PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer

Abstract

Epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy in the western world, has been historically treated with surgery followed by chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most active new targeted therapies for the treatment of EOC. PARPis’ mechanism of action relies on their ability to interfere with DNA repair events leading ultimately to cell death, the biological concept known as synthetic lethality. Initially developed as maintenance therapy in patients with a response after platinum-based chemotherapy in a recurrent setting, PARPis are now approved as the frontline treatment strategy. The aim of this chapter is to examine PARPis’ antineoplastic activity and the clinical development studies that lead to their approval, as well as the safety and the management of adverse events associated with this new class of drugs. Lastly, the rational considerations for the use of PARPis in the frontline setting are discussed.

1. Introduction

Epithelial ovarian cancer (EOC) is the second most common and the most lethal gynecologic malignancy responsible worldwide for ≈ 207,000 deaths [1]. EOC affects mainly postmenopausal women and is typically diagnosed at an advanced stage due to the absence of specific symptoms compounded with no effective early screening modalities that allow to detect the disease when it is localized [2, 3].

Several studies have demonstrated that advanced EOC represents a heterogeneous group of malignancies with complex molecular and genetic features associated with specific pathogenic pathways alteration and phenotypic clinical behavior [4]. High-grade serous ovarian carcinomas (HGSOC) represent the most common histotype and are linked to poor prognosis [4]. The vast majority of HGSOC arises from the fallopian tube (FT) as a precursor known as serous tubal intraepithelial carcinoma [5]. Moreover, several findings suggested that FT and primary peritoneal cancer (PPC) share the same pathobiology and genetic aberrations associated with HGSOC. As such, patients diagnosed with “pelvis serous carcinoma” should be considered as collectively having the same disease and, therefore, they should receive uniform treatment options [5].

Furthermore, the Cancer Genome Atlas (TCGA) project has identified that approximately 50% of HGSOC exhibits defects in homologous recombination repair (HRR) pathway, which is major biochemical machinery for the repair of DNA double-strand breaks (DSBs) in mammalian cells [6]. DSBs represent the most serious manifestation of DNA damage because, if left unrepaired, they can lead to genomic instability, which is considered one of the main features of carcinogenesis [7]. Given that breast cancer gene (BRCA)1 and (BRCA)2 are the tumor suppressor genes (wild-type BRCA allele is lost during tumorigenesis) involved at different stages of HRR, carriers of deleterious heterozygous germline mutations in the BRCA1 and BRCA2 genes have significantly elevated risks of developing breast, ovarian, and other cancers [7]. At the same time, tumors that exhibit homologous recombination deficiency (HRD) are susceptible to specific systemic treatments, including poly ADP-ribose polymerase (PARP) inhibitors (PARPis) [8].

Poly(ADP-ribose)polymerases (PARPs) are a family of nuclear ubiquitous enzymes, which regulate the biological functions of a variety of proteins by catalyzing their posttranslational modification, named PARylation, using NAD+ as substrate [9]. By post-transcriptionally modifying multiple proteins, PARPs act as signal transducers, contributing to the regulation of various cellular functions including the signaling pathway that leads to the resolution of DNA strand breaks. In this context, PARPs play as promoters of genomic integrity and stability, activating different mechanisms for DNA repair, stabilizing replication forks, and modeling the chromatin structure [10].

PARP1 is the most abundant and studied member of the PARP family, accounting for 80–90% of total PARP activity in the cell, and it is also known as the major PAR-producing enzyme in eukaryotes [11, 12, 13]. PARP1 is centrally involved in the early response to cellular oxidative and genotoxic stress, to which cells are constantly exposed [10]. In this context, PARP1 acts as a crucial DNA damage sensor, participating in the DNA damage response (DDR), the network of molecular pathways that maintain the genomic integrity by recognizing DNA damages and orchestrating their repair [14]. In DDR, PARP1’s first action is to trigger the repair of DNA single-strand breaks (SSBs) to ensure cellular genomic stability. Indeed, if not repaired, SSBs are likely to be converted, during DNA replication, into DSBs, the most harmful form of DNA damage that led to the genomic instability, eventually responsible for the development of many diseases, including cancer [10, 15].

In addition, PARP1 promotes the repair of DNA DSBs through the high-fidelity homologous recombination (HR), by activating and recruiting multiple proteins such as ATM, Mre11, and Nbs11 to DSB lesions, and simultaneously inactivating DNA-dependent protein kinases that favor the more error-prone nonhomologous end-joining (NHEJ) [16].

Suppression of PARP1 leads to the accumulation of unrepaired DNA SSBs and the stalling of replication forks [17]. The persistence of SSBs culminates in the collapse of stalled replication forks into highly cytotoxic DSBs. HR is considered the highest fidelity machinery to repair DSBs and indispensable to maintain the genomic integrity. HR, as a complex mechanism, involves a large number of proteins that operate from the DSBs detection to the effective DNA repair. In this context, BRCA1 and BRCA2 are crucial players to guarantee HR high efficiency. Indeed, both proteins interact with many HR effectors, participating in the DSB detection and guiding the formation of the complex that effectively repairs the DNA strand. BRCA2 is even more important since it is responsible for the recruitment and loading onto the DNA strand of RAD51, the recombinase, defined as the catalytic core of HR, that guides homology search and strand invasion.

