PARP-inhibitors in epithelial ovarian cancer: Actual positioning an future expectations
H´el`ene Vanacker a, b, Philipp Harter c, Sana Intidhar Labidi-Galy d, e, Susana Banerjee f,
Ana Oaknin g, Domenica Lorusso h, Isabelle Ray-Coquard a, b,*
a Centre L´eon B´erard, Lyon, France
b University Claude Bernard Lyon 1, France
c Department of Gynecology & Gynecologic Oncology, Ev. Kliniken Essen-Mitte, Essen, Germany
d Department of Oncology, Hˆopitaux Universitaires de Gen`eve, Switzerland
e Faculty of Medicine, Swiss Cancer Center Leman, Geneva, Switzerland
f Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, United Kingdom
g Vall d’Hebron Institute of Oncology, Barcelona, Spain
h Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy

A R T I C L E I N F O

Keywords: Ovarian cancer PARP inhibitor Olaparib Niraparib
Rucaparib, Veliparib BRCA
HRD
A B S T R A C T

Poly-(ADP)-ribose polymerase inhibitors (PARPi) are a class of oral anticancer drugs first developed as “syn- thetically lethal” in cancers harboring BRCA1/BRCA2 inactivating mutations. In high-grade serous or endome-
trioid ovarian cancers (HGOC), PARPi demonstrated benefit as maintenance therapy in relapsing BRCA-mutated and non-mutated tumors. Recently, they extended their indications to frontline maintenance therapy. This re- view summarizes the current place of PARPi (i) as maintenance or single agent in recurrent disease and (ii) frontline maintenance with different settings. We reviewed the course of biomarker identification, the challenge of overcoming resistance to PARPi and future combinations with targeted therapies, including anti-angiogenic, immune checkpoint inhibitors and DNA damage response inhibitors.

Introduction
Epithelial high-grade serous and endometrioid ovarian carcinoma (HGOC) are the most frequent subtype of epithelial ovarian cancers (EOC). They are characterized by diagnosis at advanced stage in most patients and poor prognosis. Despite standard therapeutic strategy consisting of optimal debulking surgery (with the aim of no residual disease) and a combination of paclitaxel and platinum-based chemo- therapy, the disease relapses in about 70% of patients within two-years. The response to platinum chemotherapy and the progression/relapse- free interval (PFI) from last platinum therapy shapes the prognostic and therapeutic strategy of relapsing patients. Patients with platinum-
±
refractory or platinum-resistant disease (PFI < 6 months) would receive single-agent non-platinum chemotherapy bevacizumab with
low response rate and survival not exceeding 16 months [1,2]. Patients who are platinum-sensitive (PFI > 6 months) receive a platinum-based
therapy and had a median survival of 30 months [3].
HGOC had a unique genomic profile characterized by the ubiquitous presence of TP53 mutations (>95%) [4,5] and high genomic instability with half of the cases harboring “BRCAness” phenotype. This phenotype is secondary to defects in the DNA-damage repair (DDR) pathway,
particularly the homologous-recombination (HR) pathway. The most frequent alterations of HR pathway in HGOC are: i) inactivation of BRCA1 and BRCA2 genes due to germline or somatic mutations (mut- BRCA1/2), or hypermethylation of the promoter of BRCA1 (14%, 6% and 10% respectively); ii) inactivation of cognate genes such as RAD51C/D, CDK1/2, Fanconi anemia genes, CDK12, EMSY amplifica- tion (leading to abrogation of BRCA2 function) and overexpression of specific miRNAs, among others [6]. BRCA1/2 and cognates are tumor- suppressor genes involved in HR, an error-free mechanism of repair of DNA double-strand breaks. HR deficiency leads to genomic scars named HRD phenotype, participating into tumor initiation and evolution. This deficiency also mediates cellular vulnerability, exploited through

* Corresponding author.
E-mail addresses: [email protected] (H. Vanacker), [email protected] (P. Harter), [email protected] (S.I. Labidi-Galy), Susana. [email protected] (S. Banerjee), [email protected] (A. Oaknin), [email protected] (D. Lorusso), [email protected] (I. Ray-Coquard).

https://doi.org/10.1016/j.ctrv.2021.102255

Received 25 January 2021; Received in revised form 22 June 2021; Accepted 22 June 2021
Available online 15 July 2021
0305-7372/© 2021 Elsevier Ltd. All rights reserved.

Abbreviation
EMA European Medicines Agency FDA Food and Drug Administration
FIGO International Federation of Gynecology and Obstetrics mBRCA BRCA mutation
HRR homologous-recombination repair
HRD homologous-recombination repair deficiency HRP homologous-recombination repair proficiency LOH loss of heterozygosity
ORR overall response rate OS overall survival
PARP Poly-(ADP)-ribose polymerase PARPi PARP inhibitor
PFI platinum-free interval
PFR progression-free rate PFS progression free survival RFS relapse-free survival
HGOC high-grade serous and endometrioid ovarian carcinomas

“synthetic lethality”, a concept where simultaneous inactivation of two
HRD but not exclusively, as revealed in HR-proficient populations developed below. The clinical proof-of-concept of PARP inhibition and
“synthetic lethality” was first reported in the phase I trial of olaparib in
germline BRCA1/2 mutated (germline mBRCA) tumors [12]. To date, PARPi class encompass a dozen of compounds, five of which have been approved: olaparib, niraparib, rucaparib, talazoparib and veliparib. They share similarities but have different chemical structures, preclini- cal effect, pharmakockinetics and clinical doses [13]. Aside from the catalytic effect, the off-rate PARP-1 trapping effect on DNA remains poorly understood. It has been thought that trapping could generate DNA cytotoxic lesions, especially in tumor cells with deficiencies in repair of DSBs. Recently, Levani Zandarashvli et al established how the cytotoxic and PARP-trapping effect could rely on the allosteric desta- bilization of a helical regulatory domain, located adjacent to the cata- lytic domain [14]. However, this effect is highly variable among PARPi and induces PARP-1 trapping independently from this allosteric effect (eg: talazoparib, olaparib), suggesting that there is still a lot to discover and fine-tune toward this class of drugs.
Clinical management of toxicities
The clinical efficacy and management of toxicity is modulated by the pharmacological differences between PARPi. Overall, they are better tolerated than chemotherapy, with few changes in the quality of life of
patients treated with PARPi compared to placebo [15]. All PARPi

