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Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: A multistudy analysis of response rates and safety


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Background: The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy. Patients and methods: This analysis evaluated pooled data from two Phase I trials (NCT00516373 [Study 2]; NCT00777582 [Study 24]) and four Phase II trials (NCT00494442 [Study 9]; NCT00628251 [Study 12]; NCT00679783 [Study 20]; NCT01078662 [Study 42]) that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer. All patients had a documented gBRCAm and were receiving olaparib 400 mg monotherapy twice daily (capsule formulation) at the time of relapse. Objective response rate (ORR) and duration of response (DoR) were evaluated using original patient outcomes data for patients with measurable disease at baseline. Results: Of the 300 patients in the pooled population, 273 had measurable disease at baseline, of whom 205 (75%) had received ≥3 lines of prior chemotherapy. In the pooled population, the ORR was 36% (95% CI: 30, 42) and the median DoR was 7.4 months (95% CI: 5.7, 9.1). The ORR among patients who had received ≥3 lines of prior chemotherapy was 31% (95% CI: 25, 38), with a DoR of 7.8 months (95% CI: 5.6, 9.5). The safety profile of olaparib was similar in patients who had received ≥3 lines of prior chemotherapy compared with the pooled population; grade ≥3 adverse events were reported in 54% and 50% of patients, respectively. Conclusion: Durable responses to olaparib were observed in patients with relapsed gBRCAm ovarian cancer who had received ≥3 lines of prior chemotherapy. Clinical trial numbers:, NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662.
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Annals of Oncology 27: 10131019, 2016
Published online 8 March 2016
Olaparib monotherapy in patients with advanced
relapsed ovarian cancer and a germline BRCA1/2
mutation: a multistudy analysis of response rates
and safety
U. A. Matulonis1*, R. T. Penson2, S. M. Domchek3, B. Kaufman4, R. Shapira-Frommer4,
M. W. Audeh5,S.Kaye
6, L. R. Molife6, K. A. Gelmon7, J. D. Robertson8,, H. Mann8,
T. W. Ho9& R. L. Coleman10
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston;
Department of Hematology/Oncology, Massachusetts General Hospital, Boston;
of Medicine, Basser Research Center and Abramson Cancer Center, Philadelphia, USA;
Division of Oncology, Sheba Medical Center, Tel HaShomer, Israel;
Division of
Medical Oncology, Cedars-Sinai Medical Center, Los Angeles, USA;
Drug Development Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton, UK;
Department of Medical Oncology, BC Cancer Agency, Vancouver, Canada;
Global Medicines Development, AstraZeneca, Maccleseld, UK;
Global Medicines
Development, AstraZeneca, Wilmington;
Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center,
Houston, USA
Received 22 December 2015; revised 26 February 2016; accepted 3 March 2016
Background: The PARP inhibitor olaparib (Lynparza) demonstrates antitumor activity in women with relapsed
ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to
explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior
Present afliation: Kesios Therapeutics Ltd, London, UK.
*Correspondence to: Dr Ursula A. Matulonis, The Susan F. Smith Center for Womens
Cancers, Dana-Farber Cancer Institute, 450 Brookline Avenue, Y1421, Boston, MA
02215, USA. Tel: +1-617-632-2334; E-mail:
Annals of Oncology original articles
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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Patients and methods: This analysis evaluated pooled data from two phase I trials [NCT00516373 (study 2);
NCT00777582 (study 24)] and four phase II trials [NCT00494442 (study 9); NCT00628251 (study 12); NCT00679783
(study 20); NCT01078662 (study 42)] that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer. All
patients had a documented gBRCAm and were receiving olaparib 400 mg monotherapy twice daily (capsule formulation)
at the time of relapse. Objective response rate (ORR) and duration of response (DoR) were evaluated using original patient
outcomes data for patients with measurable disease at baseline.
Results: Of the 300 patients in the pooled population, 273 had measurable disease at baseline, of whom 205 (75%) had
received 3 lines of prior chemotherapy. In the pooled population, the ORR was 36% [95% condence interval (CI)
3042] and the median DoR was 7.4 months (95% CI 5.79.1). The ORR among patients who had received 3 lines of
prior chemotherapy was 31% (95% CI 2538), with a DoR of 7.8 months (95% CI 5.69.5). The safety prole of olaparib
was similar in patients who had received 3 lines of prior chemotherapy compared with the pooled population; grade 3
adverse events were reported in 54% and 50% of patients, respectively.
Conclusion: Durable responses to olaparib were observed in patients with relapsed gBRCAm ovarian cancer who had
received 3 lines of prior chemotherapy. NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662.
Key words: olaparib, monotherapy, ovarian cancer, BRCA1/2 mutation, pooled analysis
Ovarian cancer is the fth most common cancer in women in
developed countries, causing 15 000 deaths per year in the
United States [1,2]. The majority of women who are diagnosed
with high-grade serous ovarian cancer (HGSOC), which is
the most common histological subtype, are diagnosed at an
advanced stage of the disease. Following cytoreductive surgery,
patients with advanced-stage cancer are normally treated with
platinum- and taxane-based chemotherapy regimens; initially,
>75% of patients will exhibit a clinical response, with most of
these patients eventually relapsing [35]. Patients with plat-
inum-sensitive relapsed ovarian cancer [recurrence after a plat-
inum-free interval (PFI) of 6 months] are typically treated
with platinum-based regimens, but the time to progression gen-
erally shortens with consecutive therapies such that patients ex-
perience progressively shorter treatment-free intervals between
relapses [6]. Regardless of whether patients have platinum-sen-
sitive or platinum-resistant (PFI of <6 months) cancer, the
median duration of progression-free survival (PFS) after succes-
sive treatments typically leaves patients with little or no chemo-
therapy-free interval and cumulative toxicities [6,7].
Currently, there is a clinical need and urgency for additional
treatments that are well tolerated and that can improve out-
comes for ovarian cancer patients who have received multiple
lines of chemotherapy. Olaparib (Lynparza, AstraZeneca) is
an oral poly(ADP-ribose) polymerase (PARP) inhibitor that has
documented antitumor activity among women with relapsed
ovarian cancer who have a germline BRCA1/2 mutation (gBRCAm)
[8,9]. The capsule formulation of olaparib is currently approved
in the United States for patients who have relapsed ovarian
cancer and a gBRCAm and who have received 3 lines of prior
chemotherapy. To further evaluate the efcacy and safety of
olaparib in this setting, we carried out a pooled analysis of
patients from completed single-agent olaparib trials.