In case of PARP inhibition, HR acts as a compensatory pathway to maintain the genomic integrity and guarantee cell survival [16]. Normal cells are BRCA-proficient, thus able to efficiently repair DSBs and survive under PARP inhibition. On the contrary, cancers harboring BRCA1 or BRCA2 mutations become HR-defective and highly vulnerable to the effects of PARP inhibition, facing a genomic instability that turns into cell death [18]. This relationship has been defined as synthetic lethality (SL) and it has been exploited as a strategy to selectively target cancers with somatic and germline BRCA1 and BRCA2 mutations [18]. The concept of SL was originally derived from genetic studies on gene-to-gene interactions and their consequent impact on cell viability. According to this genetic principle, two genes are synthetic lethal if their simultaneous mutation causes cell death, while the mutation of either gene alone is compatible with cell viability. (Figure 1).

Figure 1.

Concept of synthetic lethality.

This SL relationship can be explained by the presence of a buffering effect, which links two genes and is lost in case of simultaneous mutation. The SL concept can be extended to proteins encoded by synthetic lethal genes and, in turn, to the cellular pathways. According to this, SL has been exploited for drug discovery to selectively treat cancers, harboring a specific gene mutation, with drugs targeting the synthetic lethal partner. Notably, taking advantage of a mutation present only in cancer cells, SL approach promises to be selective, killing cancer cells while sparing normal ones.

The evidence of a synthetic lethal interaction between PARP inhibition and BRCA1/2 mutation suggested a clinical strategy to treat cancers with loss-of-function mutations in either BRCA1 or BRCA2 genes with PARPis as drugs [14, 16]. PARP1 is the primary target of clinically used PARPis. Initially, PARP1 inhibitors were developed to be used as potentiators of DNA damaging chemo- or radiotherapeutic agents [14, 19]. Later, PARPis revealed their potential as single agents in the treatment of BRCAness tumors with an HR-defective condition. BRCAness refers to tumors with specific genomic signatures (other than BRCA mutation) that cause HR-deficiency and thus susceptibility to SL of PARPis [20]. PARPis block the catalytic activity of PARP1 by directly binding to the NAD+ pocket, responsible for the synthesis of PAR chains. For this reason, the originally proposed mechanism of action (MOA) to explain the SL effect, described PARPis as direct inhibitors of the PARylation, which causes the impairment of DNA repair proteins and the phenocopying effect of deleting PARP1 [19]. Indeed, persistent unrepaired DNA breaks can cause the collapse of replication forks with the formation of DSBs, not repaired by HR-deficient cells. However, the most credited MOA of PARPis is their ability to trap PARP1 on DNA strand, ultimately preventing its release from the DNA strand by the inhibition of autoPARylation and PARP1 conformational change. The trapped PARP1 acts as an obstacle, causing unstable replication forks and consequent accumulation of DNA lesions, which are eventually repaired by error-prone mechanisms in HR-deficient cells [19]. This mechanism explains the PARPis cytotoxic effect and most likely accounts for the SL effect in BRCAness tumors.

This chapter examines the clinical development studies, which lead to PARPis approval, the safety and the management of adverse events associated to this new class of drugs, and rational consideration that should guide the use of PARPis in the frontline setting.

2. PARPis and clinical trials

Currently, three PARPis are approved for the treatment of EOC: olaparib, rucaparib, and niraparib. All these drugs are available for the management of recurrent disease as monotherapies, whereas only olaparib and niraparib are approved as frontline maintenance options after a response to platinum-based chemotherapy. Lastly, olaparib is the only approved drug in combination with bevacizumab as a first-line maintenance strategy for a subset of patients whose cancer is associated with HRD status (Table 1).

2.1 Recurrent setting

2.1.1 Maintenance therapy in the recurrent setting

Lynparza® (olaparib) is a first-in-class, small molecule, PARPi approved initially as monotherapy for maintenance treatment of patients in response to their most recent platinum-based regimen in olaparib (capsule formulation) in platinum-sensitive, relapsed, BRCA-mutated HGSOC in the EU based on the results of Study 19.[21] In 2014, there were no agents for maintenance treatment of EOC after a response to platinum-containing regimens, and standard of care (SOC) was not clearly established in this setting.

Preliminary studies indicated the olaparib exerted anti-cancer activity in BRCA-negative tumor having a defect in the HR pathway other than related to BRCA mutation (BRACAness phenotype) [22]. Upon these premises, the aim of phase II Study 19 was designed to assess efficacy and safety of olaparib monotherapy as maintenance treatment in patients with platinum-sensitive, relapsed, HGSOC who had a response to their most recent platinum-based chemotherapy [23]. No prospective BRCA testing was required for eligibility for this study, which enrolled 265 patients who had received two or more platinum-based regimens and had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib (400 mg twice daily) or placebo until the primary endpoint progression-free survival (PFS) defined as the time from randomization (on completion of chemotherapy) until the objective assessment of disease progression according to response evaluation criteria in solid tumors (RECIST) guidelines or death. In terms of efficacy results, median PFS in study 19 was significantly longer with olaparib than with placebo (8.4 months vs. 4.8 months; hazard ratio [HR] for progression or death, 0.35; 95%: confidence interval [CI], 0.25 to 0.49; P < 0.001) [23].

Furthermore, a prespecified exploratory analysis of all efficacy endpoints performed according to BRCA mutation status demonstrated that patients with a BRCA mutation had the greatest PFS benefit from treatment with olaparib maintenance therapy compared with placebo. For patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11.2 months [95% CI 8.3–not calculable] vs. 4.3 months [3.0–5.4]; HR 0.18 [95% CI 0.10–0.31]; p < 0.0001) [24]. In December 2014, olaparib was approved in the EU for the maintenance treatment of adults with platinum-sensitive, relapsed, HGSOC, FT, and PPC who are in complete or partial response to platinum-based chemotherapy and BRCA mutation-positive (germline and/or somatic).