genes causes death, whereas inactivation of either gene is compatible
display a dose-dependent hematologic toxicity, with a class-effect

with viability [7]. The last decade witnessed the rapid development of poly(ADP-ribose) polymerases (PARP) inhibitors (PARPi), a new class of oral agents first developed to induce death by synthetic lethality in deficient BRCA1/BRCA2 cancer cells [6]. Impairing response to DNA single-strand breaks with PARPi and/or DNA double-strand breaks (DSBs) with alkylating/platinum chemotherapy brought a remarkable anticancer efficacy in BRCA mutated cancer cells [8].
Hence, for HGOC patients, in addition to the backbone carboplatin- paclitaxel chemotherapy and complete debulking surgery (when possible), two classes of targeted therapies were approved in the maintenance setting in the last decade. In early 2010′ s, the anti-
angiogenic agent Bevacizumab was approved for frontline treatment and maintenance in high-risk disease stage IV or stage IIIB/C (according to FIGO 2009 classification, which corresponds to FIGO IIIA1 and IIIB-IV
according to the 2014 FIGO classification) [9–11]. More recently,
several PARPi agents have been approved after completing a platinum- based chemotherapy in advanced stages FIGO III-IV. This review aims at developing the current and future positions of PARPi in the treatment of epithelial ovarian carcinoma (EOC).
Present
The biological mechanisms of PARPi
+
PARP proteins are a set of seventeen glycosyl-transferase nuclear enzymes, composed by a N-terminal zinc finger DNA-binding domain, and a C-terminal catalytic domain, which can link ADP-ribose from NAD to acceptor proteins (an enzymatic reaction that can be repeated into poly-ADP-ribosylation, so called PARylation). Upon endogenous or exogenous stress such as replication stress or DNA damage (single or double-strand breaks), PARP bound to DNA and secondarily recruits PARylation-prone proteins. This rapid and timely regulated post- translational modification allows a multistep DNA-damage related process including a final PARP auto-PARylation and release. The whole processes are involved in DNA repair, chromatin modulation, tran-
scription and replication regulation – including PARylation of histones and protection of replication fork – DNA integrity maintenance/repair,
and cell fate. PARP-1, the most abundant PARP nuclear protein has emerged as an effective clinical target for a growing list of cancers, especially in case of deficiency in DNA repair – mainly approached by
macrocytic anemia (as a maintenance, grade 3 anemia was 7% with veliparib, 20% with rucaparib and olaparib, 30% with niraparib). Nir-
≥
≥
aparib requires particular attention to grade 3 neutropenia and throm- bocytopenia (grade 3 was 20% and 40% respectively while <10% with the other PARPi)[16]. Thus, it is reasonable to wait for a good hema- tologic recovery between 3 and 9 weeks following the last cycle of chemotherapy before initiating maintenance with PARPi. Acute myeloid
leukemia/myelodysplastic syndrome (AML/MDS) is a long-term toxicity of particular interest, occurring in less than 3% in the early trials with PARPi. After 5 years follow-up, the SOLO1 study reported an incidence
of AML/MDS of less than <1.5% in the olaparib arm compared to an
≥
ever-reached rate of 8% with olaparib (and 4% with placebo) in chemotherapy pretreated relapsing germline mBRCA-mutated HGOC treated in the SOLO2 trial. This difference could be due to the number of previous chemotherapy lines (1 line in SOLO1 compared to 46% of the patients having received 3 lines in SOLO2). Still, there is a need for long-term scrutiny of hematologic toxicity, especially in this population
[17–20].
PARPi as single-agent in BRCA-like cancers
The first evidences of PARPi efficacy as monotherapy in clinical trials was reported in the spectrum of germline mBRCA-mutated cancers in 2009 [12]. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) delivered the last years approval for PARPi as monotherapy to treat advanced breast, ovarian and prostate cancers with BRCA mutations or other defects in DNA repair (Table 1). The first PARPi to be approved was olaparib as monotherapy in heavily pre- treated germline mBRCA HGOC patients in USA, followed by ruca-
+
parib for g/sBRCA and niraparib in g/sBRCA or platinum-sensitive HRD tumors [21–24]. Shortly after, several PARPi obtained approval in breast, prostate and pancreatic cancers (the latest as a maintenance therapy after response to platinum-chemotherapy) [25–29]. Most of PARPi clinical benefit seems related to BRCA1/2 bilallelic loss in ovarian
and breast cancer, and BRCA2 mutations in prostate and pancreatic cancer. Within a single gene, not all mutations have the same clinical phenotype as demonstrated for germline mBRCA2 [30]. Beyond BRCA genes, PARPi seems effective in tumors with mutations of RAD51C and RAD51D or high level hypermethylation of BRCA1. In castration- resistant prostate cancer, the benefit from olaparib in tumors with

Table 1
PARPis clinical approval in advanced cancers, December 2020.
Cancer type Biomarker Regimen (FDA/ EMA approved PARPI December 2020)

Outcome of PARPi Notes Reference

Breast adenocarcinoma Germline BRCA
HER-2 negative advanced breast cancer
Monotherapy (Olaparib Talazparib)
ORR = 60%
Significant PFS improvement compared to standard chemotherapy
PFS HR was 0.58 (OlympiAD) and
0.54 (EMBRACA) respectively compared to chemotherapy
[21,24]

Prostate adenocarcinoma (castration resistant)
g/s BRCA
or HRR-genes†
Monotherapy (Olaparib, Rucaparib)
ORR 33% to 50%
Significant improvement only already published in cohort A (BRCA1/2 ATM) of ProFOUND trial with Olaparib over enzalutamide /abiraterone, HR was 0.34 PFS and HR 0.69 for OS).
PFS in phase III ProFOUND
Different cohort of HRR gene†, different pretreatment regimen and assessment and phase II TRITON II trials
[22,23]

Pancreas
adenocarcinoma
gBRCA Maintenance following frontline response to frontline chemotherapy (Olaparib)
Median PFS 7.4 vs 3.8moths over placebo HR = 0.53p = 0.004
Maintenance only [25]

