European Journal of Cancer 189 (2023) 112908

Available online at www.sciencedirect.com

j o u rn a l h o mep a ge : w ww.e j cance r .c om

Original Research

Progression-free survival and safety at 3.5 years of

follow-up: results from the randomised phase 3 ]]
]]]]]]
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PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib

maintenance treatment in patients with newly diagnosed
ovarian cancer
⁎
Antonio González-Martín a, , Bhavana Pothuri b, Ignace Vergote c,
Whitney Graybill d, Domenica Lorusso e, Colleen C. McCormick f,
Gilles Freyer g, Floor Backes h, Florian Heitz i,q, Andrés Redondo j,
Richard G. Moore k, Christof Vulsteke l,r, Roisin E. O’Cearbhaill m,
Izabela A. Malinowska n, Luda Shtessel n, Natalie Compton n,
Mansoor R. Mirza o, Bradley J. Monk p

a
Medical Oncology Department, Cancer Center Clínica Universidad de Navarra, Madrid, Program in Solid Tumours,
CIMA, Pamplona, and Grupo Español de Investigación en Cáncer de Ovario (GEICO), Madrid, Spain
b
Gynecologic Oncology Group (GOG Foundation), NYU Langone, Health, Department of Obstetrics & Gynecology,
Perlmutter Cancer Center, New York, NY, USA
c
Belgium and Luxembourg Gynaecological Oncology Group (BGOG), Department of Gynaecology and Obstetrics,
Division of Gynaecological Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium
d
GOG, Gynecologic Oncology, Medical University of South Carolina, Charleston, SC, USA
e
Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO), Fondazione Policlinico Gemelli
IRCCS and Catholic University of Sacred Heart, Rome, Italy
f
GOG, Legacy Medical Group Gynecologic Oncology, Portland, OR, USA
g
Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), HCL Cancer Institute Department of
Medical Oncology, Lyon University, Lyon, France
h
Division of Gynecologic Oncology, Ohio State University, Columbus, OH, USA
i
AGO Study Group and the Department for Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte, Essen,
Germany
j
GEICO, Department of Medical Oncology, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain
k
Division of Gynecologic Oncology, Wilmot Cancer Institute, Department of Obstetrics and Gynecology, University of
Rochester, Rochester, NY, USA
l
BGOG, Department of Medical Oncology and Hematology, AZ Maria Middelares, Gent, Belgium
m
GOG, Gynecologic Medical Oncology, Memorial Sloan Kettering Cancer Center, and Department of Medicine, Weill
Cornell Medical College, New York, NY, USA
n
GSK, Middlesex, UK

⁎
Correspondence to: Medical Oncology Department, Clínica Universidad de Navarra, Madrid, Program in Solid Tumours, CIMA, Pamplona,
and Grupo Español de Investigación en Cáncer de Ovario (GEICO), Madrid, Spain.

https://doi.org/10.1016/j.ejca.2023.04.024
0959-8049/© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/
licenses/by/4.0/).
2 A. González-Martín et al. / European Journal of Cancer 189 (2023) 112908

o
Department of Oncology, Rigshospitalet–Copenhagen University Hospital and Nordic Society of Gynaecological
Oncology, Copenhagen, Denmark
p
HonorHealth Research Institute, University of Arizona College of Medicine, Phoenix Creighton University, Phoenix,
AZ, USA
q
Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of
Gynaecology, Berlin, Germany
r
Department of Molecular Imaging, Pathology, Radiotherapy & Oncology, Center for Oncological Research, Antwerp
University, Antwerp, Belgium

Received 10 March 2023; Received in revised form 18 April 2023; Accepted 19 April 2023
Available online 3 May 2023

KEYWORDS Abstract Purpose: To report updated long-term efficacy and safety from the double-blind,
Advanced ovarian placebo-controlled, phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016).
cancer; Methods: Patients with newly diagnosed advanced ovarian cancer with complete or partial
Niraparib; response (CR or PR) to first-line platinum-based chemotherapy received niraparib or placebo
PARP inhibitor; once daily (2:1 ratio). Stratification factors were best response to first-line chemotherapy re­
Maintenance therapy gimen (CR/PR), receipt of neoadjuvant chemotherapy (yes/no), and homologous re­
combination deficiency (HRD) status (deficient [HRd]/proficient [HRp] or not determined).
Updated (ad hoc) progression-free survival (PFS) data (as of November 17, 2021) by in­
vestigator assessment (INV) are reported.
Results: In 733 randomised patients (niraparib, 487; placebo, 246), median PFS follow-up
was 3.5 years. Median INV-PFS was 24.5 versus 11.2 months (hazard ratio, 0.52; 95%
confidence interval [CI], 0.40–0.68) in the HRd population and 13.8 versus 8.2 months (ha­
zard ratio, 0.66; 95% CI, 0.56–0.79) in the overall population for niraparib and placebo,
respectively. In the HRp population, median INV-PFS was 8.4 versus 5.4 months (hazard
ratio, 0.65; 95% CI, 0.49–0.87), respectively. Results were concordant with the primary
analysis. Niraparib-treated patients were more likely to be free of progression or death at
4 years than placebo-treated patients (HRd, 38% versus 17%; overall, 24% versus 14%). The
most common grade ≥ 3 treatment-emergent adverse events in niraparib patients were
thrombocytopenia (39.7%), anaemia (31.6%), and neutropenia (21.3%). Myelodysplastic
syndromes/acute myeloid leukaemia incidence rate (1.2%) was the same for niraparib- and
placebo-treated patients. Overall survival remained immature.
Conclusions: Niraparib maintained clinically significant improvements in PFS with 3.5 years
of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of pro­
gression irrespective of HRD status. No new safety signals were identified.
© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC
BY license (http://creativecommons.org/licenses/by/4.0/).