This analysis included women with relapsed ovarian, fallopian tube or peri-
toneal cancer and a documented gBRCAm who received olaparib 400 mg b.i.d.
(capsule) monotherapy at the time of relapse. Women whowere enrolled in six
prospective clinical trials were included (Table 1). Data from the individual
trials have been reported previously [814].
This analysis was conducted using original patient outcomes data, based
on assessment denitions in the respective trials. The denitions for object-
ive response rate (ORR), duration of response (DoR), and criteria for den-
ing measurable disease were similar across the studies. ORR was dened as
the percentage of patients with at least one imaging assessment demonstrat-
ing a complete response (CR) or partial response (PR) that was conrmed at
least 4 weeks later, using Response Evaluation Criteria in Solid Tumors
(RECIST). DoR was dened as the time from the rst documented response
(CR/PR) until documented progression, by RECIST, or death; if a patients
disease did not progress following a response, the patient was censored at
their last evaluable tumor assessment (RECIST) date. The time of the initial
response was dened as the latest date contributing towards the rst visit re-
sponse of CR/PR.The response was assessed using RECIST v1.1 criteria.
BRCA mutation status was determined by various methods dependent on
the study. Across all six studies, local gBRCAm testing was conducted and
recorded on case report forms at study enrollment. For study 12, gBRCAm
status was established retrospectively by Myriad Genetics Laboratories, Inc.
with the Clinical Laboratory Improvement Amendments (CLIA)- and
College of American Pathologists (CAP)-certied Integrated BRACAnalysis®
test, using blood samples provided by patients who consented to testing.
Throughout the trials, safety and tolerability were assessed by adverse
events (AEs) and changes in laboratory parameters according to National
Cancer InstituteCommonTerminologyCriteriafor AEs (NCI CTCAE; v3.0).
statistical methodology
ORR and DoR were calculated for the pooled group, and for individual
studies, from the subset of patients with measurable disease at baseline.
Patients were also analyzed according to the number of prior chemothera-
pies received and their platinum sensitivity status ( patients whose tumor
responded to the most recent platinum-containing chemotherapy with a
treatment-free interval of >6 months were classied as sensitive; patients ex-
periencing relapse 6 months after platinum-based treatment or whose im-
mediate previous regimen was platinum were classied as resistant). For
those patients participating in study 42 for whom the therapy before ran-
domization was not platinum-based chemotherapy, platinum sensitivity
status was obtained retrospectively from the study sites.
ORR was summarized and 95% condence intervals (CIs) for binomial
proportions were calculated using the ClopperPearson (exact) method. The
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Table 1. Summary of studies and patients included in the pooled analysis [814]
Study Design Efficacy end
Patients with gBRCAm
ovarian cancer treated with
olaparib 400 mg b.i.d., N
Patients with
measurable disease at
baseline, N
Patients with measurable disease at
baseline who received 3 lines of
prior chemotherapy, N
Phase I studies
(study 2;
First-in-human study with efficacy expansion
(200 mg b.i.d.)
Response rate 58
(study 24;
Formulation comparison (capsule and tablet):
crossover study with efficacy expansion
Tumor shrinkage 77
20 11
Phase II olaparib monotherapy studies
(study 9;
Noncomparative, proof-of-concept trial (200 mg
b.i.d., 400 mg b.i.d.)
Response rate 58 33
33 26
(study 12;
Open-label, randomized trial of olaparib versus
PLD in patients who had failed prior platinum
therapy (200 mg b.i.d., 400 mg b.i.d.)
PFS 97 32
32 16
(study 20;
Open-label, nonrandomized trial (400 mg b.i.d.) Response rate 91
17 12
(study 42;
Open-label, nonrandomized trial (400 mg b.i.d.) Response rate 317 193
167 137
Total 300 273 205
Patients from efficacy expansion only.
Local germline testing.
Capsule-dosed patients only.
Local germline testing and/or retrospective Myriad BRACAnalysis® testing.
Sixty-five patients with ovarian cancer and 26 with breast cancer.
b.i.d., twice daily; gBRCAm, germline BRCA mutation; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin.
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median DoR was calculated from the onset of response using the Kaplan
Meier technique.
Three hundred women were included in the pooled patient set
and were evaluable for safety. Of these, 273 had measurable
disease at baseline [by computed tomography (CT)/magnetic
resonance imaging] and were evaluable for response. The ma-
jority of patients (223/300, 74.3%) had received 3 lines of prior
chemotherapy and, of these, 205 had measurable disease at
baseline (Table 1).
Demographics and baseline characteristics for patients with
measurable disease at baseline and for patients with measurable
disease at baseline who had received 3 lines of prior chemo-
therapy were similar (Table 2).
In the pooled set of patients with measurable disease at baseline
(n= 273), the ORR was 36% and median DoR was 7.4 months
(Table 3). In the subset of patients with measurable disease
at baseline who had received 3 lines of prior chemotherapy
(n= 205), the ORR was 31% and median DoR was 7.8 months
(Table 3). For both platinum-sensitive and platinum-resistant
cancers, the ORR declined as the number of prior lines of treat-
ment increased (Figure 1). Similar ndings were observed from
individual studies (supplementary Table S1, available at Annals
of Oncology online). Olaparib treatment benets were observed
in platinum-sensitive (platinum sensitive, but ineligible to
receive further platinum-based chemotherapy) and platinum-
resistant patients (Table 3). As shown in Table 3, the ORR
declined as the number of prior lines of treatment increased; the
ORR for patients treated with one prior regimen was 50% and
dropped to 24% for patients who had received 6 prior regi-
mens. There was also a reduction in DoR as the number of prior
lines of treatment increased (Table 4).
treatment duration
In the overall pooled set (n= 300), the median duration of
olaparib treatment was 177 days (range 1819 days). In the
subset of patients who had received 3 lines of prior chemother-
apy (n= 223), the median duration of treatment was 168 days
(range 1819 days).
The most common AEs and grade 3 AEs are shown in Table 5.
In the overall pooled safety set (n= 300), grade 3 AEs were
experienced by 150 patients (50%); 85 patients (28%) had caus-
ally related grade 3 AEs. Serious AEs (SAEs) were reported in
89 (30%) patients, of whom 29 (10%) had causally related SAEs.
Compared with the pooled set, the tolerability prole was
similar for patients who had received 3 lines of prior chemo-
therapy (n= 223): grade 3 AEs were experienced by 120
patients (54%), of whom 67 patients (30%) had causally related
grade 3 AEs, and SAEs were reported in 75 (34%) patients, of
whom 26 (12%) had causally related SAEs.
