mutation)
N/A N/A 10.9 22.1
(HR 0.40, 95%
CI
0.27–0.62)
20.5 31.9
(HR 0.57, 95% CI
0.43–0.76)
17.7 37.2
(HR 0.33, 95% CI
0.25–0.45)
HRD
positive/BRCA-wildt-
ype
N/A N/A 8.2 19.6
(HR 0.50, 95%
CI
0.31–0.83)
N/A N/A 16.6 28.1
(HR 0.43, 95% CI
0.28–0.66)
BRCA1/2 mutation 13.8 49.9
(HR 0.30,
95% CI
0.23–0.41)
N/A N/A 22.0 34.7
(HR 0.44, 95% CI
0.28–0.68)
21.7 37.2
(HR 0.3, 1
95% CI 0.20–0.47)
HR-competent N/A N/A N/A N/A N/A N/A 16.2 16.6
(HR 1.00, 95% CI
0.75–1.35)
Table 4 Common and serious adverse events reported in PARP inhibitor trials [69–71]
SOLO-1 trial—olaparib group PRIMA trial—niraparib group VELIA trial—veliparib throughout group
Event Any grade
(% of patients)
Grade 3 or 4
(% of patients)
Any grade
(% of patients)
Grade 3 or 4
(% of patients)
Any grade
(% of patients)
Grade 3 or 4
(% of patients)
Anaemia 3922633164 38
Neutropenia 23 9 26 12 75 58
Thrombocytopenia 11 1 46 29 58 28
Nausea 77 1 57 1 80 8
Fatigue 63 4 35 2 69 8
Pneumonitis 2 N/A 0 N/A 0 N/A
Acute myeloid leukaemia 1 N/A 0 N/A 0.3 N/A
Myelodysplatic syndrome 0 N/A 0.2 N/A 0* N/A
*There was an incidence of myelodysplastic syndrome in 1 patient (0.2%) in veliparib combination only group in this trial [71]
Curr Oncol Rep (2020) 22: 64 Page 7 of 14 64
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Table 5 Ongoing first-line phase III clinical trials involving immune checkpoint inhibitors with combination regimens
Trial name GOG3015/ENGOT OV39 FIRST trial/
ENGOT Ov-44
DUO-O/
ENGOT Ov-46
ENGOT Ov-43/
MK7339-001
ATHENA
Trial identifier NCT03038100 NCT03602859 NCT03737643 NCT03740165 NCT03522246
Histology Epithelial Epithelial Epithelial Epithelial Epithelial
FIGO stage III–IV III–IV III–IV III–IV III–IV
ECOG PS 0–20–10–20–10–2
Investigational drugs Atezolizumab Dorstarlimab
Niraparib
Durvalumab
Olaparib
Pembrolizumab
Olaparib
Nivolumab
Rucaparib
Control
arm-chemotherapy
phase
IV paclitaxel
+ IV carboplatin
+ IV bevacizumab
+ IV a tezolizumab placeb o
Arm 1:
Standard of care
chemotherapy
+ IV dorstarlimab
placebo
Arm 1:
IV paclitaxel
+IV
carboplatin
+IV
bevacizumab
+IV
durvalumab
placebo
Arm 3:
IV paclitaxel
+ IV carboplatin
± IV bevacizumab
+ IV pembrolizumab
placebo
N/A
Control
arm-maintenance
phase
IV bevacizumab
+ IV a tezolizumab placeb o
Arm 1:
IV dorstarlimab
placebo
+ PO niraparib
placebo
Arm 1:
IV
bevacizumab
+IV
durvalumab
placebo
+ PO olaparib
placebo
Arm 3:
± IV bevacizumab
+ IV pembrolizumab
placebo
+ PO olaparib placebo
Arm D:
IV nivolumab placebo
+ PO rucaparib
placebo
Experimental arm
(1)-chemotherapy
phase
IV paclitaxel
+ IV carboplatin
+ IV bevacizumab
+ IV atezolizumab (1200 mg,
three-weekly)
Arm 2:
Standard of care
chemotherapy
+ IV dorstarlimab
placebo
Arm 2:
IV paclitaxel
+IV
carboplatin
+IV
bevacizumab
+IV
durvalumab
Arm 1:
IV paclitaxel
+ IV carboplatin
± IV bevacizumab
+ IV pembrolizumab
(200 mg, three
weekly)
N/A
Experimental arm
(1)-maintenance
phase
IV bevacizumab
+ IV atezolizumab (1200 mg,
three-weekly)
Arm 2:
IV dorstarlimab
placebo
+ PO niraparib
Arm 2:
IV
bevacizumab
+IV
durvalumab
+ PO olaparib
placebo
Arm 1:
± IV bevacizumab
+ IV pembrolizumab
(200 mg,
three-weekly)
+ PO olaparib
(300 mg,
twice-daily)
Arm A:
IV nivolumab
(four-weekly)
+ PO rucaparib
(twice-daily)
Experimental arm
(2)-chemotherapy
phase
N/A Arm 3:
Standard of care
chemotherapy
+ IV dorstarlimab
Arm 3/patients
with
tBRCAm:
IV paclitaxel
+IV
carboplatin
±IV
cevacizumab
+IV
durvalumab
Arm 2:
IV paclitaxel
+ IV carboplatin
± IV bevacizumab
+ IV pembrolizumab
N/A
Experimental Arm
(2)-maintenance
phase
N/A Arm 3:
IV
dorstarlimab +