1. Introduction inhibitor niraparib for first-line maintenance therapy in

patients with newly diagnosed advanced OC who re­
Most patients with ovarian cancer (OC) have advanced sponded to first-line platinum-based chemotherapy. In
disease at diagnosis, which places them at a high risk for the PRIMA primary analysis, the median duration of
disease recurrence and death [1,2]. In patients with dis­ follow-up was 13.8 months. Niraparib maintenance
tant disease at diagnosis, the estimated 5-year survival treatment significantly extended progression-free sur­
rate is approximately 30% [2]. For patients with newly vival (PFS) assessed by blinded independent central re­
diagnosed advanced OC, the treatment landscape has view (BICR) compared with placebo in patients with
expanded to include maintenance therapy with poly homologous recombination–deficient (HRd) tumours
(ADP-ribose) polymerase (PARP) inhibitors and anti­ (21.9 versus 10.4 months; hazard ratio, 0.43; 95% con­
angiogenic treatments given alone or in combina­ fidence interval [CI], 0.31–0.59; P < 0.001) and in the
tion [3,4]. overall population (13.8 versus 8.2 months; hazard
The phase 3 PRIMA/ENGOT-OV26/GOG-3012 ratio, 0.62; 95% CI, 0.50–0.76; P < 0.001) [5]. Con­
(PRIMA) trial demonstrated the efficacy of the PARP sistent with the known safety profile of niraparib, the
 A. González-Martín et al. / European Journal of Cancer 189 (2023) 112908 3

most common grade ≥ 3 treatment-emergent adverse amendment on November 27, 2017, incorporated an
events (TEAEs) were haematologic in nature [5]. individualised starting dose (ISD) based on baseline
Based on the primary analysis results from PRIMA, body weight and platelet count, with patients with a
niraparib was approved for the maintenance treatment of baseline body weight < 77 kg or baseline platelet
patients with newly diagnosed advanced OC who re­ count < 150,000/μl assigned to a starting dose of 200 mg
sponded to first-line platinum-based chemotherapy re­ QD and patients with a baseline body weight ≥ 77 kg or
gardless of biomarker status [6,7]. However, data on the baseline platelet count ≥ 150,000/μl assigned to 300 mg
long-term benefits and safety of niraparib for first-line QD. Crossover between treatment arms was not per­
maintenance treatment are lacking, and overall survival mitted. Patients who discontinued from the study could
(OS) remains immature. To address this knowledge gap, receive subsequent treatments at the investigator’s dis­
we report here the final PFS data and long-term safety cretion. The study was performed in accordance with
findings from an updated ad hoc analysis performed the tenets of the Declaration of Helsinki, Good Clinical
using data from the November 17, 2021, clinical cutoff Practices, and all local laws under the auspices of an
date. The updated analysis also allowed for the longer independent data and safety monitoring committee; all
observation of patients who received an individualised patients gave informed written consent [5].
starting dose, which was introduced through a protocol
amendment ≈ 16 months after study initiation.
2.2. Outcomes