In the overall pooled analysis, a total of 113 (38%) patients
had AEs leading to dose interruptions, with the most common
causes being vomiting [21 (7%) patients] and anemia [12 (4%)
patients]. For the subset of patients who had received 3 lines of
prior chemotherapy, 89 (40%) patients had AEs leading to dose
interruptions; the most common causes were vomiting [18 (8%)
patients] and anemia [11 (5%) patients]. Overall, 15 patients
(5%) experienced at least one AE that led to discontinuation of
study treatment. All of these patients had received 3 lines of
prior chemotherapy (7% in this subgroup). In the overall pooled
analysis, eight (3%) patients had an AE leading to death, either
on treatment or within 30 days of discontinuing treatment, and
all had received 3 lines of prior chemotherapy. Three patients
were included in both groups (i.e. these three patients had an
AE leading to death and discontinued treatment due to an AE).
The AEs leading to death were: sepsis, intestinal perforation,
suture rupture, acute leukemia in a patient who had a diagnosis
of myelodysplastic syndrome at study entry, acute myeloid leu-
kemia (AML), cerebrovascular accident, chronic obstructive pul-
monary disease and pulmonary embolism. The patients who
experienced acute leukemia and AML had received two and
three prior lines of platinum-based chemotherapy, respectively;
in addition, the patient with acute leukemia had also received
cyclophosphamide and doxorubicin. The incidence of each AE
leading to death was 0.3% in the overall pooled set (0.4% in the
subgroup of patients who had received 3 lines of chemother-
apy). None of the AEs leading to death was considered causally
related to olaparib.
A high proportion of patients experienced CTCAE grade 2
decreases in hemoglobin (pooled patient set, 46%; 3 prior
lines subset, 51%) and lymphocytes ( pooled patient set, 47%;
3 prior lines subset, 49%).
Table 2. Patient demographics and baseline characteristics for
patients with measurable disease
Pooled patient set
(N= 273)
Patients receiving 3 lines of
prior chemotherapy (N= 205)
Median age
(range), years
56 (2979) 56 (3579)
Age group
<50 63 (23.1) 46 (22.4)
50 to <65 155 (56.8) 116 (56.6)
65 55 (20.1) 43 (21.0)
ECOG performance status
0 156 (57.1) 114 (55.6)
1 107 (39.2) 81 (39.5)
2 9 (3.3) 9 (4.4)
Unknown 1 (0.4) 1 (0.5)
Site of tumor
Ovary 255 (93.4) 191 (93.2)
Fallopian tube 5 (1.8) 4 (2.0)
Peritoneum 7 (2.6) 7 (3.4)
5 (1.8) 2 (1.0)
Missing 1 (0.4) 1 (0.5)
All values represent n(%) unless stated otherwise.
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ORR, %
(n= 18)
(n= 50)
(n= 74)
Previous lines of chemotherapy received
(n= 44)
(n= 32)
Total (n= 273)
Sensitive (n= 75)
Resistant (n= 119)
(n= 55)
Figure 1. ORR by number of lines of prior chemotherapy. nnumbers show total population; condence lines represent 95% CIs for total population.
Table 3. ORR and DoR by number of lines of prior chemotherapy and by platinum sensitivity status
Patient population Confirmed responders,
ORR (95% CI)
DoR (95% CI)
DoR, range (Min,
DoR >12 months
Pooled set (with measurable
97/273 36 (30, 42) 7.4 (5.79.1) 1.7, 20.0 31.3
Platinum sensitive
36/75 48 (36, 60) 7.8 (5.69.5) 1.8, 20.0 30.0
Platinum resistant 33/119 28 (20, 37) 7.4 (4.912.9) 1.8, 17.3 34.1
Platinum status unknown
28/79 35 (25, 47) 7.3 (5.69.5) 1.7, 16.6 29.1
12 prior chemotherapy
33/68 49 (36, 61) 7.4 (5.511.0) 1.7, 19.7 30.9
Platinum sensitive
14/22 64 (41, 83) 7.4 (4.7NC) 3.6, 19.7 23.7
Platinum resistant 5/10 50 (19, 81) 8.3 (3.9NC) 2.6, 14.7 25.0
Platinum status unknown
14/36 39 (23, 57) 6.8 (3.9NC) 1.7, 16.6 38.1
3 prior chemotherapy regimens 64/205 31 (25, 38) 7.8 (5.69.5) 1.8, 20.0 31.3
Platinum sensitive
22/53 42 (28, 56) 7.8 (5.613.5) 1.8, 20.0 33.0
Platinum resistant 28/109 26 (18, 35) 7.4 (4.912.9) 1.8, 17.3 36.6
Platinum status unknown
14/43 33 (19, 49) 7.3 (5.59.5) 3.7, 13.9 19.0
Includes censored observations.
Calculated using KaplanMeier methodology.
Platinum sensitive, but ineligible to receive further platinum-based chemotherapy.
Platinum status unknown relates to patients in whom the most recent therapy before olaparib was not platinum based.
DoR, duration of response; Max, maximum; Min, minimum; NC, not calculable; ORR, objective response rate.
Table 4. DoR by number of lines of prior chemotherapy
Prior lines of chemotherapy Confirmed responders, N(%) DoR (95% CI) (months) DoR, range (Min, Max)
DoR >12 months (%)
1 prior regimen 9/18 (50) 8.0 (5.5, NC) 3.7, 16.6 25.0
2 prior regimens 24/50 (48) 6.8 (3.9, NC) 1.7, 19.7 30.4
3 prior regimens 27/74 (36) 7.8 (5.6, NC) 1.8, 20.0 35.2
4 prior regimens 15/44 (34) 9.5 (6.7, 12.9) 4.1, 13.2 29.6
5 prior regimens 9/32 (28) 4.9 (3.7, 13.5) 2.9, 16.6 33.3
614 prior regimens 13/55 (24) 5.6 (5.3, NC) 3.7, 17.3 27.7
Includes censored observations.
Calculated using KaplanMeier methodology.
DoR, duration of response; Max, maximum; Min, minimum; NC, not calculable.
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This study reports the pooled data from six trials presented to
the US Food and Drug Administration (FDA) in support of
the accelerated approval for the capsule formulation of olaparib,
as the rst-in-class PARP inhibitor, which was granted on
19 December 2014. These pooled data demonstrate similar
benet with respect to ORR and DoR compared with patients
who have relapsed gBRCAm ovarian cancer and who have
received 3 lines of prior chemotherapy, which is the current
US label; ORR for this patient population was 31%, with
responses in both platinum-sensitive and platinum-resistant
cancer, and a DoR of 7.8 months.