PO niraparib
Arm 3/patients
with
tBRCAm:
±IV
bevacizumab
+IV
durvalumab
+ PO olaparib
Arm 2:
± IV bevacizumab
+ IV pembrolizumab
(200 mg,
three-weekly)
+ PO olaparib placebo
Arm B:
IV nivolumab placebo
+ PO rucaparib
(twice-daily)
N/A N/A N/A N/A Arm C:
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Overall, the outcomes of these trials show that patients with
known BRCA1/2 mutations benefit from PARP inhibitors as
maintenance monotherapy after a response to first-line plati-
num-based chemotherapy. In addition, those patients with
HRD tumours benefit from niraparib or veliparib, and have
similar risks of adverse effects (Table 4). Although further
analysis of OS is awaited in all three trials, surrogate markers
of OS including time-to-first subsequent therapy (TFST),
progression-free survival 2 (PFS2) and time-to-second subse-
quent therapy (TSST) suggest early indications of long-term
survival benefit [69••]. It is becoming increasingly important
to test all patients for germline and somatic BRCA1/2 muta-
tions at diagnosis to help guide maintenance options, and re-
cent approval in the USA of the Myriad myChoice® CDx
represents an additional biomarker for assessment in BRCA
wildtype patients.
Immunotherapy
Immune checkpoint blockade with anti-CTLA-4 and/or anti-
PD-1/PD-L1 inhibitors is not routinely used in the manage-
ment of HGS carcinoma at present. Early phase trials have
reported relatively disappointing response rates of between
10 and 20% [76–78]. Indeed, the randomised first-line phase
III trial, JAVELIN Ovarian 100 trial (NCT02718417) was
prematurely discontinued due to insufficient activity. This trial
had been recruiting patients with stage III–IV EOC that were
due to start platinum-based chemotherapy. Patients were to be
randomised to receive 3-weekly avelumab (an anti-PD-L1 an-
tibody) during chemotherapy or during chemotherapy and as
maintenance therapy or chemotherapy alone. As a result of the
interim results of JAVELIN Ovarian 100, another randomised
phase III trial, JAVELIN Ovarian PARP 100 trial
(NCT03642132), investigating avelumab plus the PARP in-
hibitor, talazoparib, was also prematurely discontinued [79].
BRCA-mutated HGS carcinoma and TP53-mutated EOC
often contain increased number of tumour-infiltrating lym-
phocytes and express PD-1/PD-L1 [80,81], suggesting that
immune checkpoint inhibitors should be effective. However,
copy number variation is more common than neoantigen for-
mation in HGS and hence checkpoint inhibitors used alone
have not yielded meaningful activity. In an attempt to over-
come this problem, multiple trials have been initiated that aim
to boost the immune response through concurrent administra-
tion of immune oncology agents with PARP and/or VEGF
inhibitors (Table 5).
Combination First-Line Maintenance
Treatment
Recent clinical trials in EOC have started to evaluate combi-
nations of VEGF and PARP inhibitors. An initial randomised
phase II treatment trial described increased PFS and OS in
patients with recurrent platinum-sensitive EOC that were
treated with a combination of cediranib (30 mg, once daily)
plus olaparib (capsules; 200 mg, twice-daily) compared to
olaparib alone. Importantly, this benefit was more evident in
patients with no BRCA1/2 mutation [82,83]. Mechanistic
studies have shown that the increased activity of combination
therapy is related to hypoxia-driven reduction in the proteins
involved in HR repair, which then resulted in reduced BRCA
expression and function, sensitising BRCA1/2 wild-type cells
to PARP inhibitors [84].