2. Materials and methods The primary end-point was PFS assessed by BICR
analysed by hierarchical testing, first in patients with
2.1. Trial design HRd tumours and then in the overall population (see
González-Martín et al. for additional details) [5]. PFS
per investigator assessment, safety outcomes, and pa­
The study design and primary analyses results for the
PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) tient-reported outcomes were secondary end-points.
have been published previously [5]. Briefly, PRIMA was Adverse events (AEs) were graded according to the
National Cancer Institute Common Terminology Cri­
a phase 3, randomised, double-blind placebo-controlled
trial in which niraparib maintenance treatment was teria for Adverse Events, version 4.03. In this ad hoc
evaluated in adult patients with newly diagnosed, ad­ analysis, investigator-assessed PFS was evaluated in the
HRd and overall populations, and long-term safety
vanced (International Federation of Gynecology and
Obstetrics stage III/IV), high-grade serous or en­ findings are reported for the overall population. Addi­
dometrioid ovarian, primary peritoneal, or fallopian tional ad hoc analyses for PFS by prespecified subgroups
and for safety by starting dose are also reported.
tube cancer (collectively referred to as OC) who re­
sponded to first-line platinum-based chemotherapy.
Within 12 weeks of completion of first-line treatment, 2.3. Statistical analyses
patients were randomised 2:1 to receive niraparib or
placebo orally once daily (QD) until progressive disease PFS was defined as the time from randomisation after
or intolerable toxicity; patients who were benefitting completion of platinum-based chemotherapy to the
from treatment were eligible to continue receiving earliest date of objective disease progression on imaging
treatment beyond the planned 3-year treatment dura­ (Response Evaluation Criteria in Solid Tumors, version
tion. Patients were stratified by clinical response after 1.1) or by clinical criteria of progression, or death from
first-line platinum-based chemotherapy (complete or any cause. Clinical disease progression occurred if pa­
partial response), receipt of neoadjuvant chemotherapy tients had cancer antigen 125 progression according to
(yes or no), and tumour homologous recombination Gynecologic Cancer Intergroup-criteria and had either
deficiency (HRD) status (deficient versus proficient or identification of new lesions or growth of existing lesions
not determined) per the myChoice® HRD test (Myriad determined through diagnostic imaging or definitive
Genetics, Inc, Salt Lake City, UT). Tumours that had a clinical signs and symptoms of disease progression. PFS
deleterious BRCA mutation (BRCAm), a genomic in­ was analysed with a stratified log-rank test using stra­
stability score ≥ 42, or both were considered HRd; tu­ tification factors from randomisation and summarised
mours that were BRCA wild-type and had a genomic using Kaplan-Meier methodology. Hazard ratios with
instability score < 42 were considered HR-proficient 95% CIs were estimated using a stratified Cox propor­
(HRp). Per the initial protocol, all patients received a tional hazards model, with stratification factors used in
fixed-starting dose (FSD) of 300 mg QD. The protocol randomisation. Analyses were performed using data
4 A. González-Martín et al. / European Journal of Cancer 189 (2023) 112908

from the November 17, 2021, clinical cutoff date. The (Fig. 1). In total, 45 patients (9.2%) and 82 patients
statistical methodology for the updated analysis was (33.3%) in the niraparib and placebo arms, respectively,
prespecified per the PRIMA statistical analysis plan; the went on to receive subsequent PARP inhibitor therapy
inclusion of an updated PFS analysis from the updated during the follow-up period after progression.
data cut was not prespecified. The prespecified final
analysis for PRIMA will occur when OS data reach 3.2. Investigator-assessed PFS
maturity; additional PFS analyses are not planned at the
time of the OS analysis. The median investigator-assessed PFS in the HRd po­
pulation was 24.5 months in the niraparib arm versus
3. Results 11.2 months in the placebo arm (hazard ratio, 0.52;
95% CI, 0.40–0.68; P < 0.001; Fig. 2A). In the overall
3.1. Patients and duration of follow-up population, the median PFS was 13.8 months in the
niraparib arm versus 8.2 months in the placebo arm
A total of 733 patients with primary advanced OC who (hazard ratio, 0.66; 95% CI, 0.56–0.79; P < 0.001;
were at high risk for disease progression were enroled in Fig. 2B). These results were consistent with the primary
PRIMA (Table S1). The primary analysis clinical cutoff analysis investigator-assessed and BICR-assessed PFS
date was May 17, 2019, with a median duration of results (Table S2).
follow-up of 13.8 months (≈ 1.2 years) [5]. For the Niraparib treatment also increased investigator-as­
November 17, 2021, clinical cutoff date, the median sessed PFS compared with placebo across biomarker
duration of follow-up was ≈ 3.5 years (niraparib, subgroups (Fig. 3). The greatest treatment benefit was
41.6 months; placebo, 41.9 months). In the overall seen in patients with BRCAm HRd tumours, with a
population, 103 patients (21.3%) in the niraparib arm median PFS of 31.5 months in the niraparib arm versus
and 39 patients (16.0%) in the placebo arm had a study 11.5 months in the placebo arm (hazard ratio, 0.45;
treatment duration longer than 3 years. At the time of 95% CI, 0.32–0.64). In patients with BRCA wild-type
this analysis, 79 patients (16.3%) were receiving nir­ HRd tumours, the median PFS was 19.4 months in the
aparib, and 27 patients (11.1%) were receiving placebo niraparib arm versus 10.4 months in the placebo arm

c c

c c

Fig. 1. Patient disposition for homologous recombination-deficient (HRd) and overall populations. aIncludes 2 patients who experienced
a temporary dose interruption because of an adverse event and who subsequently discontinued treatment. bIncludes 1 patient who also
experienced an adverse event (ascites) at the time of discontinuation. cIncludes patients who discontinued because of investigator decision
or non-adherence. AE, adverse event; HRnd, homologous recombination status not determined; HRp, homologous recombination-
proficient.
 A. González-Martín et al. / European Journal of Cancer 189 (2023) 112908 5

Fig. 2. Kaplan-Meier estimates of investigator-assessed progression-free survival (PFS) by treatment arm in the (A) homologous re­
combination-deficient (HRd) population and (B) overall population. CI, confidence interval; mPFS, median progression-free survival.
6 A. González-Martín et al. / European Journal of Cancer 189 (2023) 112908

Fig. 3. Kaplan-Meier estimates of investigator-assessed progression-free survival (PFS) by treatment arm for (A) homologous re­
combination-deficient (HRd)/BRCA mutated (BRCAm), (B) HRd/BRCA wild-type (BRCAwt), and (C) homologous recombination-
proficient (HRp) populations. CI, confidence interval.