However, when subgroups of patients are examined based on
the number of prior chemotherapy lines, a notable nding was
the inverse relationship between treatment lines and outcomes,
as measured by ORR and DoR. This was particularly notable for
patients who had received 4 prior lines (the ORR for patients
receiving four, ve and 6 prior lines was 34%, 28% and 24%,
respectively). DoR was similarly affected; patients who received
ve prior lines of previous treatment had a DoR of 4.9 months.
It is possible that the DoR might be driven by the development
of resistance, rather than simply reecting the number of lines
of prior chemotherapy received. In this retrospective analysis, it
is not possible to disentangle the extent by which multiple sub-
sequent lines of therapy have enriched for tumors that are more
responsive to anticancer therapy from the anticipated diminish-
ing returns on tumor response [6]. However, when considering
targeted therapies, such as olaparib, treatment in later lines of
relapse was still associated with the durable benet.
Platinum sensitivity is a known and important predictive
factor of response to treatment generally in ovarian cancer and,
in particular, appears to be an important but not universal pre-
dictor of response to PARP inhibitors. In earlier-line therapy,
the reported response rate to olaparib (400 mg b.i.d. capsules) in
gBRCAm patients with platinum-sensitive disease is 6063%
[13,15], which is double the reported response rate in patients
with gBRCAm platinum-resistant disease (33%) [13]. Our pooled
data showed similar ndings with ORR being higher in platinum-
sensitive compared with platinum-resistant patients; however, our
data examined only patients with a gBRCAm. In study 20, Gelmon
et al. reported on the use of olaparib in patients with HGSOC or
with triple-negative breast cancer who were either gBRCAwild
type (gBRCAwt) or who had an unknown BRCA mutation status;
both of these histologies are thought to harbor impaired homolo-
gous recombination repair (HRR) and, thus, exhibit a BRCA-like
phenotype, which may confer sensitivity to PARP inhibitors. In
(4/12; 33%) was much better than that observed in gBRCAwt plat-
inum-resistant patients without a gBRCAm (1/26; 4%), demon-
strating the importance of a gBRCAm for PARP inhibitor activity
regardless of platinum resistance status.
In this pooled analysis, there was a relatively large number of
patients with unknown platinum status. This is an increasingly
common problem with later-line therapy. We can use the classi-
cation of originally platinum sensitiveat rst recurrence,
which is applicable to approximately two thirds of patients, but
this does not reect the phenotype of the tumor as treatment is
started. If a platinum-resistant patient receives another nonplati-
num treatment, which may be effective for some time, and then
receives olaparib, it is unclear whether they should still be classi-
ed as platinum resistant, with a longer PFI. When platinum
sensitivity is dened strictly by both objective response (using
RECIST) and by no progression within the last 6 months, in
contrast to more loosely dened clinical or marker (CA-125)
criteria, many patients cannot be strictly categorized because, as
in this patient population, most patients do not have regular CT
A rapid improvement in correlative translational science will
determine predictive factors (in addition to using the presence
of a gBRCAm and/or a tumor BRCAm) for improved outcomes
using personalized therapies in patients with ovarian cancer.
Genomic scarring is one such BRCA-like signatureassay that
uses comprehensive genomic analysis (next-generation sequen-
cing) to identify genome-wide loss of heterozygosity as a marker
of HRR deciency in ovarian cancer patients and to prospective-
ly predict response to PARP inhibitors [16,17]. This may both
broaden the group of patients who benet from PARP inhibitors
and reduce our reliance on increasingly less-well-dened and
potentially misleading clinical classications like platinum sen-
sitivity. Indeed, acquired mutations in nuclear excision repair
genes may confer PARP insensitivity in the setting of platinum
resistance [18].
Olaparib has an acceptable and manageable safety prole in
patients who have received 3 lines of chemotherapy. In this
pooled analysis, the safety prole was very similar to previous
reports and AEs were generally low-grade nausea, vomiting and
fatigue; manageable without discontinuation of olaparib treat-
ment; and readily treated, empirically, by oncologists. The in-
creasing numbers of patients beyond study 42 who have been
treated with olaparib after multiple prior lines of myelotoxic
therapy addresses the concern about myelodysplastic syndrome
being an uncommon but serious side-effect and further quanti-
es the magnitude of risk. The incidence of AML in this analysis
Table 5. AEs (any grade) in >15% of patients or grade 3 AEs in
>5% of patients in either the pooled patient set or in patients
receiving 3 lines of prior chemotherapy
Adverse event, N(%) Pooled patient set
(N= 300)
Patients receiving 3
lines of prior
(N= 223)
All grades Grade 3 All grades Grade 3
Any 294 (98) 150 (50) 220 (99) 120 (54)
Nausea 196 (65) 7 (2) 142 (64) 6 (3)
Fatigue 184 (61) 20 (7) 130 (58) 15 (7)
Vomiting 116 (39) 10 (3) 95 (43) 8 (4)
Diarrhea 90 (30) 4 (1) 69 (31) 2 (1)
Anemia 85 (28) 43 (14) 66 (30) 33 (15)
Abdominal pain 79 (26) 16 (5) 57 (26) 15 (7)
Decreased appetite 65 (22) 2 (1) 50 (22) 2 (1)
Dyspepsia 58 (19) 0 44 (20) 0
Dysgeusia 53 (18) 0 35 (16) 0
Headache 53 (18) 0 33 (15) 0
Constipation 47 (16) 3 (1) 36 (16) 3 (1)
Cough 44 (15) 0 35 (16) 0
 | Matulonis et al. Volume 27 | No. 6 | June 2016
original articles Annals of Oncology
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(<1%) does not appear to exceed the background risk caused
by prior treatment with platinum-based chemotherapy and
anthracyclines [19].
This study pools data from six olaparib studies, so the hetero-
geneity between studies could introduce bias. However, the
study protocols were generally similar, used common eligibility
criteria and did not allow signicant deviations.
The FDA approval of olaparib addressed an unmet medical
need based on a surrogate measure (tumor response) for survival.
SOLO3 (NCT02282020) is a prospective open-label trial, using
physicians choice single-agent chemotherapy as the control,
which aims to conrm the observed clinical benet of olaparib in
a patient population similar to that reported here. This ongoing
phase III trial uses the oral tablet formulation of olaparib, so is
also designed to serve as a registration trial for this formulation.