Ovarian high grade serous/ endometrioid adenocarcinoma
g/s BRCA
or platinum- sensitive HRD diseases
Platinum-response following platinum- sensitive recurrence

Frontline maintenance
Monotherapy (Olaparib Niraparib Rucaparib)
[No EMA approval] Maintenance Platinum-sensitive recurrence (Olaparib
Niraparib Rucaparib) Maintenance Frontline response following chemotherapy
-ORR = 34% to 72% according to BRCA /
HRD and PFI

Reduction risk of progression/death in all studies
-g/sBRCA > 70%
-BRCAwt HRD > 60%
-HRP > 37%
See Table 2
≥2-3 lines of prior chemotherapy,
- in gBRCA with PFI of 6–12 months, PFS HR 0.62 over non- platinum chemotherapy
All studies were consistent with a variable but significant benefit of PARPIs in all subgroups
[17–20]

[20,31–33,94]

g/sBRCA: germline/somatic deleterious mutation of BRCA; HR: Hazard ratio; ORR objective response rate, PFI: platinum-free interval; PFS: progression free survival.
†HRR-mutated gene selected in prostate cancer trials: BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L (+CHEK1 the PROFound trial; + NBN FANCA in the Triton II trial).

mutations in DDR pathway was mainly driven by BRCA2 [26,31]. Recent analyses revealed that the impact of BRCA mutations on HRD phenotype is histo-specific, (rather than histo-agnostic), with HRD phenotype mainly observed in breast and ovarian cancers [32]. The frequencies of somatic inactivation of the second allele of BRCA genes vary according to the tissue of origin, with the highest frequencies in HGOC [33,34]. Thus, it was not surprising that PARPi showed the highest benefit in HGOC, definitely changing the natural history of the disease with an unprecedented improvement in PFS as a maintenance therapy (Table 1).

Moving from recurrence to first line maintenance
The first signal suggesting benefit from PARPi in relapsing platinum- sensitive HGOC was reported in the phase I study led by by Gelmon et al investigating olaparib in relapsing breast and ovarian cancer [35]. Post- hoc exploratory analyses revealed that olaparib activity was mostly in platinum-sensitive disease, regardless of BRCA status. Consequently, the randomized phase II study 19 explored the potential of olaparib as a maintenance therapy in relapsing platinum-sensitive HGOC [36]. Other arguments that favor the development PARPi as maintenance following platinum-based response are: (i) a sequential development spares the hematologic toxicity – with exception of reduced dose of Veliparib; (ii) progressive HGOC is often aggressive and associated with ascites or bowel occlusion which are hardly compatible with oral therapy, (iii) unlike doublet chemotherapy, PARPi-maintenance is compatible with mean-term good quality of life.
Maintenance in relapsed HGOC
The first full approvals for PARPi as a maintenance therapy was based on the results of four randomized trials: three phase III and one
phase II studies [36–39]. Although all four studies had some differences in design, they were largely similar as illustrated in a dedicated review [40]: they enrolled women with recurrent HGOC in complete/partial
response (CR/PR) to the ultimate platinum-based therapy and they were randomized to either PARPi or placebo. The ARIEL3, NOVA, and Study 19 trials enrolled all comers while SOLO2 enrolled only those with BRCA-mutated cancers (mostly germline mutations). For platinum- sensitive PARPi-naive patients responding to platinum rechallenge (a
kind of a ‘double’ platinum-selection), PARPi maintenance dramatically
prolonged PFS (>1 year) and lead to a trend toward prolonged OS (>1
year, although statistically non-significant) according to the updated results of SOLO2 trial [41]. PARPi maintenance was effective in all subgroups, although the degree of benefit in terms of PFS was higher in BRCA mutated and HRD than HR proficient (HRP) (Table 1) [42].
Frontline maintenance: 2020′ s approvals
The benefit from PARPi in frontline maintenance was an important stake, first demonstrated in SOLO1 study, for women with BRCA- mutated (99% were germline), advanced disease in CR/PR after front- line platinum-based therapy. Almost all patients (95%) had normalized
CA-125 levels before entering the study. Maintenance with olaparib led to a hazard ratio of 0.30 (95% CI, 0.23–0.41) and a median PFS (not including time of chemotherapy) of approximately 56 months versus
13.8 months with placebo, leading to rapid approval by the FDA and the EMA in 2019; OS is not mature [43,44].
The 2019 ESMO annual meeting was a momentum in the treatment of HGOC with the results of 3 randomized phase III trials investigating first line maintenance therapy with PARPi in all comers advanced stages
HGOC been presented in the plenary session [45–47]. The 3 trials had
differences in inclusion criteria, PARPi single/combination regimen, slightly different primary endpoint and pre-planned subgroup analysis