To confirm olaparib benefits in the same setting using tablets as opposed to the previous capsule formulation, the double-blinded, randomized, and placebo-controlled phase III SOLO-2 trial was planned. This study enrolled 295 platinum-sensitive relapsed patients with high-grade serous or endometrioid EOC, PT, or PPC, preselected for BRCA1/BRCA2 mutations who were in response to their most recent platinum-based chemotherapy after ≥2 lines of treatment. Participants were randomized 2:1 to maintenance olaparib (300 mg twice daily; tablet) or placebo. The primary endpoint for this study was investigator-assessed PFS. The trial met its primary endpoint with a median PFS of 19.1 months vs. 5.5 months (HR 0.30; 95% CI 0.22 to 0.41; P < 0.0001), substantially exceeding the efficacy results seen in Study 19 [25]. Despite SOLO-2 study enrolled only patients with BRCA mutations, based upon the combined results of both Study 19 and SOLO-2 US Food and Drug Administration (FDA) in 2017 and European Medicines Agency (EMA) in 2018 granted approval to olaparib for the maintenance treatment regardless of BRCA mutation status [26].

Zejula® (niraparib) is an oral, small molecule inhibitor of PARP enzymes, including PARP-1 and PARP-2 [27]. After niraparib 300 mg demonstrated preliminary antitumor activity in ovarian cancer patients in phase 1 dose-escalation study, phase III NOVA trial sought to establish the efficacy and safety of niraparib in patients with platinum-sensitive, recurrent, histologically confirmed ovarian cancer as maintenance treatment following complete or partial response to platinum-based chemotherapy [28]. Different from SOLO-2 trial, NOVA study enrolled two independent cohorts based on the presence or absence of a germline BRCA (gBRCA) mutation (gBRCAm) according to BRCA analysis testing (Myriad Genetics, Inc.) from tumor and blood samples. In each cohort (n = 203 for gBRCAm cohort and n = 350 non-gBRCAm cohort), patients were randomly assigned to receive 300 mg of niraparib once daily or placebo in 28-day cycles until disease progression or unacceptable toxicity. Primary endpoint was PFS in intent-to-treat (ITT) analyses of the three predefined primary efficacy populations namely gBRCAm cohort, the HRD-positive subgroup of the non-gBRCAmcohort, and the overall non-gBRCAm cohort. Patients in the niraparib group had a significantly longer median PFS than did those in the placebo group; 21.0 vs. 5.5 months in the gBRCAm cohort (HR, 0.27; 95% CI, 0.17–0.41) and 12.9 months vs. 3.8 months in the non-gBRCAm cohort for patients who had tumors with HRD (HR, 0.38; 95% CI, 0.24–0.59). Finally, the median PFS also favored the niraparib group in the overall non-gBRCAm cohort, 9.3 months vs. 3.9 months (HR ratio, 0.45; 95% CI, 0.34–0.61; P < 0.001 for all three comparisons) [28].

The overall results of this study indicated that, among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of PFS was significantly longer among those receiving niraparib compared to those receiving placebo. In March 2017, niraparib received its first FDA and EMA approval for the maintenance treatment of adult patients with recurrent EOC, FT, or PPC who are in a complete or partial response to platinum-based chemotherapy regardless of BRCA mutations or HRD status [27].

Rubraca® (rucaparib) is an oral, small molecule inhibitor of PARP enzymes, including PARP-1, −2, and − 3 [29]. Like the other two PARPis, rucaparib was demonstrated to exert synthetic lethality in cells with HRD [29]. Data of efficacy as maintenance treatment of recurrent EOC was established in phase III ARIEL-3 study, where 564 patients with recurrent platinum-sensitive, high-grade serous or endometrioid ovarian carcinoma had completed at least two platinum-based chemotherapy regimens with response to the last regimen were included [30]. Patients were randomly assigned to receive rucaparib 600 mg twice daily or a placebo after stratification by HRD status, latest progression-free interval, and response to the latest platinum-based regimen. HRD combined tumor BRCA status as well as the percentage of genome-wide loss of heterozygosity (LOH) with the use of Foundation Medicine’s T5 next-generation sequencing (NGS) assay.

For patients with BRCA mutations, median PFS in the rucaparib group was 16.6 months compared to 5.4 months in the placebo group (HR 0.23; 95% CI 0.16–0.34; p < 0.0001). In patients with HRD tumors, patients receiving rucaparib also had improved PFS compared to placebo (13.6 months vs. 5.4 months; HR 0.32; 95% CI 0.24–0.42; p < 0.0001). In the ITT population, the median PFS was 10.8 months in the rucaparib group vs. 5.4 months in the placebo group (HR 0.36; 95% CI 0.30–0.45; p < 0.0001) [30]. Based on these data, in 2018, the FDA and EMA granted rucaparib a new indication concerning maintenance treatment for platinum-sensitive relapsed high-grade epithelial ovarian cancer in patients who are in response to platinum-based chemotherapy regardless of BRCA or HRD status [30].