The six trials involved in this analysis were sponsored by
AstraZeneca. We thank Ben Clarke, from Mudskipper Business
Ltd, who provided medical writing assistance funded by
This work was supported by AstraZeneca. No grants were
UAM has consulted for AstraZeneca. RLC has research funding
from AstraZeneca and Clovis Oncology and is supported by the
Ann Rife Cox Chair in Gynecology. JDR is a former employee
of AstraZeneca and owns stock in AstraZeneca. HM and TWH
are employees of AstraZeneca and own stock in AstraZeneca.
All remaining authors have no conicts of interest.
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Volume 27 | No. 6 | June 2016 doi:10.1093/annonc/mdw133 | 
Annals of Oncology original articles
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... H omologous recombination (HR) deficiency confers exquisite sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), which have been therapeutically exploited in both ovarian and breast tumors carrying loss-of-function mutations in HR pathway genes, most commonly BRCA1 and BRCA2 1 . Based on a substantial progressionfree survival (PFS) benefit, three PARPi have gained FDA approval for BRCA-mutated ovarian cancer in both adjuvant and metastatic settings [2][3][4][5] . Moreover, maintenance treatment with olaparib was shown to confer unprecedented overall survival benefit for patients with BRCA-mutated relapsed ovarian cancer 6 . ...
Full-text available
PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer. PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism.
... PARP inhibitors have demonstrated remarkable clinical results recently in phase I/II trials. In particular, BRCA1 and BRCA2 linked platinum-resistant patients with ovarian cancer treated with olaparib [73]. Other PARP inhibitors, such as veliparib, niraparib, and rucaparib, have also been evaluated in patients with platinum-resistant ovarian cancer, with overall response rates (ORRs) ranging from 20% to 27% in patients with mBRCA [74][75][76]. ...
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Ovarian cancer is the fifth leading cause of cancer deaths in women and is regarded as one of the most difficult cancers to treat. Currently, studies are being conducted to develop therapeutic agents for effective treatment of ovarian cancer. In this review, we explain the properties of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-MET) and how the signaling pathway of HGF/c-MET is activated in different cancers and involved in tumorigenesis and metastasis of ovarian cancer. We present the findings of clinical studies using small chemicals or antibodies targeting HGF/c-MET signaling in various cancer types, particularly in ovarian cancer. We also discuss that HGF/c-MET-targeted therapy, when combined with chemo drugs, could be an effective strategy for ovarian cancer therapeutics.
... This phase 2 trial evaluates the efficacy of olaparib in 299 patients with advanced breast, ovarian, prostate, and pancreatic cancers harboring BRCA1 and/or BRCA2 mutations. The results in gBRCAm ovary cancer patients show notable antitumor activity and durable responses [121,143]. ...
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Deficiency in DNA damage response (DDR) genes leads to impaired DNA repair functions that will induce genomic instability and facilitate cancer development. However, alterations of DDR genes can serve as biomarkers for the selection of suitable patients to receive specific therapeutics, such as immune checkpoint blockade (ICB) therapy. In addition, certain altered DDR genes can be ideal therapeutic targets through adapting the mechanism of synthetic lethality. Recent studies indicate that targeting DDR can improve cancer immunotherapy by modulating the immune response mediated by cGAS-STING-interferon signaling. Investigations of the interplay of DDR-targeting and ICB therapies provide more effective treatment options for cancer patients. This review introduces the mechanisms of DDR and discusses their crucial roles in cancer therapy based on the concepts of synthetic lethality and ICB. The contemporary clinical trials of DDR-targeting and ICB therapies in breast, colorectal, and pancreatic cancers are included.
... BRCA1/2 deficiency remains the strongest predictor of PARPi sensitivity [35] although abrogation of other key HR genes including FA Complementation Group A (FANCA) [36], DNA Repair Protein RAD51 homolog 1 (RAD51) [37], X-ray Repair Cross Complementing 2 (XRCC2) and X-ray Repair Cross Complementing 3 (XRCC3) [38] and DNA Polymerase Delta 4 (POLD4) [39] have been linked to platinum and/or PARPi responses. Furthermore, not all BRCA mutant tumours are HR deficient and many HR-proficient tumours can initially respond well to PARPi [40][41][42][43][44] which has been attributed to the involvement of PARP in other non-DDR associated mechanisms including chromatin remodelling [45]. Unfortunately, as with platinum-based chemotherapy, primary and acquired resistance to PARPi is common [35,40,46,47]. ...
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Epigenetic therapies describe drug molecules such as DNA methyltransferase, histone methyltransferase and histone acetylase/deacetylase inhibitors, which target epigenetic mechanisms such as DNA methylation and histone modifications. Many DNA damage response (DDR) genes are epigenetically regulated in cancer leading to transcriptional silencing and the loss of DNA repair capacity. Epigenetic marks at DDR genes, such as DNA methylation at gene promoters, have the potential to be used as stratification biomarkers, identifying which patients may benefit from particular chemotherapy treatments. For genes such as MGMT and BRCA1, promoter DNA methylation is associated with chemosensitivity to alkylating agents and platinum coordination complexes, respectively, and they have use as biomarkers directing patient treatment options. In contrast to epigenetic change leading to chemosensitivity, DNA methylation of DDR genes involved in engaging cell death responses, such as MLH1, are associated with chemoresistance. This contrasting functional effect of epigenetic modification on chemosensitivity raises challenges in using DNA-demethylating agents, and other epigenetic approaches, to sensitise tumours to DNA-damaging chemotherapies and molecularly targeted agents. Demethylation of MGMT/BRCA1 could lead to drug resistance whereas demethylation of MLH1 could sensitise cells to chemotherapy. Patient selection based on a solid understanding of the disease pathway will be one means to tackle these challenges. The role of epigenetic modification of DDR genes during tumour development, such as causing a mutator phenotype, has different selective pressures and outcomes compared to epigenetic adaptation during treatment. The prevention of epigenetic adaptation during the acquisition of drug resistance will be a potential strategy to improve the treatment of patients using epigenetic therapies.
... Olaparib, formerly referred to as AZD2281 or KU0059436, was the first PARPi introduced into clinical practice, which was initially approved as a maintenance therapy in platinum-sensitive relapsed ovarian cancer [26] and later approved for treatment of BRCA-mutated (HR-deficiency) breast and ovarian cancers [27][28][29]. Recently, several studies indicated that a combination of Olaparib with CDK4/6i displayed therapeutic synergy in MYC highly expressed breast and ovarian cancers with HR proficiency [22,23], which represents a new treatment paradigm in these cancers beyond HR-deficiency. ...