regarding all comers/BRCA/HRD status (Table 2). All 3 demonstrated significantly improved PFS in the intention-to-treat population. As of December 2020, the FDA and EMA approved niraparib for the mainte- nance treatment in advanced EOC, who are in a CR/PR after first-line platinum-based chemotherapy and olaparib in combination with bev- acizumab as first-line maintenance treatment for advanced HGOC who are in CR/PR to first-line platinum-based chemotherapy and whose cancer is associated with HRD status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. Veliparib has no approved label in combination nor maintenance.
Looking at the poor median PFS in the control arms with placebo, all experts agree to support maintenance therapy for all patients in 1st line after completion of platinum-based chemotherapy [48]. First line maintenance with PARPi in mBRCA is not avoidable. The best mainte- nance therapy with PARPi or a combination of PARPi and bevacizumab in HRD tumors remains to be determined as long as patients are can- didates to receive bevacizumab (access/availability issues and absence of medical contraindication).
Emerging questions of frontline maintenance
+
+
The maximal benefit with PARPi was seen in the g/sBRCA subgroups of the 4 trials, followed by HRD and HRP where PAOLA-1 reported no difference with its bevacizumab control arm (Fig. 1). As SOLO1, PRIMA and Velia used PARPi in monotherapy, these results opened the question for the need of bevacizumab in such population. Since only a random- ized trial could address this question, we have indirect arguments to be considered: (i) the relative magnitude of effect in the BRCA-mutated population in PAOLA-1 (predefined subgroup analysis) was almost identical to PRIMA and SOLO1, despite inclusion of bevacizumab in both the control and experimental arms; (ii) in the population-adjusted indirect comparison (PAIC) of PAOLA-1 recently presented, the combi- nation olaparib bevacizumab suggested a higher and long-lasting PFS benefit compared to olaparib alone, bevacizumab alone or placebo, with a 3-years progression-free rate of 75.2%, 60%, 57%, and 27% respec- tively, suggesting a 29% reduction of risk with bevacizumab olaparib compared to olaparib alone in BRCA-mutated population [49]; (iii) for HRD subgroup, the exploratory analysis of PAOLA-1 in the high risk group (FIGO stage IV or stage III disease with upfront surgery and re- sidual disease or neoadjuvant-chemotherapy) reached a median PFS of 36 months with the combination compared to 15.9 months with bev-
acizumab alone. Although indirect trials’ comparison are cautious as the
populations of PAOLA-1 and PRIMA could be biased and different, the
median PFS was 20.9 months for niraparib alone versus 10.4 months with placebo in this “higher-risk” population corresponding to PRIMA inclusion criteria and the regular indication of bevacizumab by EMA and FDA before PARPi approval [9,10].
As stated previously, PARPi has activity beyond BRCA-mutations, with other alterations leading to platinum-response and PARPi- sensitivity. In the PRIMA trial, for HRP population, a very modest ab- solute PFS benefit of 2.7 months was observed with niraparib compared
=
to placebo (8.1 vs 5.4 months; HR 0.68, 95% CI, 0.49–0.94) and a short median PFS in both treatment arms [50]. However, the PRIMA
trial included only HGOC patients with measurable PDS residual disease or IDS patients, i.e. high risk advanced stage. In the PAOLA-1 trial there was no signal of activity in the HRP subgroup but median PFS exceeded
16 months in both arms, and the subsequent analyses of above- mentioned ‘higher-risk’ HRP population still had a 13.8 months PFS in the active bevacizumab control arm [51]. Results in this population in the VELIA trial fall somewhere between PRIMA and PAOLA-1, although the absolute median PFS should not be compared because of the
different starting points for the definition of PFS and knowing the pa- tients were not selected as responders as veliparib was proposed throughout the chemotherapy. While these observations are provoca- tive, they are post hoc exploratory analyses (in the case of PAOLA-1 and VELIA). Therefore, no definitive conclusions should be drawn. The 3 trials showed that frontline PARPi provided the same spectrum of
adverse events as for recurrence, and combinations with chemotherapy or bevacizumab tend to increase their occurrence, including severe anemia (31% for niraparib; 17% in olaparib bevacizumab; up to 40% for veliparib chemotherapy). The balance between safety and benefit needs to be integrated in our daily practice and lead to discontinuation of treatments in the trials (12% in PRIMA; 20% in PAOLA-1, 10% in SOLO1 and 26% in VELIA).
+
+
± ±
Although OS data are not mature yet, there may be a remnant effect of frontline strategy since PFS2 (survival on subsequent therapy following progression on front-line therapy) was significantly longer in the PARPi arm ( bevacizumab) over placebo arm ( bevacizumab) in SOLO1, PRIMA and PAOLA-1 , knowing some control-arm patients had a
cross over to PARPi (36% in PAOLA-1)[52–54]. Recently, the PFS2 of
the HRD population of PAOLA-1 trial was reported to be significantly prolonged in all stages [55]. OtherMmature PFS2 and OS data of these frontline trials are awaited.
Are there clinical factors predictive for response to PARPi? In the 4 randomized trials, all clinical subgroups (age, FIGO stage, upfront versus
interval debulking surgery, residual disease after surgery or not, com- plete versus partial response to initial platinum-based CT ± bev- acizumab) benefited from PARPi—based maintenance compared to
placebo or bevacizumab. Although the definition of complete versus partial response was different between the 4 trials (CA-125 elevation, time of randomization), the observed HR was consistently higher for patients in CR after chemotherapy than those in PR. In a recent subgroup analyses, the timing of the surgery (upfront) and the absence of residual disease seemed to be the group more likely to benefit the most from olaparib and bevacizumab [51]. Overall, several parameters will determine the choice of maintenance therapy according to BRCA/HRD status, bevacizumab accessibility, residual disease after surgery and response to chemotherapy.
The pursuit to selection of biomarkers
Although PARPi have led to major PFS benefit in women with HGOC, particularly BRCA1/2-mutated HGOC, patient selection remains a challenge. HRD assays are unable to formally identify patients who do not benefit from PARPi. Besides HRD, DNA replication stress induced by either loss of tumor suppressor gene, oncogene amplification or indirect
immune-modulation may be involved in PARPi efficacy [56–58]. The
first developed HRD assay was the myChoice CDx (Myriad Genetics), that was designed to determine HRD status through detection of BRCA1/ 2 deleterious mutations and evaluation of genomic instability combining three parameters: loss of heterozygosity [LOH], telomeric-allelic
≥ ≥
imbalance [TAI] and large-scale state transitions [LST]. The 3 all comers’ front-line trials with PARPi used the myChoice test to determine HRD status with threshold 33 for VELIA and 42 in PRIMA and PAOLA-1. This difference in thresholds had a slight impact on the prevalence of HRD status that appeared marginally higher in VELIA
+
(55%) than in PRIMA (51%) and PAOLA-1 (48%). The other available test is Foundation Medicine’s FoundationFocus CDx BRCA LOH, used in the ARIEL trials. It detects BRCA1/2 mutations and HRD through the percentage of the genome affected by LOH (score ≥16 is considered as HRD ) [59]. Unlike Mychoice test, Foundation Medicine’s LOH did not take into account the polyploidy of cells. No prospective data have
evaluated the correlation between both tests. Recent guidelines high- lighted that the different HRD tests are not equivalent nor inter- changeable, and no HR repair panel of genes showed correlation with HRD scars [58,60]. Limitations of HRD tests included a proportion of
samples with ‘unknown’ status, the possibility of false negatives, limited use on biopsies after neoadjuvant chemotherapy and high costs, pre-
venting their re-imbursement in many countries. Several academic groups are attempting to develop HRD tests to identify patients with mutations in HR genes (by whole-exome or shallow (low-coverage) whole-genome sequencing, RAD51 foci, RNA-sequencing, computa- tional approaches and machine learning). Such tests require validation