(hazard ratio, 0.66; 95% CI, 0.44–1.00). Patients with The treatment benefit of niraparib was also observed
tumours that were HRp also benefited from niraparib across most of the subgroups examined, including pa­
treatment compared with placebo (median PFS, 8.4 tients considered at higher risk of progression because of
versus 5.4 months; hazard ratio, 0.65; 95% CI, a partial response to first-line platinum-based che­
0.49–0.87). motherapy (hazard ratio, 0.63; 95% CI, 0.47–0.86),
 A. González-Martín et al. / European Journal of Cancer 189 (2023) 112908 7

Fig. 4. Forest plot of hazard ratios for investigator-assessed progression-free survival (PFS). 1L, first-line; BRCAm, BRCA mutated;
BRCAwt, BRCA wild-type; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; FSD, fixed starting dose; HR, hazard
ratio; ISD, individualised starting dose; HRD, homologous recombination deficiency; HRd, homologous recombination-deficient; HRnd,
homologous recombination status not determined; HRp, homologous recombination-proficient; NACT, neoadjuvant chemotherapy.

receipt of neoadjuvant chemotherapy (hazard ratio, 3.4. Safety

0.68; 95% CI, 0.55–0.84), or having stage IV disease at
diagnosis (hazard ratio, 0.88; 95% CI, 0.65–1.18; Fig. 4). Niraparib safety findings were consistent with the pri­
Patients who received an ISD also benefited from nir­ mary analysis; no new safety signals were observed [5].
aparib treatment (hazard ratio, 0.71; 95% CI, Long-term monotherapy was associated with a low rate
0.53–0.97). of discontinuations due to AEs (Table 1); compared
with the primary analysis, 11 additional patients dis­
3.3. OS continued niraparib because of a TEAE (includes 2
patients who initially experienced a treatment interrup­
OS remained immature at 30.8% for the HRd popula­ tion but subsequently discontinued study treatment all
tion and 41.2% for the overall population at the time of together). Implementation of the ISD generally im­
this data cutoff. The prespecified final analysis for proved safety, with reductions in the proportions of
PRIMA will be performed when OS data reach maturity niraparib-treated patients who experienced grade ≥ 3
(60.0%) for the overall population. TEAE (62.7% versus 78.4%) and treatment-related
8 A. González-Martín et al. / European Journal of Cancer 189 (2023) 112908

Table 1
Overall safety in the overall population and by niraparib starting dose.
AEs, n (%) Niraparib
Overall FSD ISD Placeboa
(n = 484) (n = 315) (n = 169) (n = 244)
TEAE
Any grade 479 (99.0) 313 (99.4) 166 (98.2) 229 (93.9)
Grade ≥ 3 353 (72.9) 247 (78.4) 106 (62.7) 56 (23.0)
Grade ≥ 4 146 (30.2) 119 (37.8) 27 (16.0) 7 (2.9)
TRAE
Any grade 467 (96.5) 307 (97.5) 160 (94.7) 175 (71.7)
Grade ≥ 3 321 (66.3) 230 (73.0) 91 (53.8) 21 (8.6)
Grade ≥ 4 143 (29.5) 117 (37.1) 26 (15.4) 2 (0.8)
Serious AE
Any 186 (38.4) 130 (41.3) 56 (33.1) 39 (16.0)
Treatment-related 129 (26.7) 89 (28.3) 40 (23.7) 8 (3.3)
TEAE leading to
Dose interruption 389 (80.4) 266 (84.4) 123 (72.8) 51 (20.9)
Dose reduction 347 (71.7) 241 (76.5) 106 (62.7) 23 (9.4)
Treatment discontinuation 67 (13.8)b 41 (13.0) 26 (15.4) 7 (2.9)c
Death 5 (1.0) 3 (1.0) 2 (1.2) 2 (0.8)
AE, adverse event; FSD, fixed starting dose; ISD, individualised starting dose; TEAE, treatment-emergent adverse event; TRAE, treatment-
related adverse event.
a
Data for the overall placebo population; results were similar in patients who received a fixed or individualised starting dose. b Two additional
patients who experienced a TEAE leading to a dose interruption subsequently discontinued treatment. c Includes 1 patient who experienced the
adverse event ascites at the time of disease progression and was recorded as discontinuing treatment because of disease progression.