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In recent years, three PARP inhibitors and three CDK4/6 inhibitors have been approved by the FDA for the treatment of recurrent ovarian cancer and advanced ER-positive breast cancer, respectively. However, the clinical benefits of the PARPi or CDK4/6i monotherapy are not as satisfied as expected and benefit only a fraction of patients. Current studies have shown therapeutic synergy for combinations of PARPi and CDK4/6i in breast and ovarian cancers with homologous recombination (HR) proficiency, which represents a new synthetic lethal strategy for treatment of these cancers regardless HR status. Thus, any compounds or strategies that can combine PARP and CDK4/6 inhibition will likely have great potential in improving clinic outcomes and in benefiting more patients. In this study, we developed a novel compound, ZC-22, that effectively inhibited both PARP and CDK4/6. This dual-targeting compound significantly inhibited breast and ovarian cancer cells by inducing cell cycle arrest and severe DNA damage both in vitro and in vivo. Interestingly, the efficacy of ZC-22 is even higher than the combination of PARPi Olaparib and CDK4/6i Abemaciclib in most breast and ovarian cancer cells, suggesting that it may be an effective alternative for the PARPi and CDK4/6i combination therapy. Moreover, ZC-22 sensitized breast and ovarian cancer cells to cisplatin treatment, a widely used chemotherapeutic agent. Altogether, our study has demonstrated the potency of a novel CDK4/6 and PARP dual inhibitor, which can potentially be developed into a monotherapy or combinatorial therapy with cisplatin for breast and ovarian cancer patients with HR proficiency.
... Currently, the PARP inhibitors which have established clinical application are olaparib, rucaparib, niraparib and talazoparib (Table 1). Olaparib is used in ovarian cancer, BRCA-mutant breast cancer, BRCA-mutant pancreatic cancer and HRD-deficient prostate cancer [13][14][15][16][17][18][19][20][21][22][23]. Rucaparib is used in ovarian cancer and BRCA-mutant prostate cancer [24][25][26][27][28], and there are promising data for BRCA-mutant pancreatic cancer [29]. ...
Full-text available
Gliomas are the most common malignant primary brain tumor in adults. Despite advances in multimodality therapy, incorporating surgery, radiotherapy, systemic therapy, tumor treating fields and supportive care, patient outcomes remain poor, especially in glioblastoma where median survival has remained static at around 15 months, for decades. Low-grade gliomas typically harbor isocitrate dehydrogenase (IDH) mutations, grow more slowly and confer a better prognosis than glioblastoma. However, nearly all gliomas eventually recur and progress in a way similar to glioblastoma. One of the novel therapies being developed in this area are poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors belong to a class of drugs that target DNA damage repair pathways. This leads to synthetic lethality of cancer cells with coexisting homologous recombination deficiency. PARP inhibitors may also potentiate the cytotoxic effects of radiotherapy and chemotherapy, and prime the tumor microenvironment for immunotherapy. In this review, we examine the rationale and clinical evidence for PARP inhibitors in glioma and suggest therapeutic opportunities.
Yamin Shu,1 Xucheng He,2 Yanxin Liu,3 Pan Wu,4 Qilin Zhang5 1Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pharmacy, Pengzhou Second People’s Hospital, Pengzhou, People’s Republic of China; 3Department of Pharmacy, Pengzhou People’s Hospital, Pengzhou, People’s Republic of China; 4Department of Pharmacy, Qionglai Maternal & Child Health and Family Planning Service Center, Qionglai, People’s Republic of China; 5Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Qilin Zhang, Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, People’s Republic of China, Tel +86-02785726073, Email qilinzhang88@163.comBackground: Olaparib, the world’s first poly ADP-ribose polymerase (PARP) inhibitor (PARPi), has been approved for treatment of ovarian cancer, breast cancer, pancreatic cancer and prostate cancer by FDA. The current study was to assess olaparib-related adverse events (AEs) of real-world through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS).Methods: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS) algorithms were employed to quantify the signals of olaparib-associated AEs.Results: Out of 8,450,009 reports collected from the FAERS database, 6402 reports of olaparib-associated AEs were identified. A total of 118 significant disproportionality preferred terms (PTs) conforming to the four algorithms simultaneously were retained. The most common AEs included anemia, thrombocytopenia, nausea, decreased appetite, blood creatinine increased and dermatomyositis, which were corresponding to those reported in the specification and clinical trials. Unexpected significant AEs as interstitial lung disease, Pneumocystis jirovecii pneumonia, folate deficiency, renal impairment and intestinal obstruction might also occur. The median onset time of olaparib-related AEs was 61 days (interquartile range [IQR] 14– 182 days), and most of the cases occurred within the first 1 month after olaparib initiation.Conclusion: Results of our study were consistent with clinical observations, and we also found potential new and unexpected AEs signals for olaparib, suggesting prospective clinical studies were needed to confirm these results and illustrate their relationship. Our results could provide valuable evidence for further safety studies of olaparib.Keywords: olaparib, PARP inhibitor, pharmacovigilance, data mining, FAERS
Full-text available
Background: Inhibitors of poly(ADP-ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel. Methods: We conducted a phase I study of talazoparib with carboplatin AUC5-6 and paclitaxel 80 mg/m2 days 1, 8, 15 of 21-day cycles in patients with advanced solid tumors. Patients enrolled using a 3 + 3 design in two cohorts with talazoparib for 7 (schedule A) or 3 days (schedule B). After induction with 4-6 cycles of triplet therapy, patients received one of three maintenance options: (a) continuation of triplet (b) carboplatin/talazoparib, or (c) talazoparib monotherapy. Results: Forty-three patients were treated. The MTD for both schedules was talazoparib 250mcg daily. The main toxicity was myelosuppression including grade 3/4 hematologic treatment-related adverse events (TRAEs). Dose modification occurred in 87% and 100% of patients for schedules A and B, respectively. Discontinuation due to TRAEs was 13% in schedule A and 10% in B. Ten out of 22 evaluable patients in schedule A and 5/16 patients in schedule B had a complete or partial response. Twelve out of 43 patients received ≥6 cycles of talazoparib after induction, with a 13-month median duration of maintenance. Conclusion: We have established the recommended phase II dose of Talazoparib at 250mcg on a 3- or 7-day schedule with carboplatin AUC6 and paclitaxel 80 mg/m2 on days 1, 8, 15 of 21-day cycles. This regimen is associated with significant myelosuppression, and in addition to maximizing supportive care, modification of the chemotherapy component would be a consideration for further development of this combination with the schedules investigated in this study.
