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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: ClinicalTrials.gov, NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662.
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4. Monk BJ, Poveda A, Vergote I et al. Anti-angiopoietin therapy with trebananib for
recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind,
placebo-controlled phase 3 trial. Lancet Oncol 2014; 15: 799808.
5. Kumar S, Mahdi H, Bryant C et al. Clinical trials and progress with paclitaxel in
ovarian cancer. Int J Womens Health 2010; 2: 411427.
6. NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer V.2.2014. Fort
Washington, PA: National Comprehensive Cancer Network 2014.
7. Coleman RL, Monk BJ, Sood AK, Herzog TJ. Latest research and treatment of
advanced-stage epithelial ovarian cancer. Nat Rev Clin Oncol 2013; 10: 211224.
8. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:
228247.
9. Cella DF, Tulsky DS, Gray G et al. The Functional Assessment of Cancer Therapy
scale: development and validation of the general measure. J Clin Oncol 1993; 11:
570579.
10. Basen-Engquist K, Bodurka-Bevers D, Fitzgerald MA et al. Reliability and validity of
the functional assessment of cancer therapy-ovarian. J Clin Oncol 2001; 19:
18091817.
11. Brooks R. EuroQol: the current state of play. Health Policy 1996; 37: 5372.
12. Michiels B, Molenberghs G, Bijnens L et al. Selection models and pattern-mixture
models to analyse longitudinal quality of life data subject to drop-out. Stat Med
2002; 21: 10231041.
13. Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in
EQ-5D utility and VAS scores in cancer. Health Qual Life Outcomes 2007; 5: 70.
14. Monk BJ, Minion L, Lambrechts S et al. Incidence and management of edema
associated with trebananib (AMG 386). Gynecol Oncol 2013; 130: 636641.
15. Stockler MR, Hilpert F, Friedlander M et al. Patient-reported outcome results
from the open-label phase III AURELIA trial evaluating bevacizumab-containing
therapy for platinum-resistant ovarian cancer. J Clin Oncol 2014; 32:
13091316.
16. Pujade-Lauraine E, Hilpert F, Weber B et al. Bevacizumab combined with
chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-
label randomized phase III trial. J Clin Oncol 2014; 32: 13021308.
17. Burger RA, Brady MF, Bookman MA et al. Incorporation of bevacizumab in the
primary treatment of ovarian cancer. N Engl J Med 2011; 365: 24732483.
18. Monk BJ, Dalton H, Farley JH et al. Antiangiogenic agents as a maintenance
strategy for advanced epithelial ovarian cancer. Crit Rev Oncol Hematol 2013; 86:
161175.
19. Perren TJ, Swart AM, Psterer J et al. A phase 3 trial of bevacizumab in ovarian
cancer. N Engl J Med 2011; 365: 24842496.
20. Stark D, Nankivell M, Pujade-Lauraine E et al. Standard chemotherapy with or
without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from
the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised
trial. Lancet Oncol 2013; 14: 236243.
Annals of Oncology 27: 10131019, 2016
doi:10.1093/annonc/mdw133
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
1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston;
2
Department of Hematology/Oncology, Massachusetts General Hospital, Boston;
3
Department
of Medicine, Basser Research Center and Abramson Cancer Center, Philadelphia, USA;
4
Division of Oncology, Sheba Medical Center, Tel HaShomer, Israel;
5
Division of
Medical Oncology, Cedars-Sinai Medical Center, Los Angeles, USA;
6
Drug Development Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton, UK;
7
Department of Medical Oncology, BC Cancer Agency, Vancouver, Canada;
8
Global Medicines Development, AstraZeneca, Maccleseld, UK;
9
Global Medicines
Development, AstraZeneca, Wilmington;
10
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
chemotherapy.
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: ursula_matulonis@dfci.harvard.edu
Annals of Oncology original articles
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com.
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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.
ClinicalTrials.gov: NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662.