The only trial to assess the combination of PARP and
VEGF inhibition in first-line management of EOC is
PAOLA-1 [85••]. In this randomised phase III trial, 806 wom-
en with FIGO stage III–IV high-grade serous or endometrioid
ovarian cancers (95.8% HGS) had responded to first-line plat-
inum-taxane chemotherapy, and bevacizumab were
randomised to receive either ongoing 3-weekly bevacizumab
(15 mg/kg) as maintenance for a maximum of 15 months total
with olaparib (300 mg, twice-daily) for up to 24 months, or
bevacizumab with placebo. Tumour samples were analysed
for BRCA mutation and HRD testing prior to randomisation,
with an HRD score of ≥42 indicating a positive result. A PFS
benefit was demonstrated in the combination arm
Tabl e 5 (continued)
Trial name GOG3015/ENGOT OV39 FIRST trial/
ENGOT Ov-44
DUO-O/
ENGOT Ov-46
ENGOT Ov-43/
MK7339-001
ATHENA
Experimental arm
(3)-maintenance
phase
IV nivolumab
(four-weekly)
+ PO rucaparib placebo
Primary outcome PFS in intention to treat (ITT)
population
PFS in programmed cell death-ligand
1 (PD-L1)-positive subpopulation
OS in ITT population
OS in PD-L1-positive population
PFS PFS–in
non-tBRCA-
m patients
PFS
OS
PFS
Curr Oncol Rep (2020) 22: 64 Page 9 of 14 64
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(investigator-assessed PFS: 22.1 versus 16.6 months, HR
0.59, 95% CI 0.49–0.72), with the most profound PFS advan-
tagebeingreportedinpatientswithBRCA1/2mutations
(Table 3)[85••]. The main criticism of PAOLA-1 was that
there was no single agent olaparib maintenance monotherapy
arm included, which made it difficult to determine if the PFS
advantage in patients with HRD tumours was due to synergy
between bevacizumab-olaparib or olaparib alone.
Results from phase III trials combining immune checkpoint
inhibitors with VEGF or PARP inhibitors in first-line manage-
ment of EOC are eagerly awaited (Table 5). The rationale for
use of PARP inhibitors is the increased DNA damage in cells,
which might increase neoantigen formation and hence the
effects of immunotherapy [86]. In contrast, VEGF inhibitors
act by converting an immunosuppressive tumour microenvi-
ronment (TME) to an immunosupportive one, potentially in-
creasing sensitivity to immunotherapy [87,88]. If the results
of combinational agents prove effective, it will be critical to
develop biomarkers that will optimise treatment of the right
patients so that cost-effectiveness is delivered.
Conclusion
The first-line treatment of HGS carcinoma now builds on the
well-established backbone of surgery and paclitaxel/platinum-
based chemotherapy. Surgery can be carried out upon diagno-
sis or after NACT. The role of IP chemotherapy and HIPEC
remains undefined.
Maintenance monotherapies with bevacizumab and PARP
inhibitors have demonstrated progression-free survival bene-
fits in certain clinically and molecularly defined subgroups.
Key questions remain over the benefits of combination regi-
mens and whether molecularly targeted biomarkers can opti-
mise patient stratification. Nevertheless, 70% of patients are
likely to develop recurrent disease and require further treat-
ment. Bevacizumab has proven effective in the re-use setting
[89] but trials on the re-use of PARP inhibitors are currently
ongoing (NCT03136987). Therefore, based on current evi-
dence, it is vital to decide which drugs should be used upfront
and which should be saved for use in relapse.
Recent phase III trials highlight the future need for
randomised trials on the re-use of maintenance therapies, the
upfront testing of BRCA and HRD status and the ongoing
development of biomarkers for use of VEGFi.
Compliance with Ethical Standards
Conflict of Interest Andrew R. Clamp has received research funding
from AstraZeneca, has received compensation from AstraZeneca and
Tesaro for service as a consultant and has received non-financial support
from AstraZeneca, Clovis Oncology, and Tesaro.
Reem D. Mahmood, Robert D. Morgan, Richard J. Edmondson and
Gordon C. Jayson declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing, adap-
tation, distribution and reproduction in any medium or format, as long as
you give appropriate credit to the original author(s) and the source, pro-
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