Table 2
Main characteristics of SOLO1, VELIA PRIMA PAOLA-1 trials.
SOLO1 [38] PRIMA [42] PAOLA 1 [40] VELIA [41]

Population of newly diagnosed ovarian high- grade cancers
Random. 1:2 Olaparib
vs placebo

BRCA1/2 mutated, Response to platinum-based CT without bevacizumab
Random. 1:2 Niraparib
vs placebo

Response to CT
Stage III or IV with visible residual tumor after primary debulking surgery, inoperable stage III disease, or any stage IV disease, and those who had received neoadj. CT (**)
Random. 1:2
Olaparib + bevacizumab vs placebo + bevacizumab

Response to CT + beva. Stage III or IV irrespective of surgical outcome
> Secondary analyses
looked at clinical higher* and lower-risk** subgroups
Random. 1:1:1

Veliparib + CP → veliparib
=‘throughout’
vs veliparib + CP → placebo vs placebo + CP → placebo Response to CT
Stage III/IV high-grade serous undergoing primary or interval debulking sugery

PARPi maintenance duration recommendation
24 months continued if not CR at 24 m
36 months 24 months 24 months

HRD testing BRCAnalysis® test; Myriad myChoice® test BRCA and/or HRD score ≥ 42 myChoice® test BRCA
and/or HRD score ≥ 42
Primary endpoint PFS (investigator assessed) HRD-positive population, followed hierarchically All comers ITT
myChoice® test BRCA

and/or HRD score ≥ 33

Patients profiles

-Stage IV
- Primary/ interval surgery
-macroscopic residual disease
ITT HR

(95 %CI)
Median PFS (months) since random.
PFS by clinical-risk

N = 391
17%
64% /34%

28%

0.30
(0.23–0.41)
13.8 vs NE
After 6 to 9 cycles of CT
analyses by the all-comer population

N = 733
35%
23%/ none 100%
0.62
(0.5–0.76)
8.2 vs 13.8

After 6 to 9 cycles of CT

pre-planned analysis, stratified on BRCA, pre- defined HRD status analyses
N = 806
30%
51%/42%

44%

0.59
(40.9–0.72)
16.6 vs 22.1

After 6 to 9 cycles of CT
BRCA-mutated population followed hierarchically analyses by HRD and all-comer population

N = 1140
22%
68% /28%

31%

0.68
(0. 56–0.83)
17.3 vs 23.5

Since C1 CT

subgroups
*Higher-risk clinical disease
**Lower-risk clinical disease
NR HR = 0.62: 8.2 vs 13.8mo.
none
HR = 0.60: 14.7 vs 20.3 NR
mo.
HR = 0.46: 22.9 vs 39.3
mo.

mBRCA
-HR (95 %CI)
⦁ Median PFS (months)
⦁ clinical subgroups for PFS
*Higher-risk clinical disease
**Lower-risk clinical disease
HRD (incl. mBRCA)
- HR (95 %CI)
⦁ Median PFS (months)
⦁ clinical subgroups for PFS
*Higher-risk clinical disease
**Lower-risk clinical disease
BRCAwt-HRD
-HR (95 %CI)
-Median PFS (months)

HRP/Unknown

-HR (95 %CI)
-Median PFS (months)
⦁ clinical subgroups for PFS
*Higher-risk clinical disease
100% of patients = IT
0.30
13.8 vs NE

/

/

/
30% of patients
0.40
11 vs 22

* Idem whole population

**Not included

0.43
10.4 vs 21.9

* Idem HR = 0.43; 10.4 vs 21.9mo.
**Not included

0.50
8.2 vs 19.6

0.68

5.4 vs 8.1 (HRDneg only)

* Idem HR = 0.68; 5.4 vs 8.1mo.
**Not included
30% of patients
0.31
21.7 vs 37.2

*HR:0.37; 19.4 vs 36 mo
**HR:0.11: 22.2 vs NE

0.33
17.7 vs 37.2

*HR = 0.39: 16 vs 36 mo.
**HR = 0.15: 22 vs NE mo.

0.43
16.6 vs 28.1

0.92

16 vs 16.9

*HR = 0.93 ns 13.3 vs 15.6
**HR = 1.3 ns 23.3 vs 22.9
26% of patients
0.44
22 vs 34.7

NR

0.57
20.5 vs 31.9

NR

0.74

19.8 vs 22.9 0.81
11.5 vs 15

NR

(continued on next page)

Table 2 (continued )

**Lower-risk clinical disease
AEs in PARPi arm

SOLO1 [38] PRIMA [42] PAOLA 1 [40] VELIA [41]

- Grade ≥ 3 (%) 39 70
Leading to Dose
-Reduction (%) 28 71
-Discontinuation (%) 12 12
57 -Combo = Throughout 88% Throughout maintenance :
41 24
20 19

AEs: Adverse events; CT: chemotherapy; mBRCA: germline/somatic deleterious mutation of BRCA; HR: Hazard ratio; HRD: homologous recombination deficient; HRP: homologous recombination proficient according to Myriad myChoice® test (BRCA deleterious mutation and/or HRD score ≥ 42 for PAOLA-1 and PRIMA, or ≥ 33 for VELIA); ITT: intention to treat population; NE: not evaluable; ns: non ss statistically significant; NR: not reported; ORR objective response rate, PFI: platinum-free interval; PFS: progression free survival; ss statistically significant.
*Clinically higher-risk group (FIGO stage IV or stage III disease with upfront surgery and residual disease or neoadjuvant-chemotherapy).
** Clinically lower-risk FIGO stage III disease with upfront surgery and complete resection.