2.1.2 Treatment of recurrent epithelial ovarian cancer

In the US, the first indication for the clinical use of PARP inhibitors in EOC was given for the treatment setting (non-maintenance) of recurrent disease. In 2014, under FDA’s accelerated approval pathway, olaparib received its first indication for the treatment of women with recurrent ovarian cancer with gBRCAm who received three or more prior lines of chemotherapy [31]. This approval was based on the analysis of 137 patients from Study 42 which included subjects with measurable BRCA-deficient recurrent disease treated with a median of 3.4 prior lines of chemotherapy [32]. The objective response rate (ORR) for patients in this cohort with measurable disease was 34% (95% CI, 26–42%) and the median duration of response was 7.9 months (95% CI, 5.6–9.6 months). Of note, this accelerated approval was not restricted to either the platinum-sensitive or platinum-resistant disease setting. The justification is the assumption that olaparib would have a better response rate and favorable safety profile as compared with available single-agent chemotherapeutic options given usually in this setting [31]. Along with the drug, the FDA also approved a molecular companion diagnostic test, BRACAnalysis CDx (Myriad Genetics, Inc.) to detect the presence of gBRCA mutations in blood samples [31].

Accelerated approvals were contingent on the results of phase III confirmatory trial SOLO-3. This open-label study was conducted to compare olaparib with non-platinum chemotherapy in patients with gBRCAm platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy [33]. Approximately 266 patients were randomly assigned 2:1 to olaparib 300 mg twice a day or physician’s choice (PC) single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). The primary end point was ORR in the measurable disease analysis set assessed by blinded independent central review (BICR). The key secondary end point was PFS assessed by BICR in the ITT population. The BICR-assessed ORR was 72.2% with olaparib versus 51.4% with PC, for an odds ratio of 2.53 (95% CI 1.40–4.58; P = 0.002). Median PFS was 13.4 months with olaparib versus 9.2 months with chemotherapy (HR 0.62, 95% CI 0.43–0.91; P = 0.013) [33]. As of August 2022, the manufacturer of olaparib, AstraZeneca (AZ) has released a Dear HCP Letter informing HCPs that a recent subgroup analysis indicated a potential detrimental effect on OS for olaparib compared to the chemotherapy control arm in SOLO3. AZ is having active discussions with FDA about revisions to the olaparib US prescribing information label and are planning to voluntarily withdraw the late line treatment indication. At the time of publishing, olaparib still holds an active indication for late line treatment [34].

Additionally, rucaparib received FDA accelerated approval in 2016 for treatment of recurrent BRCA-associated EOC based on combined data from two single-arm trials Study 10 and ARIEL2 [35]. The combined analyses included 106 patients with BRCA mutations (germline or somatic) and advanced EOC who had received at least two prior platinum-based chemotherapy regimens. The ORR for treatment with rucaparib 600 mg orally twice a day was 54%, with a median duration of response (DOR) of 9.2 months. As expected, ORR was greatest for those with platinum-sensitive disease (66%; 95% CI: 54–76%) and lowest in platinum-refractory patients (0%; 95% CI: 0–41%). Rucaparib received accelerated approval based on ORR and DOR seen in phase II trials. At the same time, approval of a companion diagnostic test, FoundationFocus CDx _BRCA (Foundation Medicine, Inc.) to detect tumor BRCA1 and BRCA2 mutations (germline and/or somatic) was granted [36].

Continued approval of rucaparib in this indication was contingent upon of demonstration of clinical benefit in confirmatory phase 3 trial, ARIEL4 conducted in germline or somatic BRCA mutated patients with relapsed, HGSOC, FT, or PPC that had received at least 2 prior chemotherapy regimens, with at least 1 of which being platinum-based. Treatment with rucaparib was administered at 600 mg twice daily in the investigational arm (n = 233), and in the control arm (n = 116), weekly paclitaxel was given for those who were platinum-resistant or partially sensitive, and platinum-based chemotherapy monotherapy or doublet regimen was given to those who were fully sensitive to platinum. The investigator-assessed median PFS in the efficacy population was 7.4 months (95% CI, 7.3–9.1) with rucaparib in comparison with 5.7 months (95% CI, 5.5–7.3) with chemotherapy (HR, 0.64; 95% CI, 0.49–0.84; P = 0.001). In the ITT population, the median PFS was the same at 7.4 months (95% CI, 6.7–7.9) and 5.7 months (95% CI, 5.5–6.7) in the rucaparib and chemotherapy arms, respectively, but showed a hazard ratio of 0.67 (95% CI, 0.52–0.86; P = 0.0017) [37]. As of June 2022, the manufacturer of rucaparib, Clovis has released a Dear HCP Letter informing HCPs that they have voluntarily withdrawn rucaparib's late line treatment indication in consultation with FDA after a detrimental effect of OS was observed for rucaparib compared to the chemotherapy control arm in the ARIEL-4 trial. Clovis has confirmed they have voluntarily requested the withdrawal of the same BRCAm OC treatment indication in EU. At the time of publishing, Rubraca's indication in later line treatment is still active in EU [38].

Lastly, the role of niraparib in later lines of treatment of patients with relapsed EOC was assessed in a single-arm study [39]. QUADRA was a multicenter, open-label, single-arm study that evaluated the safety and efficacy of niraparib in 463 patients with metastatic, relapsed, HGSOC, FT, or PPC, who were treated previously with at least 3 lines of chemotherapy. QUADRA met its primary endpoint: ORR was 24% (95% CI 16–34%) with the median DOR being 8.3 months. Of note, niraparib demonstrated efficacy beyond patients with BRCA mutation; within the cohort of 35 patients with non-BRCA-mutated tumors who were HRD-positive and platinum-sensitive, the ORR was 20%. As a result, in October 2019, niraparib received FDA approval as a monotherapy treatment for recurrent EOC who had received three or more prior chemotherapy regimens in the context of HRD-positive tumors. HRD positive status is defined by either a deleterious, suspected deleterious BRCA mutation, or genomic instability, and who has progressed more than six months after responding to the last platinum-based chemotherapy [27].