grade ≥ 3 AEs (53.8% versus 73.0%) in patients who experienced MDS/AML events are reported in Table S3.
received an ISD versus an FSD. Before MDS/AML event occurrence, 3 of 6 niraparib-
The proportions of niraparib-treated patients who treated and 3 of 3 placebo-treated patients received
experienced TEAEs leading to dose interruptions and subsequent chemotherapy, and all 3 placebo-treated
reductions were also lower with the ISD than the FSD. In patients received subsequent PARP inhibitor therapy.
the overall population, the most common grade ≥ 3
TEAEs in the niraparib arm were thrombocytopenia 4. Discussion
(39.7%), anaemia (31.6%), and neutropenia (21.3%;
Table 2). Compared with the primary analysis, 4 addi­ In this updated ad hoc analysis of the phase 3 PRIMA
tional patients experienced grade ≥ 3 thrombocytopenia, trial, maintenance treatment with niraparib resulted in a
3 additional patients experienced grade ≥ 3 anaemia, and sustained and durable PFS benefit compared with pla­
3 additional patients experienced grade ≥ 3 neutropenia in cebo in the HRd and overall populations per in­
the niraparib arm. These results are consistent with the vestigator assessment after a median of 3.5 years of
primary analysis, which found that most haematologic follow-up. Hazard ratios over the additional follow-up
toxicities in the niraparib arm occurred during the first time were consistent with the primary analysis, regard­
month of treatment. With the introduction of the ISD, less of biomarker status. In the HRd and HRp popu­
the proportions of patients who experienced grade ≥ 3 lations, respectively, a clinically meaningful 48% and
events of thrombocytopenia, anaemia, and neutropenia 35% reduction of the risk of progression or death was
were reduced from 49.2% to 21.9%, from 36.2% to 23.1%, observed. Niraparib-treated patients were also notably
and from 24.8% to 14.8%, respectively (Table 2). more likely to be free of progression or death at 4 years
Myelodysplastic syndromes (MDS) or acute myeloid than placebo-treated patients in both the HRd (38%
leukaemia (AML) events were reported in the same versus 17%) and overall (24% versus 14%) populations.
proportion of patients in the niraparib (6/484, 1.2%) and Long-term niraparib monotherapy was associated with
placebo arms (3/244, 1.2%). In these patients, the a low rate of discontinuations due to TEAEs. No new
duration of study treatment ranged from 3.7 to safety signals were reported with additional follow-up,
29.7 months and from 4.9 to 7.4 months and the time to and AE findings were consistent with those of the pri­
onset of MDS/AML event from the last study treatment mary analysis. The additional follow-up also confirmed
ranged from 0.1 to 42.7 months and from 19.8 to that the ISD improved the safety profile of niraparib
29.2 months in the niraparib and placebo arms, respec­ without sacrificing the PFS benefit. Taken together, the
tively. BRCAm and HRD status data for patients who data confirm the efficacy and tolerability of niraparib
 A. González-Martín et al. / European Journal of Cancer 189 (2023) 112908 9