in large cohorts, but show promise as a faster and cheaper alternative to sequencing. The European Network of Gynecological Oncological Trial Groups (ENGOT) is currently leading an international effort to develop academic tests using tumor samples from the PAOLA-1 trial as a vali- dation cohort. Knowing the HRD status before completing primary chemotherapy could guide treatment decisions and prognosis estimation.
Future perspective
New expectations from PARPi maintenance Would PARPi cure some patients?
+
The ever-reached rate of PFS under frontline PARPi questioned the possibility that PARPi added to standard optimal treatment (complete cytoreductive surgery and adjuvant chemotherapy) could contribute to cure a proportion of HGOC patients. Beyond BRCA-mutated patients in SOLO1, PRIMA and PAOLA-1, the clinically lower-risk (absence of re- sidual disease at primary debulking surgery) HRD population in PAOLA- 1 who received a maintenance therapy combining bevacizumab ola- parib reached 90% progression-free rate at 2 years [51,52]. The long- term benefit of this strategy does not seem to fall after the completion
of the 2-years maintenance. Long-responders or even “cured” patients
need to be confirmed within the next years. Eventually, PARPi could be personalized to be shorten or extended according to individual long- term characteristics.
PARPi as an oral adjuvant treatment to cure early stages. This is one of the next years’ challenge, especially in BRCA-mutated patients. The place of postoperative adjuvant chemotherapy has been questioned those last years in early-stage I-II, which represent around 30% of newly diagnosed epithelial ovarian carcinomas but only 8% of HGOG [61]. The
efficacy of adjuvant platinum-based chemotherapy in prolonging OS and PFS has been demonstrated in a Cochrane systematic review [62]. Recommendations for adjuvant chemotherapy have various levels of evidence and depend on several factors: FIGO stage, tumor grade and histological type. To date, chemotherapy is recommended for women
with a high-risk of recurrence (all stages > IC2, all grade 3 including
stage IA, and IB or IC grade 2 or 3), based on ICON1 and ACTION pro- spective trials [63,64]. Because of significant impairment of patients’ quality of life under standard carboplatin-paclitaxel therapy due to al- opecia, neurotoxicity and severe cytopenia, an alternative with oral PARPi adjuvant treatment is an appealing option, to be balanced with
the risk of AML/MDS toxicity mentioned above. Assuming benefit for HGOC on a macro or micro metastatic disease, we can expect an efficacy of PARPi in early stage HGOC which are enriched in BRCA-mutated tumors. The other subtypes, including low grade serous, endometrioid, clear cell and mucinous carcinoma have different tumor biology; their low reliance on DDR pathway may explain a reduced sensitivity to chemotherapy and PARPi [65].
The question of chemoprevention of ovarian cancer is also a question
to challenge, especially for germline mBRCA carriers. To date, prophy- lactic salpingo-oophorectomy is recommended at 40–45 years old for germline mBRCA carriers, which do not preclude earlier onset and generates complications of precocious estrogen lack. Currently, no agent showed chemo-preventive properties against HGOC in interventional
trials [66]. As PARPi had relevant toxicity and is expensive, it is unlikely that they will play a relevant role in this setting.
Re-challenge by PARPi after PARPi
Because PARPi development is recent, no standard treatment is established for patients progression under PARPi. Recent real-world data suggest cross resistance with chemotherapy administered after
PARPi in heavily pretreated mBRCA1/2 patients. The ORR to chemo- therapy was low, estimated to 22% if PFI > 12 months and 11% if PFI 6–12 months, respectively. This observation needs to be confirmed in larger studies [67]. The efficacy of re-challenge with PARPi as a main-
tenance is yet not settled. To date, only a small retrospective series in heavily pre-treated patients mainly exposed to veliparib reported objective responses in 3/22 patients (13%, all BRCA-mutated), 3/22 being progressive and 13/22 (59%, with various BRCA status) had stable disease, including 3 of them being remarkably stable over a year [68]. With the advent of PARPi in frontline maintenance for all newly diag- nosed platinum-responsive HGOC, there is a need for dedicated ran- domized trials to address this question. The OReO/ENGOT Ov-38 trial (NCT03106987) is currently evaluating efficacy and safety of mainte- nance retreatment with olaparib over placebo, while the DUETTE trial recently tested placebo vs olaparib vs olaparib combined with an ATR- inhibitor (ceralasertib) in pretreated platinum-sensitive relapsing HGOC (NCT04239014). One would expect that benefit varies according to (i) effective PARPi exposure at the time of progression (efficient dose vs low-dose or stopped due to tolerance or completion of frontline), (ii) mBRCA/HRD/PFI, possibly according the frontline versus recurrent setting of PARPi.

Overcoming PARPi resistance
Resistance to PARPi occurs de novo or after a variable duration of exposure to the drug. Understanding the mechanism of resistance is warranted for developing novel therapeutic sequences and combination,
and enhancing patient’s outcome. The impact of residual disease on
resistance is probable since a better reduction of risk of progression with PARPi over placebo has been observed in patients with optimal surgery compared to residual disease. Multiple mechanisms of resistance have been described, mainly in BRCA-mutated and HRD in vitro and in vivo models [69]. Some are common with resistance to chemotherapy like
the overexpression of drug-efflux transporters MDR1/PgP[70]. Pro- cesses related to the reversion of one of the two pillars of “synthetic lethality” have also been documented, through reversion of DDR

Fig. 1. Frontline maintenance in PRIMA, SOLO-1 and PAOLA-1 trials: primary analysis: median PFS (months).

deficiency or PARP1 inhibition. Hence, in vitro screening reported re- sistances due to point mutations of PARP1 [71] or its reversal PAR
glycohydrolase enzyme, restoring PAR formation [72]. Restauration of HR-pathway through “reversion mutations” or epigenetic modifications have been described for BRCA1/2, RAD51C/D and PALB2 [73–75]. HRR may also be restored through loss of alternate NHEJ pathway (e.g. loss of
TP53BP1, RIF1 or REV7) [76,77]. Mechanisms stabilizing replication forks strengthen DDR and may lead to PARPi resistance, as described for MRE11 and MUS81 genes. Once again, some resistance mechanisms are common with resistance to platinum and could be already present at the instauration of PARPi, as it has been shown for BRCA reversion muta- tions, the only one documented mechanism of resistance in the clinics [75,78,79].
New combinations of PARPi
Multiple empirically or biologically-informed strategies of PARPi combination are currently investigated in order to enhance efficacy and avoid resistance (Table3).
Combination with anti-angiogenic agents
+
Since bevacizumab maintenance improved PFS in HGOC with hardly overlapping toxicity with PARPi, combining PARPi with anti-angiogenic agents is of interest either (i) as double maintenance, or (ii) as a chemo- free treatment. As a chemotherapy-free regimen, the association of niraparib bevacizumab reached a median PFS of 11.9 months in platinum-sensitive recurrent disease, and doubled median PFS of

Table 3
Selected ongoing clinical trials of combination in ovarian cancer.