High-grade serous ovarian cancer is the deadliest gynecologic malignancy due to progression to resistant disease. Claudin-4 is classically defined as a tight junction protein and is often associated with epithelial cancers. Claudin-4 is aberrantly expressed in nearly 70% of all ovarian cancer tumors and conveys a worse overall prognosis. Elevated claudin-4 expression correlates to increased DNA repair activity and resistance to DNA damaging agents. PARP inhibitors are emerging as an effective therapeutic option for patients with ovarian cancer and function by promoting DNA damage. The study examines the relationship between claudin-4 expression and the response to PARP inhibitors using both genetic and pharmacologic inhibition of claudin-4 in in vitro and ex vivo models of ovarian cancer to examine DNA repair markers and functional activity. Genetic inhibition of claudin-4 results in the downregulation of several DNA damage repair effectors, including 53BP1 and XRCC1. Claudin-4 knockdown did not change homology-directed repair but inhibited nonhomologous end-joining and reduced 53BP1 foci formation. In 15 primary ovarian cancer tumors, higher claudin-4 expression significantly correlated to a dampened PARP inhibitor-mediated antiproliferation response. Further, claudin-4 inhibition in high claudin-4 tumors sensitized tumor sections to PARP inhibition. These data highlight that claudin-4 expression in ovarian cancer tumors could serve as both a marker of PARP inhibitor response and a therapeutic target to improve PARP inhibitor response.
Full-text available
Background: Ovarian cancer is the sixth most common cancer in women world-wide. Epithelial ovarian cancer (EOC) is the most common; three-quarters of women present when disease has spread outside the pelvis (stage III or IV). Treatment consists of a combination of surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women with advanced disease will relapse. PARP (poly (ADP-ribose) polymerase) inhibitors (PARPi), are a type of anticancer treatment that works by preventing cancer cells from repairing DNA damage, especially in those with breast cancer susceptibility gene (BRCA) variants. PARPi offer a different mechanism of anticancer treatment from conventional chemotherapy. Objectives: To determine the benefits and risks of poly (ADP-ribose) polymerase) inhibitors (PARPi) for the treatment of epithelial ovarian cancer (EOC). Search methods: We identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (Central 2020, Issue 10), Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to October 2020), Embase (1990 to October 2020), ongoing trials on,,, the National Research Register (NRR), FDA database and pharmaceutical industry biomedical literature. Selection criteria: We included trials that randomised women with EOC to PARPi with no treatment, or PARPi versus conventional chemotherapy, or PARPi together with conventional chemotherapy versus conventional chemotherapy alone. Data collection and analysis: We used standard Cochrane methodology. Two review authors independently assessed whether studies met the inclusion criteria. We contacted investigators for additional data. Outcomes included overall survival (OS), objective response rate (ORR), quality of life (QoL) and rate of adverse events. Main results: We included 15 studies (6109 participants); four (3070 participants) with newly-diagnosed, advanced EOC and 11 (3039 participants) with recurrent EOC. The studies varied in types of comparisons and evaluated PARPi. Eight studies were judged as at low risk of bias in most of the domains. Quality of life data were generally poorly reported. Below we present six key comparisons. The majority of participants had BRCA mutations, either in their tumour (sBRCAmut) and/or germline (gBRCAmut), or homologous recombination deficiencies (HRD) in their tumours. Newly diagnosed EOC Overall, four studies evaluated the effect of PARPi in newly-diagnosed, advanced EOC. Two compared PARPi with chemotherapy and chemotherapy alone. OS data were not reported. The combination of PARPi with chemotherapy may have little to no difference in progression-free survival (PFS) (two studies, 1564 participants; hazard ratio (HR) 0.82, 95% confidence interval (CI 0).49 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months' 63% with PARPi versus 69% for placebo). PARPi with chemotherapy likely increases any severe adverse event (SevAE) (grade 3 or higher) slightly (45%) compared with chemotherapy alone (51%) (two studies, 1549 participants, risk ratio (RR) 1.13, 95% CI 1.07 to 1.20; high-certainty evidence). PARPi combined with chemotherapy compared with chemotherapy alone likely results in little to no difference in the QoL (one study; 744 participants, MD 1.56 95% CI -0.42 to 3.54; moderate-certainty evidence). Two studies compared PARPi monotherapy with placebo as maintenance after first-line chemotherapy in newly diagnosed EOC. PARPi probably results in little to no difference in OS (two studies, 1124 participants; HR 0.81, 95%CI 0.59 to 1.13; moderate-certainty evidence) (alive at 12 months 68% with PARPi versus 62% for placebo). However, PARPi may increase PFS (two studies, 1124 participants; HR 0.42, 95% CI 0.19 to 0.92; low-certainty evidence) (no evidence of disease progression at 12 months' 55% with PARPi versus 24% for placebo). There may be an increase in the risk of experiencing any SevAE (grade 3 or higher) with PARPi (54%) compared with placebo (19%)(two studies, 1118 participants, RR 2.87, 95% CI 1.65 to 4.99; very low-certainty evidence), but the evidence is very uncertain. There is probably a slight reduction in QoL with PARPi, although this may not be clinically significant (one study, 362 participants; MD -3.00, 95%CI -4.48 to -1.52; moderate-certainty evidence). Recurrent, platinum-sensitive EOC Overall, 10 studies evaluated the effect of PARPi in recurrent platinum-sensitive EOC. Three studies compared PARPi monotherapy with chemotherapy alone. PARPi may result in little to no difference in OS (two studies, 331 participants; HR 0.95, 95%CI 0.62 to 1.47; low-certainty evidence) (percentage alive at 36 months 18% with PARPi versus 17% for placebo). Evidence is very uncertain about the effect of PARPi on PFS (three studies, 739 participants; HR 0.88, 95%CI 0.56 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months 26% with PARPi versus 22% for placebo). There may be little to no difference in rates of any SevAE (grade 3 or higher) with PARPi (50%) than chemotherapy alone (47%) (one study, 254 participants; RR 1.06, 95%CI 0.80 to 1.39; low-certainty evidence). Four studies compared PARPi monotherapy as maintenance with placebo. PARPi may result in little to no difference in OS (two studies, 560 participants; HR 0.88, 95%CI 0.65 to 1.20; moderate-certainty evidence)(percentage alive at 36 months 21% with PARPi versus 17% for placebo). However, evidence suggests that PARPi as maintenance therapy results in a large PFS (four studies, 1677 participants; HR 0.34, 95% CI 0.28 to 0.42; high-certainty evidence)(no evidence of disease progression at 12 months 37% with PARPi versus 5.5% for placebo). PARPi maintenance therapy may result in a large increase in any SevAE (51%) (grade 3 or higher) than placebo (19%)(four studies, 1665 participants, RR 2.62, 95%CI 1.85 to 3.72; low-certainty evidence). PARPi compared with chemotherapy may result in little or no change in QoL (one study, 229 participants, MD 1.20, 95%CI -1.75 to 4.16; low-certainty evidence). Recurrent, platinum-resistant EOC Two studies compared PARPi with chemotherapy. The certainty of evidence in both studies was graded as very low. Overall, there was minimal information on the QoL and adverse events. Authors' conclusions: PARPi maintenance treatment after chemotherapy may improve PFS in women with newly-diagnosed and recurrent platinum-sensitive EOC; there may be little to no effect on OS, although OS data are immature. Overall, this is likely at the expense of an increase in SevAE. It is disappointing that data on quality of life outcomes are relatively sparse. More research is needed to determine whether PARPi have a role to play in platinum-resistant disease.