2.2 Frontline maintenance treatment

After the positive results achieved for relapsed disease, four Phase III studies investigated the role of PARP inhibitors as maintenance therapy following platinum-based chemotherapy in newly diagnosed advanced EOC (Table 2). The outcomes of these studies redesigned the treatment landscape of EOC offering several therapeutic options to patients in the frontline setting.

Agent	Maintenance	Later line treatment
Olaparib	Study 19 (EU); • Recurrent	Study 42, SOLO-3 (US); • BRCAm
	SOLO-2 (US); • Recurrent
	SOLO-1 (US, EU); • BRCAm front-line
	PAOLA-1 (US, EU); • HRD front-line
Rucaparib	ARIEL3 (US, EU); • Recurrent	Study 10, ARIEL2, ARIEL4 (EU); • BRCAm
Niraparib	NOVA (US, EU); • Recurrent	QUADRA (US); • HRD
	PRIMA (US, EU); • Frontline

Table 1.

Current PARPi approved indications in ovarian cancer.

Trial name	Patients (n) and randomization	Median PFS duration (primary endpoint and biomarker subgroups)
SOLO-1 [40]	391 (olaparib vs. placebo; maintenance)	All patients have BRCA1/2 mutations; Not reached vs. 13.8 months; HR 0.30, 95% CI 0.23–0.41; p < 0.001
PAOLA-1 [41]	806 (olaparib plus bevacizumab; vs. placebo plus bevacizumab)	ITT: 22.1 months vs. 16.6 months (HR 0.59, 95% CI 0.49–0.72; p < 0.001) HRD-positive: 37.2 months vs. 17.7 months (HR 0.33, 95% CI 0.25–0.45) HRD-negative: 16.6 months vs. 16.2 months (HR 1.00, 95% CI 0.75–1.35)
PRIMA [42]	733 (niraparib vs. placebo maintenance)	HRD-positive: 21.9 months vs. 10.4 months (HR 0.43, 95% CI 0.31–0.59; p < 0.001) ITT: 13.8 months vs. 8.2 months (HR 0.62, 95% CI 0.50–0.76; p < 0.001) HRD-negative: 8.1 months vs. 5.4 months (HR 0.68, 95% CI 0.49–0.94)
VELIA [43]	1140 (chemotherapy only [control] vs. veliparib combination only vs. veliparib throughout)	Veliparib throughout vs. control: BRCA1/2-mutated: 34.7 months and 22.0 months (HR 0.44, 95% CI 0.28–0.68; p < 0.001) HRD-positive: 31.9 months and 20.5 months (HR 0.57, 95% CI 0.43–0.76; p < 0.001) ITT: 23.5 months and 17.3 months (HR 0.68, 95% CI 0.56–0.83; p < 0.001) HRD-negative: HR 0.81, 95% CI 0.60–1.09
ATHENA-MONO [44]	538 (rucaparib vs. placebo maintenance)	HRD-positive: 28.7 months vs. 11.3 months (HR 0.47; 95% CI: 0.31–0.72; p = 0.0004) ITT:20.2 months vs. 9.2 months (HR, 0.52; 95% CI, 0.40–0.68; P < .0001) HRD-negative: 12.1 months vs. 9.1 months (HR, 0.65; 95% CI, 0.45–0.95)

Table 2.

Results of Phase III Trials for PARPi maintenance in front-line setting.

The evidence for the use of olaparib maintenance as a SOC for women with newly diagnosed advanced ovarian cancer and BRCA mutation is derived from the result of SOLO-1 trial [40]. In this double-blind, placebo-controlled, multicenter trial newly diagnosed stage III or IV, high-grade serous or endometrioid ovarian, FT, PPC, and germline BRCA mutations in complete response (CR) or partial response (PR) after platinum-based chemotherapy were randomized 2:1 to olaparib at 300 mg twice daily (n = 260) versus placebo (n = 131) for up to 2 years or until disease progression. At the primary analysis cutoff date of May 2018 the median PFS for patients treated with olaparib was not reached compared to 13.8 months for patients treated with placebo (HR, 0.30; 95% CI, 0.23–0.41; P < 0.001). Based on this data, in December 2018, olaparib received regulatory approval in the 1st-line maintenance setting for BRCAm advanced ovarian cancer in the US. The same indication has been granted in the EU in June 2019 [45].

Longer-term follow-up data from SOLO-1 revealed that the benefit of olaparib was sustained after treatment was stopped, with 48% of women treated with olaparib remaining progression-free for 5 years compared to 21% of placebo patients. Median PFS was 56·0 months (95% CI 41·9-not reached) for olaparib versus 13·8 months (11·1–18·2) for placebo (HR 0.33 [95% CI 0.25–0.43]) [46].