Key words: olaparib, monotherapy, ovarian cancer, BRCA1/2 mutation, pooled analysis
introduction
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.
methods
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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original articles Annals of Oncology
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Table 1. Summary of studies and patients included in the pooled analysis [814]
Study Design Efficacy end
point
Patients,
N
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
D0810C00002
(study 2;
NCT00516373)
First-in-human study with efficacy expansion
(200 mg b.i.d.)
Response rate 58
a
5
b
43
D0810C00024
(study 24;
NCT00777582)
Formulation comparison (capsule and tablet):
crossover study with efficacy expansion
Tumor shrinkage 77
a
20
b,c
20 11
Phase II olaparib monotherapy studies
D0810C00009
(study 9;
NCT00494442)
Noncomparative, proof-of-concept trial (200 mg
b.i.d., 400 mg b.i.d.)
Response rate 58 33
b
33 26
D0810C00012
(study 12;
NCT00628251)
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
d
32 16
D0810C00020
(study 20;
NCT00679783)
Open-label, nonrandomized trial (400 mg b.i.d.) Response rate 91
e
17
b
17 12
D0810C00042
(study 42;
NCT01078662)
Open-label, nonrandomized trial (400 mg b.i.d.) Response rate 317 193
b
167 137
Total 300 273 205
a
Patients from efficacy expansion only.
b
Local germline testing.
c
Capsule-dosed patients only.
d
Local germline testing and/or retrospective Myriad BRACAnalysis® testing.
e
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.
results
patients
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).
efcacy
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).
safety
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
Parameters
a
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)
Primary
peritoneal
5 (1.8) 2 (1.0)
Missing 1 (0.4) 1 (0.5)
a
All values represent n(%) unless stated otherwise.
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100
90
80
70
60
50
ORR, %
40
30
20
10
0
1
(n= 18)
2
(n= 50)
3
(n= 74)
Previous lines of chemotherapy received
4
(n= 44)
5
(n= 32)
Total (n= 273)
Sensitive (n= 75)
Resistant (n= 119)
6–14
(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,
N
ORR (95% CI)
(%)
DoR (95% CI)
(months)
DoR, range (Min,
Max)
a
DoR >12 months
(%)
b
Pooled set (with measurable
disease)
97/273 36 (30, 42) 7.4 (5.79.1) 1.7, 20.0 31.3
Platinum sensitive
c
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
d
28/79 35 (25, 47) 7.3 (5.69.5) 1.7, 16.6 29.1
12 prior chemotherapy
regimens
33/68 49 (36, 61) 7.4 (5.511.0) 1.7, 19.7 30.9
Platinum sensitive
c
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
d
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
c
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
d
14/43 33 (19, 49) 7.3 (5.59.5) 3.7, 13.9 19.0
a
Includes censored observations.
b
Calculated using KaplanMeier methodology.
c
Platinum sensitive, but ineligible to receive further platinum-based chemotherapy.
d
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)
a
DoR >12 months (%)
b
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
a
Includes censored observations.
b
Calculated using KaplanMeier methodology.
DoR, duration of response; Max, maximum; Min, minimum; NC, not calculable.
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discussion
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
study20,theresponserateinplatinum-resistantgBRCAmpatients
(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
scans.
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
chemotherapy
(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.
acknowledgements
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
AstraZeneca.
funding
This work was supported by AstraZeneca. No grants were
received.
disclosure
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.
references
1. GLOBOCAN statistics. 2012. http://globocan.iarc.fr/Pages/fact_sheets_population.
aspx (21 March 2016, date last accessed).
2. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;
64: 929.
3. Khalique S, Hook JM, Ledermann JA. Maintenance therapy in ovarian cancer. Curr
Opin Oncol 2014; 26: 521528.
4. Liu J, Matulonis UA. New strategies in ovarian cancer: translating the molecular
complexity of ovarian cancer into treatment advances. Clin Cancer Res 2014; 20:
51505156.