d
Table 2 Includes anaemia, haemoglobin decreased, red blood cell de­
Most common AEs in the overall population and by niraparib creased, haematocrit decreased, and anaemia macrocytic.
e
starting dose. Includes neutropenia, neutrophil count decreased, febrile neu­
tropenia, and neutropenic sepsis.
Most common Niraparib f
Includes hypertension, blood pressure increased, and blood pres­
TEAE, n (%)b
Overall FSD ISD Placeboa sure fluctuation.
(n = 484) (n = 315) (n = 169) (n = 244)
c
Thrombocytopenia
Any grade 325 (67.1) 233 (74.0) 92 (54.4) 12 (4.9)
Grade ≥ 3 192 (39.7) 155 (49.2) 37 (21.9) 1 (0.4) maintenance therapy and support the use of niraparib in
Grade ≥ 4 130 (26.9) 111 (35.2) 19 (11.2) 1 (0.4) accordance with treatment recommendations [8].
Anaemiad In patients with newly diagnosed advanced OC who
Any grade 315 (65.1) 227 (72.1) 88 (52.1) 48 (19.7) respond to first-line platinum-based chemotherapy,
Grade ≥ 3 153 (31.6) 114 (36.2) 39 (23.1) 5 (2.0)
Grade ≥ 4 3 (0.6) 2 (0.6) 1 (0.6) 0
there is strong evidence to support the use of main­
Nausea tenance treatment with PARP inhibitor monotherapy.
Any grade 282 (58.3) 189 (60.0) 93 (55.0) 73 (29.9) In addition to the results from the PRIMA and PRIME
Grade ≥ 3 6 (1.2) 4 (1.3) 2 (1.2) 2 (0.8) trials that demonstrated the benefit of niraparib across
Grade ≥ 4 0 0 0 0 biomarker subgroups [5,9], results from the SOLO-1
Neutropeniae
Any grade 209 (43.2) 149 (47.3) 60 (35.5) 19 (7.8)
trial demonstrated the PFS benefit of olaparib mono­
Grade ≥ 3 103 (21.3) 78 (24.8) 25 (14.8) 4 (1.6) therapy in patients with BRCAm disease [10]. More
Grade ≥ 4 36 (7.4) 28 (8.9) 8 (4.7) 1 (0.4) recently, the ATHENA-Mono/GOG-3020/ENGOT-
Constipation OV45 trial results demonstrated that rucaparib sig­
Any grade 202 (41.7) 144 (45.7) 58 (34.3) 52 (21.3) nificantly extended PFS compared with placebo in the
Grade ≥ 3 2 (0.4) 1 (0.3) 1 (0.6) 0
Grade ≥ 4 0 0 0 0
HRd and overall populations [11]. Although median
Fatigue PFS was longer with rucaparib in the ATHENA-Mono
Any grade 177 (36.6) 119 (37.8) 58 (34.3) 76 (31.1) trial than with niraparib in PRIMA, these trials cannot
Grade ≥ 3 11 (2.3) 7 (2.2) 4 (2.4) 1 (0.4) be directly compared because of differences in trial de­
Grade ≥ 4 0 0 0 0 sign, patient population, and clinical risk factors for
Headache
Any grade 133 (27.5) 94 (29.8) 39 (23.1) 41 (16.8)
disease progression [5,11,12].
Grade ≥ 3 2 (0.4) 1 (0.3) 1 (0.6) 0 The literature on the long-term benefits and safety of
Grade ≥ 4 0 0 0 0 first-line PARP inhibitor maintenance is beginning to
Insomnia take shape, with long-term data from SOLO-1 and
Any grade 124 (25.6) 86 (27.3) 38 (22.5) 37 (15.2) PAOLA-1 being released [13,14]. In the 7-year SOLO-1
Grade ≥ 3 5 (1.0) 5 (1.6) 0 1 (0.4)
Grade ≥ 4 0 0 0 0
analysis, OS data remained immature in this BRCAm
Abdominal pain only population. Although not statistically significant, a
Any grade 119 (24.6) 82 (26.0) 37 (21.9) 79 (32.4) clinically meaningful benefit with olaparib maintenance
Grade ≥ 3 10 (2.1) 5 (1.6) 5 (3.0) 1 (0.4) treatment was observed compared with placebo (7-year
Grade ≥ 4 0 0 0 0 OS rate, 67.0% versus 46.5%) [13]. In PAOLA-1, the OS
Vomiting
Any grade 118 (24.4) 82 (26.0) 36 (21.3) 32 (13.1)
benefit of olaparib plus bevacizumab maintenance
Grade ≥ 3 4 (0.8) 4 (1.3) 0 2 (0.8) therapy was restricted to the HRd population (hazard
Grade ≥ 4 0 0 0 0 ratio, 0.62; 95% CI 0.45–0.85), but the efficacy con­
Arthralgia tribution of bevacizumab to maintenance PARP in­
Any grade 100 (20.7) 66 (21.0) 34 (20.1) 62 (25.4) hibitor remains unclear [14]. In contrast to SOLO-1 in
Grade ≥ 3 3 (0.6) 3 (1.0) 0 0
Grade ≥ 4 0 0 0 0
which patients with BRCAm tumours with no evidence
Hypertensionf of disease at 2 years stopped olaparib [10], PRIMA
Any grade 99 (20.5) 70 (22.2) 29 (17.2) 22 (9.0) enroled an all-comer population and patients without
Grade ≥ 3 35 (7.2) 26 (8.3) 9 (5.3) 5 (2.0) disease progression were eligible to receive niraparib for
Grade ≥ 4 0 0 0 0 3 years or more [5]. In this PRIMA analysis, the PFS
Diarrhoea
Any grade 95 (19.6) 69 (21.9) 26 (15.4) 60 (24.6)
benefit of niraparib was found to be sustained and
Grade ≥ 3 4 (0.8) 1 (0.3) 3 (1.8) 1 (0.4) durable after a median of 3.5 years of follow-up across
Grade ≥ 4 0 0 0 0 biomarker subgroups, and results were consistent with
AE, adverse event; FSD, fixed starting dose; ISD, individualised those of the primary analysis. Although direct com­
starting dose; TEAE, treatment-emergent adverse event. parisons of PRIMA and SOLO-1 remain difficult be­
a
Data for the overall placebo population; results were similar in cause of differences in patient populations, study design,
patients who received a fixed or individualised starting dose.
b and duration of follow-up, data from both trials in­
The most common TEAEs reported in ≥ 20% of niraparib-treated
patients in the overall population. dicate long-term benefit from PARP inhibitor main­
c
Includes thrombocytopenia and platelet count decreased. tenance monotherapy treatment [5,10,13]. Importantly,
10 A. González-Martín et al. / European Journal of Cancer 189 (2023) 112908