Shortly after, niraparib also demonstrated to improve PFS as first-line maintenance therapy vs. placebo in patients with newly diagnosed advanced ovarian cancer at high risk for relapse who responded to platinum-based chemotherapy irrespective of HRD status. The PRIMA trial was a randomized, double-blind, phase 3 trial in which participants after achieving a response to platinum-based chemotherapy were assigned in a 2:1 ratio to receive niraparib or placebo once daily [42]. At the onset of the trial, niraparib was administered at a fixed dose of 300 mg once daily. To improve safety and tolerability, following a protocol amendment, the dosage of niraparib was reduced to 200 mg once daily in patients with a body weight of <77 kg and/or a platelet count of <150,000/mcL at baseline. The primary end point was PFS in patients who had tumors with HRD and in the overall population, as determined by hierarchical testing. HRD was defined as the presence of a deleterious BRCA gene mutation and/or a myChoice test (Myriad Genetics, Inc.) score of ≥42 out of 100 (higher scores indicate higher levels of genomic abnormality). HR-proficient namely HRD-negative patients or patients who had an undetermined HRD status were included in the overall population. In the overall population, niraparib demonstrated a median PFS of 13.8 months compared with 8.2 months in patients who received placebo, leading to a 38% reduction in the risk of disease, progression, or death (HR, 0.62; 95% CI, 0.50–0.76; P < 0.001). In a subgroup of patients whose tumors were positive for HRD, the median PFS with niraparib was 21.9 months compared with 10.4 months for placebo (HR, 0.43; 95% CI, 0.31–0.59; P < 0.001). In addition, in HRD-negative the median PFS with niraparib was 8.1 months compared with 5.4 months for placebo (HR 0.68, 95% CI 0.49–0.94) [42].

In April 2020, niraparib was approved by the FDA for frontline maintenance in patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who experience complete or partial response to platinum-based chemotherapy [47]. A few months later also EMA granted the approval of niraparib for the same indication [48].

Two randomized phase 3 trials combining bevacizumab with a carboplatin–paclitaxel doublet for newly diagnosed EOC have demonstrated to improve PFS [49, 50]. Bevacizumab received regulatory approval for stage IIIB, IIIC, and IV as induction, in combination with chemotherapy, followed by maintenance monotherapy ovarian cancer in 2011 in the EU. On the contrary, FDA approved bevacizumab only in 2018 in this setting. Under the hypothesis that bevacizumab could cause hypoxia-induced HRD in the tumor and thereby increase sensitivity to PARPis, PAOLA-1 trial was designed to compare maintenance olaparib in combination with bevacizumab versus placebo plus bevacizumab [41]. Notably, PAOLA-1 was the only trial to include an active maintenance comparator in the first-line maintenance setting. The study enrolled 806 newly diagnosed advanced EOC patients who had no evidence of residual disease and were in clinical complete or partial response after receiving chemotherapy plus bevacizumab, regardless of surgical status and BRCAm status. Participants were randomized, to either bevacizumab (continued for 15 months) alone or olaparib (continued for up to 24 months) and bevacizumab.

In the overall population, a statistically significant improvement in median PFS (primary endpoint) for olaparib plus bevacizumab vs. bevacizumab alone (22.1 vs. 16.6 months, HR = 0.59; 95% CI = 0.49–0.72; P < 0.001) was observed. In the predefined subgroups, substantial PFS benefit was observed with the combination treatment vs. bevacizumab in the HRD population (including BRCA1/2 mutant; 37.2 vs. 17.7 months; HR = 0.33; 95% CI = 0.25–0.45). Further, for the patients that were HRD positive but did not have a BRCA mutation, the median PFS was 28.1 months in the combination arm versus 16.6 months in the bevacizumab arm (HR 0.43, 95% CI 0.28–0.66). Interestingly, the median PFS for the patients who tested negative for HRD was similar between the olaparib group and placebo; 16.6 months vs. 16.2 months (HR 1.00, 95% CI 0.75–1.35) [41].

Given that a superior clinical benefit was not demonstrated with olaparib versus placebo in HR proficient patients, FDA and EMA approved olaparib in combination with bevacizumab for the maintenance treatment of adult patients with advanced EOC, FT, or PPC who are in CR or PR to front 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 [21, 49].

During PARPis development, the attempts of combining these agents with cytotoxic chemotherapy have presented several challenges due to the overlapping toxicities such as myelosuppression, which made it difficult to establish appropriate dosages [52].

Among the similar same class of compounds, veliparib is considered to be less potent PARP catalytic inhibitor and a less potent DNA-PARP trapper [51]. Given this intrinsic pharmacological feature, veliparib is the only PARPi studied in combination with platinum-based chemotherapy in EOC in the first line setting. The aim of phase III VELIA trial is to assess the safety and efficacy of veliparib in both the frontline induction (with carboplatin/paclitaxel chemotherapy) and maintenance phases in HGSOC, FT, or PPC [43].

A total of 1140 patients were enrolled and randomized into 3 arms. The first arm received carboplatin and paclitaxel plus placebo followed by placebo maintenance. Arm 2 received carboplatin and paclitaxel plus veliparib followed by placebo maintenance. The third arm was the most significant for improving PFS meeting the endpoint of the trial. Patients in this arm received carboplatin and paclitaxel plus veliparib followed by veliparib maintenance. Of note, after the 6 cycles of combination chemotherapy, patients received an additional 30 cycles of maintenance therapy with either placebo or veliparib 300 mg twice daily escalating to 400 mg twice daily if tolerated. In contrast with PRIMA, PAOLA-1, and SOLO1, the PFS (primary endpoint) of the VELIA study was calculated from the start of chemotherapy. In addition, due to the study design, patients with stable disease (not only subjects with CR or PR after carboplatin and paclitaxel) received single-agent veliparib maintenance [43].