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Platinum and PARP inhibitor (PARPi) sensitivity commonly coexist in epithelial ovarian cancer (EOC) due to the high prevalence of alterations in the homologous recombination (HR) DNA repair pathway that confer sensitivity to both drugs. In this report, we describe a unique subset of EOC with alterations in another DNA repair pathway, the nucleotide excision repair (NER) pathway, which may exhibit a discordance in sensitivities to these drugs. Specifically, 8% of high-grade serous EOC from The Cancer Genome Atlas dataset exhibited NER alterations, including nonsynonymous or splice site mutations and homozygous deletions of NER genes. Tumors with NER alterations were associated with improved overall survival (OS) and progression-free survival (PFS), compared with patients without NER alterations or BRCA1/2 mutations. Furthermore, patients with tumors with NER alterations had similar OS and PFS as BRCA1/2-mutated patients, suggesting that NER pathway inactivation in EOC conferred enhanced platinum sensitivity, similar to BRCA1/2-mutated tumors. Moreover, two NER mutations (ERCC6-Q524* and ERCC4-A583T), identified in the two most platinum-sensitive tumors, were functionally associated with platinum sensitivity in vitro. Importantly, neither NER alteration affected HR or conferred sensitivity to PARPi or other double-strand break-inducing agents. Overall, our findings reveal a new mechanism of platinum sensitivity in EOC that, unlike defective HR, may lead to a discordance in sensitivity to platinum and PARPi, with potential implications for previously reported and ongoing PARPi trials in this disease. Cancer Res; 75(4); 1-7. ©2014 AACR. ©2014 American Association for Cancer Research.
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Purpose: Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) -associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers. Patients and methods: This multicenter phase II study enrolled individuals with a germline BRCA1/2 mutation and recurrent cancer. Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ≥ three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. Olaparib was administered at 400 mg twice per day. The primary efficacy end point was tumor response rate. Results: A total of 298 patients received treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ≥ 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. The most common adverse events (AEs) were fatigue, nausea, and vomiting. Grade ≥ 3 AEs were reported for 54% of patients; anemia was the most common (17%). Conclusion: Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations. Olaparib warrants further investigation in confirmatory studies.
Previous studies have shown that vascular endothelial growth factor (VEGF) promotes progression in epithelial ovarian cancer and that blockade of VEGF inhibits growth of this tumor and metastasis. Bevacizumab is a humanized anti-VEGF monoclonal antibody that has single-agent activity in women with recurrent ovarian tumors. This multinational double-blind placebo-controlled trial was designed to evaluate the addition of bevacizumab to standard front-line ovarian cancer therapy in patients with stage III or IV epithelial ovarian cancer. All eligible patients with previously untreated incompletely resectable stage III or any stage IV epithelial ovarian cancer after maximal debulking surgery were randomized to 1 of 3 groups (control, bevacizumab-initiation treatment, and bevacizumab-throughout treatment). Each of the 3 regimens was composed of 22 three-week cycles, with intravenous infusions during first 6 cycles of both carboplatin at an area under the curve of 6 and paclitaxel at a dose of 175 mg/m2 of body-surface area (carboplatin and paclitaxel (CP) therapy). The control group received CP therapy with placebo added in cycles 2 through 22; bevacizumab-initiation group received CP therapy with addition of bevacizumab (15 mg/kg body weight) in cycles 2 through 6 and placebo in cycles 7 through 22; and the bevacizumab-throughout group received CP therapy with addition of bevacizumab (15 mg/kg body weight) in cycles 2 through 22. Progression-free survival according to treatment group was the primary study end point. A total of 1873 women were enrolled from 336 institutions in 4 countries. Analysis of progression-free survival showed mean survival of 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group. Compared with the control group, there was a lower, but statistically nonsignificant, decrease in the hazard of progression or death in the bevacizumab-initiation group (hazard ratio, 0.908; 95% confidence interval, 0.795–1.040; P = 0.16). In contrast, the hazard was significantly lower in the bevacizumab-throughout group (hazard ratio, 0.717; 95% confidence interval, 0.625–0.824; P < 0.001). At the time of the primary analysis, 76.3% of patients were alive, with no significant differences in overall survival between groups. Hypertension of grade 2 or higher that required medical intervention was significantly more common in the bevacizumab-initiation group (16.5%) and the bevacizumab-throughout group (22.9%) compared with the control group (7.2%) (P < 0.05 for both comparisons). Gastrointestinal wall disruption requiring medical therapy occurred in 2.8% of patients in the bevacizumab-initiation group, 2.6% in the bevacizumab-throughout group, and 1.2% of patients in the control group. These findings show that addition of bevacizumab during and up to 10 months after CP therapy prolongs the median progression-free survival by 4 months in patients with advanced ovarian cancer.
An improved understanding of the genomics of ovarian cancer and the separation of ovarian cancer into histologically and molecularly defined subgroups have affected drug development and clinical trial design in ovarian cancer. Active therapies that have been tested in ovarian cancer include agents that inhibit angiogenesis and poly (ADP-ribose) polymerase inhibitors (PARPi). However, no FDA drug approvals for ovarian cancer have been granted since 2006, and overall survival improvements have been difficult to achieve with new agents. The genomic complexity of ovarian cancer and modest single-agent activity of many biologic agents in this disease have led to testing of biologic agent combinations. In this article, we review recent advances in the understanding of the molecular diversity of ovarian cancer as well as emerging therapeutic strategies such as new agents and biologic combinations that attempt to target multiple aberrant pathways in this cancer. Clin Cancer Res; 20(20); 5150-6. ©2014 AACR.
Background: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. Methods: In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with, number NCT01116648. Findings: Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). Interpretation: Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. Funding: American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.