the effect of first-line PARP inhibitor maintenance by the inevitable use of subsequent treatments over an
monotherapy on OS in patients with newly diagnosed OC extended duration of follow-up.
remains an open question because mature OS data from
PRIMA, PRIME, SOLO-1, and ATHENA-Mono have 5. Conclusion
yet to be published.
In PRIMA, extended follow-up did not result in the Taken together, these data indicate that niraparib first-
detection of any new safety signals related to niraparib, line maintenance monotherapy treatment provided
and most AEs occurred during the primary analysis. durable, long-term remission in women with newly di­
Compared with the PRIMA primary analysis, five agnosed advanced OC who were at high risk for disease
additional patients in the niraparib arm and three ad­ progression or death across all biomarker subgroups.
ditional patients in the placebo arm reported MDS/ TEAE findings were consistent with those of the pri­
AML events, resulting in a total incidence of 1.2% in mary analysis, with no new safety findings.
each arm. PARP inhibitor use and platinum-based
chemotherapy are known risk factors for MDS and
AML [15,16]. In PRIMA, all nine patients who de­ Data sharing statement
veloped MDS/AML received PARP inhibitor treat­
ment as study treatment or as subsequent therapy; for GSK is committed to sharing anonymized subject-level
chemotherapy, all nine patients received first-line pla­ data from interventional trials as per GSK policies and as
tinum-based chemotherapy (inclusion criterion), and applicable. Requests for subject-level data should be done
six of nine patients received additional chemotherapy via the GSK link https://www.gsk-studyregister.com/en/.
during follow-up. In SOLO-1, after a 7-year follow-up
similar MDS/AML incidence rates of 1.5% and 0.8% CRediT authorship contribution statement
were reported for the olaparib and placebo arms, re­
spectively [13]. In PARP inhibitor clinical trials, MDS/ González-Martín: Conceptualisation, Investigation,
AML incidence rates appear to be lower in the newly Resources, Data curation, Visualisation, Writing – review
diagnosed setting compared with use in the recurrent & editing, Validation. Pothuri: Conceptualisation,
setting [5,10,13,17–19]. The potential contribution of Investigation, Resources, Data curation, Visualisation,
PARP inhibitors to MDS/AML events cannot be Writing – review & editing, Validation. Vergote:
overlooked, but additional work is needed to better Conceptualisation, Investigation, Resources, Data cura­
understand this association and what roles other tion, Visualisation, Writing – review & editing, Validation.
treatments and genetic factors play in MDS/AML de­ Graybill: Conceptualisation, Investigation, Resources,
velopment. For example, in the AGO-TR-1 study, Data curation, Visualisation, Writing – review & editing,
higher age and prior platinum-based chemotherapy Validation. Lorusso: Conceptualisation, Investigation,
lines were of higher risk to acquire clonal-hematopoi­ Resources, Data curation, Visualisation, Writing – review
esis-associated gene mutations, with an increased & editing, Validation. McCormick: Conceptualisation,
probability of PPM1D and TP53 mutations observed Investigation, Resources, Data curation, Visualisation,
in patients with germline BRCAm [20]. An additional Writing – review & editing, Validation. Freyer:
analysis also suggested that pre-existing TP53 clonality Conceptualisation, Investigation, Resources, Data cura­
may be a risk factor for MDS/AML development in tion, Visualisation, Writing – review & editing, Validation.
PARP inhibitor-treated patients [21]. In PRIMA, more Backes: Conceptualisation, Investigation, Resources, Data
patients who experienced MDS/AML events had tu­ curation, Visualisation, Writing – review & editing,
mours that were HRd than HRp, but no trend was Validation. Heitz: Conceptualisation, Investigation,
observed for BRCAm status. Resources, Data curation, Visualisation, Writing – review
The ad hoc nature of the updated and final PRIMA & editing, Validation. Redondo: Conceptualisation,
study PFS analysis should be considered when inter­ Investigation, Resources, Data curation, Visualisation,
preting our findings. The data cutoff for the analysis was Writing – review & editing, Validation. Moore:
unplanned, and the database cleaning and data re­ Conceptualisation, Investigation, Resources, Data cura­
conciliation were limited to the reported end-points. tion, Visualisation, Writing – review & editing, Validation.
Additional limitations include investigator assessment Vulsteke: Conceptualisation, Investigation, Resources,
rather than BICR assessment of disease progression and Data curation, Visualisation, Writing – review & editing,
the relatively small number of patients with data at Validation. O'Cearbhaill: Conceptualisation, Investigation,
4 years. OS data remained immature, limiting the Resources, Data curation, Visualisation, Writing – review
ability to assess the long-term benefits of niraparib & editing, Validation. Malinowska: Conceptualisation,
maintenance treatment. However, it is important to note Project administration, Investigation, Resources, Data
that long-term PFS is likely a useful surrogate for long- curation, Visualisation, Writing – original draft, Writing –
term benefit in this population because it is not affected review & editing. Shtessel: Conceptualisation, Project
 A. González-Martín et al. / European Journal of Cancer 189 (2023) 112908 11