In the primary analyses of the VELIA trial, the addition of veliparib to carboplatin-paclitaxel and continuation as maintenance therapy resulted in statistically significant improvements in PFS in the BRCAm, HRD, and ITT populations. Using myChoice assay (Myriad Genetics, Inc.), a score of ≥33 was considered to indicate HRD status. To increase the sensitivity of detecting a response to PARPi, threshold score was revised from 42 to 33. The overall study results showed a significant PFS benefit for the veliparib throughout arm versus the control arm. The median PFS for the induction and maintenance phases combined in the ITT population was 23.5 months compared with 17.3 months in the control arm (HR, 0.68; 95% CI, 0.56–0.83; P < 0.001). As expected, the magnitude of the clinical benefit was larger in subjects with BRCA mutations with a median PFS of 34.7 months compared with 22.0 months for veliparib and placebo, respectively (HR, 0.44; 95% CI, 0.28–0.68; P < 0.001). Lastly, the median PFS in the subgroup of patients with HRD was 31.9 months for the veliparib throughout arm versus 20.5 months for the chemotherapy-alone arm, with an HR of 0.57 (95% CI, 0.43–0.76; P < 0.001). Given that no benefit in terms of PFS was obtained in any stratified biomarker population looking at combination chemotherapy only arm vs. control arm these results suggest that the benefit from veliparib is gained with maintenance therapy extension [43]. Currently, no health regulatory agency has approved veliparib in any setting of advance EOC.

Finally, very recently, rucaparib monotherapy demonstrated a significant improvement in PFS when given as first-line maintenance in EOC following treatment of platinum-based chemotherapy. In the phase III ATHENA-MONO trial, 538 patients with high-grade ovarian, FT, or PPC were allocated in 4:1 fashion to either rucaparib or placebo. Rucaparib/placebo continued for a maximum of 24 months or until disease progression, unacceptable toxicity, or death [44]. The primary endpoint was investigator-assessed PFS, which was analyzed in the HRD-positive subgroup including BRCAm or BRCA wild type/LOH-high and the ITT population.

In the ITT population, the median PFS was 20.2 months with rucaparib compared to 9.2 months with placebo (HR, 0.52; 95% CI, 0.40–0.68; P < 0.0001). Further, the median PFS for the HRD-positive patient population treated with rucaparib was 28.7 months vs. 11.3 months among those who received placebo (p = 0.0004) with HR 0.47 (95% CI: 0.31–0.72). Finally, in the HRD-negative subgroup, the median PFS was 12.1 months in the rucaparib group and 9.1 months in the placebo group (HR, 0.65; 95% CI, 0.45–0.95) underscoring the benefit that rucaparib can provide to women with EOC irrespective of HRD status [44]. To date, rucaparib has not received approval in the first-line ovarian cancer maintenance setting.

3. Safety and management of adverse events of PARPis

3.1 Dosing, administration, and drug interactions

PARP inhibitors are available in oral dosing forms (tablet or capsule). The starting dose of olaparib is at 300 mg twice daily and rucaparib at 600 mg twice daily [51, 54]. Niraparib is the only once-daily PARPi with an individualized starting dose based on weight (< or ≥ 77 kg) and/or platelet count (< or ≥ 150,000/mcl) at 200 mg or 300 mg for first-line maintenance advanced EOC indication [47, 48] and 300 mg once daily for all other indications [47]. Of note, approximately 15% of patients in the NOVA study weighed <58 kg and the incidence of grade 3 or 4 adverse events was higher in the patients with lower body weight (<58 kg). As such, a starting dose of niraparib 200 mg for patients weighing less than 58 kg may be considered [48].

Olaparib may be dose adjusted to 200 mg twice daily in patients with moderate renal impairment [21, 51] and the use of olaparib is not recommended in patients with severe renal impairment [21] whereas niraparib may be dose adjusted to a starting dose of 200 mg once daily for moderate hepatic impairment [47]. No starting dose adjustment is recommended for patients with mild to moderate renal or hepatic impairment for rucaparib [52, 53] but the use of rucaparib in patients with severe renal or hepatic impairment has not been studied [55].

The coadministration of food or high-fat meal does not have clinically significant impact on pharmacokinetics, thus PARPis can be taken with or without food [21, 47, 48, 51, 54, 55].

Based on in vitro studies evidence, the concomitant use of strong or moderate CYP3A inhibitors or inducers with olaparib is not recommended [21, 51]. If the concomitant use of a CYP3A inhibitor cannot be avoided, olaparib dose shall be dose reduced [51]. Although no dose adjustment is needed for rucaparib, caution is recommended for concomitant administration with strong CYP3A and P-glycoprotein (P-gp) inhibitors [54, 55]. In contrast, niraparib is metabolized via carboxylesterases (CEs) catalyzed amide hydrolysis instead of CYP3A enzymes. There is low likelihood of clinically relevant interactions with other drugs and no dose adjustment is required [47, 48].

3.2 Adverse events associated with PARPis and management

The adverse events of PARPi are largely class effects and are well-characterized. The following section describes the most frequently observed adverse events in PARPi as a class, health care professionals (HCP) should always refer to the latest prescribing information or product information for further adverse event-related recommendations.