Strategy chemo
free
Trial name PARPi Agent When Population Phase NCT

Veliparib Platinum taxane Frontline maintenance stage III-IV HGSOC III NCT02470585

+ platinum chemo
Niraparib Platinum based chemotherapy
Frontline maintenance stage III-IV HGSOC III NCT03709316

+ Non-platinum- chemo
L-MOCA Olaparib Post chemotherapy Relapsed: maintenance
therapy after response to platinum-based chemotherapy
Veliparib Topotecan Relapsed or Refractory Ovarian Cancer
platinum sensitive relapsed (PSR)
III NCT03534453

I-II NCT01012817

ROLANDO Olaparib Liposomal doxorubicin Platinum resistant II NCT03161132

Olaparib PM1183 (lurbinect´edine) Platinum-resistant
ovarian cancer
III NCT02684318

KU- 0059436
Paclitaxel and/ or Carboplatin
>2nd line I NCT00516724

OReO Olaparib / Re-challenge maintenance Relapsed- Platinum sensitive
pretreated by olaparib Relapsed Platinum sensitive
III NCT03106987

+ Immune checkpoint
KEYLYNK Olaparib Pembrolizumab Frontline maintenance BRCAwt III NCT03740165

blockade
JAVELIN OVARIAN P100
Talazoparib Avelumab Previously untreated Stage III IV epithelial ovarian, fallopian tube, or primary peritoneal cancer
III NCT03642132

Javelin PARPi
medley
Talazoparib Avelumab Recurrent platinum sensitive
ovarian cancer with or without BRCA defect/ other solid tumors
I-II NCT03330405

ATHENA Rucaparib Nivolumab 1st line maintenance Following Response to
Front-Line Platinum- Based Chemotherapy
X ARIES Rucaparib Nivolumab Relapsed ≥ 1 prior
platinum-based therapy and have platinum- sensitive disease
III NCT03522246

III NCT03824704

X Olaparib Tremelimumab (Anti CTLA-4)
Recurrent ovarian cancer
BRCA-
deficient ovarian cancer
III NCT02571725

X Olaparib Durvalumab And Tremelimumab
Recurrent or refractory BRCA 1 or 2 III NCT02953457

+ Antiangiogenic
AND Immune
X OPAL Niraparib Bevacizumab + TSR 042
(anti PD1)
Recurrent ovarian cancer.
III NCT03574779

checkpoint blockade
+Antiangiogenic
ANITA Niraparib Atzeolizumab Platinum-sensitive Recurrent ovarian cancer maintenance
III NCT03598270

OR Immune FIRST Niraparib TSR-042 (antiPD1) Frontline maintenance all comers III NCT03602859

checkpoint blockade
DUO-O Olaparib CarboPlatin-Paclitaxel +
Durvalumab
X Olaparib MEDI4736 (anti PDL1) ±
Cediranib
Frontline maintenance III NCT03737643

Recurrent ovarian cancer

+ ATR or DUETTE Olaparib ceralasertib Recurrent platinum
sensitive maintenance
olaparib onalespib Recurrent ovarian cancer
X CAPRI Olaparib AZD6738 (ceralasertib) Recurrent ovarian
cancer
+ Pi3K

Following prior 1L or

I-II NCT02484404

I NCT02898207

II NCT04239014

+ CDK-i

X Olaparib BKM120 or BYL719

Recurrent ovarian cancer
2L maintenance Ovarian or breast cancer

I NCT01623349

EPIK-O Olaparib
(=Buparlisib or Alpelisib)
Alpelisib
Recurrent ovarian cancer
No germline BRCA mutation detected, platinum-resistant or refractory
III Awaited

X Olaparib Adavosertib (anti WEE CDK1)
+ AKT / mTOR X Olaparib mTORC1/
2 Inhibitor AZD2014 or the Oral
AKT Inhibitor AZD5363
Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
Recurrent carcinoma recurrent endometrial
adenocarcinoma (except for carcinosarcoma), recurrent HGSOC
III NCT03579316

Ib NCT02208375

+ folate receptors Rucaparib Recurrent carcinoma I NCT03552471
(continued on next page)

Table 3 (continued )
Strategy chemo
free

Trial name PARPi Agent When Population Phase NCT

FORWARD II
mirvetuximab soravtansine
Folate Receptor Alpha Positive, BRCA- mutated

Specific ovarian histology
X ROCSAN Niraparib TSR 042 (anti PD1) Recurrent Carcinosarcoma III NCT03651206

X ATARI Olaparib Ceralasertib (ATR-i) Recurrent ARID1A loss Ovarian endometrioid
and Carcinosarcoma
II NCT04065269