administration, Investigation, Resources, Data curation, (2021), and Sotio. Dr. Graybill reports advisory board
Visualisation, Writing – original draft, Writing – review & and speaker fees from GSK. Dr. Lorusso reports per­
editing, Validation. Compton: Conceptualisation, sonal fees from Amgen, AstraZeneca, Clovis Oncology,
Investigation, Resources, Data curation, Visualisation, Genmab, Immunogen, Merck, and PharmaMar; and
Writing – original draft, Writing – review & editing, grants from Merck and PharmaMar. Dr. McCormick
Validation. Mirza: Conceptualisation, Investigation, reports advisory role fees from AstraZeneca, Clovis,
Resources, Data curation, Visualisation, Writing – review GSK, ImmunoGen, and Merck. Dr. Freyer reports
& editing, Validation. Monk: Conceptualisation, personal fees from AstraZeneca, Biogaran, Bristol
Investigation, Resources, Data curation, Visualisation, Myers Squibb, Clovis Oncology, MSD, Novartis, Pfizer
Writing – review & editing, Validation. Inc., Roche Holding AG, S.A.S., and Tesaro; grants
from AstraZeneca, Mylan, and Roche Holding AG. Dr.
Declaration of Competing Interest Backes reports personal fees from Agenus, CEC
Oncology, Clovis, Eisai, Merck, AstraZeneca and GSK.
Dr. González-Martín reports support for the manu­ ImmunoGen, Myriad; grants from Clovis, Eisai,
script funding from GSK; grants or contracts from Immunogen, and Merck, Beigene, Natera. Dr. Heitz
GSK and Roche; consulting fees from Alkermes, reports honoraria from Roche, AstraZeneca, GSK,
Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, NovoCure, and PharmaMar; advisory board fees from
ImmunoGen, Merck Sharp & Dohme, MacroGenics, NovoCure; and leadership role with AGO study group.
Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Dr. Redondo reports institutional grants from Eisai,
Roche, Sotio, and Sutro; honoraria fees from PharmaMar, and Roche; honoraria fees from
AstraZeneca, Clovis, GSK, PharmaMar, and Roche; AstraZeneca, MSD, Clovis, GSK, PharmaMar, and
and support for attending meetings from AstraZeneca, Eisai; advisory board roles at AstraZeneca, MSD,
GSK, PharmaMar, and Roche. Dr. Pothuri reports in­ Clovis, GSK, PharmaMar, and Eisai; and travel support
stitutional grant support from AstraZeneca, Celsion, from AstraZeneca, GSK, and PharmaMar. Dr. Moore
Genentech/Roche, Karyopharm, Merck, Mersana, reports personal fees from Abcodia Inc, Fujirebio
GSK, Sutro, Toray, Incyte, Imab, Onconova, VBL Diagnostics Inc, and Humphries Pharmaceutical; and
Therapeutics, and Clovis Oncology; consulting fees institutional grants from Angle Plc. Dr. Vulsteke reports
from AstraZeneca, GSK, SeaGen, and Merck; advisory medical writing support to GSK; consulting fees from
board fees from Eisai, Lily, Merck, Sutro Biopharma, Atheneum Partners, Bristol Myers Squibb, GSK,
Tesaro/GSK, Astra Zeneca, and GOG Foundation. Dr. Janssen-Cilag, Leo-Pharma, Merck Sharp & Dohme,
Vergote reports institutional payments for corporate and Roche; advisory board fees from AstraZeneca,
sponsorship research from Amgen and Roche and Bayer, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp
contracted research from Genmab and Oncoinvent AS; & Dohme; and travel support from Pfizer and Roche.
institutional consulting fee payments from Amgen Dr. O’Cearbhaill reports participating in advisory
(Europe) GmbH, AstraZeneca, Carrick Therapeutics, boards with 2seventy bio, Bayer, Carina Biotech,
Clovis Oncology Inc, Deciphera Pharmaceuticals, Fresenius Kabi, Immunogen, GSK, Miltenyi Biotec,
Elevar Therapeutics, F. Hoffmann–La Roche Ltd, Regeneron, and Seattle Genetics; personal fees from
Genmab, GSK, Immunogen Inc, Mersana, Millennium GOG Foundation; travel fees from Hitech Health and
Pharmaceuticals, MSD, Novocure, Oncoinvent AS, Gathering Around Cancer, Ireland; service as a non­
Octimet Oncology, Sotio, Verastem Oncology, and compensated steering committee member for the
Zentalis; consulting fees from Deciphera PRIMA and Moonstone (niraparib) and DUO-O (ola­
Pharmaceuticals, Jazz Pharmaceuticals, and Oncoinvent parib) studies; institutional research support grants
AS; honoraria payments from Agenus, Aksebio, from Acrivon Therapeutics, AstraZeneca/Merck, Atara
AstraZeneca, Bristol Myers Squibb, Deciphera Biotherapeutics/Bayer, Genentech, Genmab, GSK,
Pharmaceuticals, Eisai, F. Hoffmann–La Roche Ltd, Gynecologic Oncology Group Foundation, Juno
Genmab, GSK, Immunogen Inc, Jazz Pharmaceuticals, Therapeutics, Kite/Gilead, Ludwig Institute for Cancer
Karyopharm, MSD, Novartis, Novocure, Oncoinvent Research, Lyell Immunopharma, Regeneron, Sellas Life
AS, Seagen, and Sotio; institutional travel support from Sciences, StemcentRx, Syndax, TapImmune Inc, and
Amgen, AstraZeneca, MSD, Roche, and Tesaro; ad­ TCR2 Therapeutics. Drs. Malinowska and Shtessel are
visory board fees from Agenus, AstraZeneca, Bristol employees of GSK. Ms. Compton is a former employee
Myers Squibb, Deciphera Pharmaceuticals (2021), Eisai, of GSK and currently receiving consulting fees from
F. Hoffmann–La Roche Ltd, Genmab, GSK, GSK. Dr. Mirza reports consulting and advisory role
Immunogen Inc, MSD, Novartis, Novocure, Seagen fees from AstraZeneca, Biocad, GSK, Karyopharm,
12 A. González-Martín et al. / European Journal of Cancer 189 (2023) 112908

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