5. Hennessy BT, Coleman RL, Markman M. Ovarian cancer. Lancet 2009; 374:
13711382.
6. Hanker LC, Loibl S, Burchardi N et al. The impact of second to sixth line therapy
on survival of relapsed ovarian cancer after primary taxane/platinum-based
therapy. Ann Oncol 2012; 23: 26052612.
7. McWhinney SR, Goldberg RM, McLeod HL. Platinum neurotoxicity pharmacogenetics.
Mol Cancer Ther 2009; 8: 1016.
8. Audeh MW, Carmichael J, Penson RT et al. Oral poly(ADP-ribose) polymerase
inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent
ovarian cancer: a proof-of-concept trial. Lancet 2010; 376: 245251.
9. Kaye SB, Lubinski J, Matulonis U et al. Phase II, open-label, randomized,
multicenter study comparing the efcacy and safety of olaparib, a poly (ADP-
ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with
BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 2012; 30:
372379.
10. Fong PC, Boss DS, Yap TA et al. Inhibition of poly(ADP-ribose) polymerase in
tumors from BRCA mutation carriers. N Engl J Med 2009; 361: 123134.
11. Fong PC, Yap TA, Boss DS et al. Poly(ADP)-ribose polymerase inhibition: frequent
durable responses in BRCA carrier ovarian cancer correlating with platinum-free
interval. J Clin Oncol 2010; 28: 25122519.
12. Mateo J, Friedlander M, Sessa C et al. Administration of continuous/intermittent
olaparib in ovarian cancer patients with a germline BRCA1/2 mutation to
determine an optimal dosing schedule for the tablet formulation. Eur J Cancer
2013; 49(2 suppl): abstr 801.
13. Gelmon KA, Tischkowitz M, Mackay H et al. Olaparib in patients with recurrent
high-grade serous or poorly differentiated ovarian carcinoma or triple-negative
breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet
Oncol 2011; 12: 852861.
14. Kaufman B, Shapira-Frommer R, Schmutzler RK et al. Olaparib monotherapy in
patients with advanced cancer and a germ-line BRCA1/2 mutation. J Clin Oncol
2015; 33: 244250.
15. Liu JF, Barry WT, Birrer M et al. Combination cediranib and olaparib versus
olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a
randomised phase 2 study. Lancet Oncol 2014; 15: 12071214.
16. McNeish IA, Oza AM, Coleman RL et al. Results of ARIEL2: a phase 2 trial to
prospectively identify ovarian cancer patients likely to respond to rucaparib using
tumor genetic analysis. J Clin Oncol 2015; 33(18 suppl): abstr 5508.
17. Swisher E, Brenton J, Kaufmann S et al. Updated clinical and preliminary
correlative results of ARIEL2, a phase 2 study to identify ovarian cancer patients
likely to respond to rucaparib. Eur J Cancer 2014; 50(6 suppl): abstr 215.
18. Ceccaldi R, OConnor KW, Mouw KW et al. A unique subset of epithelial ovarian
cancers with platinum sensitivity and PARP inhibitor resistance. Cancer Res 2015;
75: 628634.
19. Philpot NJ, Elebute MO, Powles R et al. Platinum agents and secondary myeloid
leukaemia: two cases treated only with platinum-based drugs. Br J Haematol
1996; 93: 884887.
Volume 27 | No. 6 | June 2016 doi:10.1093/annonc/mdw133 | 
Annals of Oncology original articles
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... Inhibition of PARP blocks DNA repair in BRCA-mutated ovarian cancer cells, leading to apoptosis 8 . Olaparib and niraparib are FDA-approved PARP inhibitors mainly used to treat advanced ovarian cancer harboring BRCA mutations 9,10,11 . Although PARP inhibitors can partially extend PFS in patients with ovarian cancer, unfortunately, they do not extend OS 12 . ...
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