niraparib alone, but no comparison with standard platinum-based chemotherapy was made so the phase III is awaited [39]. The combi- nation of olaparib and cediranib-an oral anti-angiogenic-was more efficient than single olaparib and reported encouraging results in platinum-sensitive relapses in a randomized-phase II trial [80]. How- ever, the phase III study showed a similar but not superior PFS of this combination as compared to standard platinum-based chemotherapy: with comparable PFS and ORR, both arms had different toxicity profiles and were still superior to the third arm of sole olaparib [81].
Combination with immunotherapy
Immune checkpoint inhibitors dramatically changed the outcome of patients whose tumors had increased tumor mutation burden [82]. Unfortunately, they brought modest activity as a single agent in EOC,
with ORR < 10% [83,84]. Several preclinical models showed that
benefit from inhibiting DDR with PARPi is partly due to changes in tumor immune microenvironment through upregulation of PD-L1 and
activation of type I interferon [85–87]. Combining PARPi and immu-
=
=
+ ≥
notherapy is attractive and tolerable and has been tested in several early phase studies [88,89]. The associations of niraparib and pembrolizumab or olaparib and durvalumab were administrated to heavily pre-treated patients. These combinations did not show unexpected adverse events and reported some activity: in the 60 evaluable patients of the TOPACIO trial, the ORR was 18%, with a 65% disease-control rate. Intriguingly, the efficacy seemed regardless of BRCA or HRD status or PD-L1 expression [89]. The association of olaparib and durvalumab reported comparable benefit with a ORR of 14% and PR SD 6 months disease control of 34% in platinum-resistant non-BRCA mutated HGOC (n 35) [90]. The MEDIOLA phase 1 dose-escalation study reported a disease control rate of 83% in 12 mBRCA1/2 heavily pretreated ovarian/triple- negative breast cancer participants [88]. The most impressive results were recently reported in with the MEDIOLA phase II trial in relapsing platinum-sensitive HGOC with the triplet olaparib, bevacizumab and anti-PD-L1 durvalumab (n 31). This combination showed an unprec- edented ORR of 77% regardless of genomic instability status [91]. Beyond the feasibility and toxicity profile of these combinations, much has to be proven to incorporate this combination as a standard option. Several trials are currently questioning the impact of triplets either in frontline or recurrence (Table3).
Combination with other DDR inhibitors
HGOC has an increased reliance on DNA replication stress and re- sponses single/double strand breaks response (ATM, Chk1, WEE1/ ATR Chk2 for single /double strand breaks respectively). These DNA repair responses are intertwined with replication stress and cell cycle regula- tion, including the inhibition of checkpoint kinases. Several drugs have been developed to inhibit these DDR kinases such as WEE1, ATR, ATM and CHK1 (Table 3). Preclinical studies suggest a synergistic or at least additive effect between them. Clinical development of the combination of these compounds is ongoing and is limited by hematologic dose-
either inhibitor alone with acceptable toxicity [92]. CHK1 inhibitor prexasertib or ATR inhibitor berzosertib and ceralasertib or ATM in- hibitors demonstrated a synergistic effect with PARP and ATR inhibitors in preclinical models, and are currently developed in early stage studies
[93–95]. A signal of activity was reported in BRCA2 mutated patients in
the AToM study, combining low dose olaparib with AZD0156 [96]. Overcoming resistance to PARPi has been reported with ATR and WEE1 inhibitors, notably in case of HRR deficiency, reproducing synthetic lethality. ATM inhibitors proved a synergistic activity with PARPi. Thus, HGOC patients with different genetic and PARPi exposure are more likely to benefit from these strategies. Combination with other onco- genic and epigenetic pathways
Combination with other cytotoxic agents are under study. Alkylating agents have a biological rationale for additive effect, such as temozo- lomide which is known to increase PARP1 trapping [97]. More standard chemotherapy of EOC aimed to reverse PARPi resistance while limiting cumulated toxicities. Finally other tracks of EOC treatment like new anti-folates are under study in combination with PARPi (Table 3).
±
Activation of the PI3K and RAS signal pathways interplay in the carcinogenesis and metastasis of HGOC, and occurs in as much as 70% of the cases, besides TP53 HRD alterations. The PI3K-AKT-mTOR interplay with HRR has been documented mainly in breast cancer models. Phase I studies reported tolerability of inhibiting PARP and
PI3Kα, AKT or mTOR and ORR were reported in HGOC. These combi-
+
nations showed an ORR of: i) 36% (10/28 in germline mBRCA patients) for olaparib + alpelisib; ii) 44% (11/25 not all being mBRCA patients) for olaparib + capivasertib and 20% (mainly non mBRCA platinum- resistant patients) for olaparib vistusertib [98–100]. Such therapeu- tic combinations with PARPi seem to be effective beyond BRCA-
associated and/or HRD tumors.
Combination with epigenetic modulators of BET bromodomain (BRD4) protein. BRD4 promotes cancer cell proliferation and survival by facilitating oncogenic transcription. BET inhibitors have been shown to suppress DDR genes. In vitro, BRD4 inhibitor restores the sensitivity to PARPi and the combination of BRD4 and PARP inhibitors demonstrated enhanced activity in multiple tumor lineages, regardless of BRCA1/2, TP53, RAS, or BRAF mutational status.

Conclusion
PARPi as a maintenance therapy has revolutionized the treatment of HGOC in the last 5 years, first for relapsing platinum-sensitive BRCA- mutated patients and rapidly extended to all comers. More recently, PARPi achieved an unprecedented improvement in PFS as a frontline maintenance therapy in BRCA-mutated that expanded to HRD HGOC. This lead to the approval in 2020 by the regulatory authorities of PARPi as frontline maintenance monotherapy for niraparib in all comers or combined with bevacizumab for olaparib in HRD tumors. Several questions remained to be unanswered: 1) what is the best maintenance
therapy for HRD population? PARPi monotherapy or a combination with

limiting toxicities. The WEE1-inhibitors AZD1775 and adavosertib
bevacizumab? Although the Hazard Ratio are comparable between the

+
were tested in EOC in a phase II, and their combination significantly enhanced activity of sole chemotherapy but at a cost of enhanced grade
>3 cytopenia. Sequential administration of PARP and WEE1 inhibitors
markedly prolonged the depth and duration of response compared with
two options, the median PFS obatiened with the combination olaparib bevacizumab is very attractive; 2) is there a need for a PARPi in the HRP population given the very modest benefit with niraparib in the PRIMA trial that included only patients with PDS and measurable residual

±
+ +
disease or IDS and this population is the most likely to have survival benefit with bevacizumab; 3) how to overcome secondary resistance to PARPi? Multiple trials investigating the combination of different agents targeting DDR are ongoing, their main limitation being hematologic toxicities [50]; 4) beyond PARPi bevacizumab, is there a place for other combinations? The impressive ORR of 77% obtained with the triplet olaparib bevacizumab durvalumab in the MEDIOLA phase II trial, irrespective of LOH-status (estimated with Foundation Medicine analysis), holds promise [91]. This combination is currently investigated as a first line maintenance therapy in the DUO-O trial (NCT03737643).

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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