3.2.1 Fatigue

Fatigue/asthenia of any grade is one of the most common class-wide adverse events of PARPis reported in 50–70% of patients in various treatment settings. Dose interruption or dose reduction may be utilized to manage fatigue/asthenia symptoms in 3–13% of patients [21, 44, 47, 48, 51, 54, 55]. Fatigue adverse events are largely mild to moderate (grade 1–2) and tend to occur early during initial phase of the PARPi therapy [56, 57].

It is important to note that patients may have baseline cancer-related fatigue as it affects 65% of patients with cancer [58]. Fatigue from chemotherapy can impact patient’s desire to start maintenance therapy. Prior to the initiation of PARPi, HCPs shall assess and screen patient for baseline fatigue and counsel patient on the risks of fatigue as an adverse event of PARPi for shared treatment decision-making [59].

Fatigue can be scored and routinely assessed as a self-report subjective score using a 10-point numerical rating scale. Pharmacological treatment of psychostimulants may be considered for a short period after thorough evaluation. Physical exercises such as walking, aerobic, and resistance exercises are recommended in non-cachectic patients. Other modalities to manage fatigue include psychoeducation to help patients by promoting self-management, adaptation, and adjustment to their existing situation and environment, and cognitive behavioral therapy. Practicing mindfulness and yoga could be an option to improve fatigue symptoms [58, 59].

3.2.2 Gastrointestinal toxicities

Gastrointestinal toxicities of nausea, vomiting, and diarrhea are frequently reported with PARPi as a class-wide adverse events.

Nausea and vomiting were reported in 53–77% and 22–40% of patients, respectively [21, 44, 47, 48, 51, 54, 55]. Nausea and vomiting were generally reported early, with the first onset within the first few months of PARPi treatment [48, 57]. Both nausea and vomiting were generally low grade (grade 1 or 2) and can be managed by dose interruption and/or dose reduction in majority of patients [21, 44, 47, 48, 51, 54, 55].

Olaparib, niraparib, and rucaparib are categorized as moderate to high emetic risks (≥30% frequency of emesis) per National Comprehensive Cancer Network® (NCCN) antiemesis guideline v2.022. While chemotherapy-induced nausea and vomiting (CINV) may seem transient, it can cause a negative impact on patient’s quality of life [60]. HCPs should assess patients who are at increased risk for CINV and counsel patients proactively. Risk factors of CINV include younger age, female sex, previous history of CINV, little or no previous alcohol use, prone to motion sickness, history of morning sickness during pregnancy, and anxiety/high pretreatment expectation of nausea. The use of single-agent prophylaxis with 5-HT3 reception agonists; granisetron, ondansetron, or dolasetron is recommended for prevention of emesis. Lorazepam may be added with or without histamine-2 blocker or proton pump inhibitor [61]. Bedtime administration of PARPi may be a potential method for managing nausea [47].

Diarrhea frequently occurred in 18–37% of patients. Grade ≥ 3 was infrequent, observed in ≤3% of patients [21, 44, 47, 48, 51, 54, 55]. For patients with mild to moderate diarrhea (grade 1–2), symptoms can be managed by oral hydration, dietary modification to avoid all lactose-containing products, high-osmolar dietary supplements, and the use of loperamide [62].

3.2.3 Hematologic toxicity

Hematologic toxicity (or myelosuppression) is a commonly recognized class-effect adverse event of PARPi that is linked to its mechanism of PARP trapping, which appears to drive cytotoxicity in healthy human bone marrow [56, 63]. Emerging clinical data suggest an inverse relationship between PARPi trapping potency and risks of myelosuppression adverse events [63]. Myelosuppression adverse events tend to occur in the early phase of PARPi maintenance treatment with median time to onset ranging from 22 to 80 days (∼first 3 treatment cycles) [21, 48, 55, 64]. Although, grade ≥ 3 hematological adverse events tend to have a later onset [21, 55].

Anemia of any grade has been reported in 34–64% of patients receiving PARPi with grade ≥ 3 observed in 20–30% of patients. Permanently discontinuation due to anemia of PARPi was seen in ≤4% of patients in clinical trials [44, 47, 51, 54]. Neutropenia of any grade has been reported in 17–42% of patients receiving PARPi, neutropenia ≥ grade 3 was observed in less than ∼20% of patients [44, 47, 51, 54]. Dose interruption or reduction may be used to manage anemia or neutropenia adverse events. For patients whose hemoglobin level falls <8 g/dL or if neutrophil count is <1000/mcL, PARPi should be held for a maximum of 28 days and blood counts or neutrophil counts to be monitored weekly until it returns to ≥9 g/dL or ≥ 1500/mcL, respectively. PARPi therapy may be resumed at a reduced dose [47].

Thrombocytopenia of any grade has been reported in ∼10–30% of patients with a higher incidence of ∼50–65% seen in patient receiving niraparib therapy [42, 45, 49, 52]. Grade ≥ 3 thrombocytopenia was more common in niraparib ranging from 20–30% compared to olaparib and rucaparib at 1–7% [44, 47, 51, 54]. For platelet count <100,000/mcL, niraparib can be held for a maximum of 28 days, platelet counts to be monitored weekly until recovery to ≥100,000/mcL. Niraparib may be resumed at the same or reduced dose but if platelet count was <75,000/mcL at the onset of adverse event occurrence, a reduced dose is recommended. If a patient experiences severe thrombocytopenia with a platelet count ≤10,000/mcL or if a patients has other risk factors of anticoagulation or antiplatelet drug use, these drugs should be held, and a platelet transfusion may be considered [47].

Overall, higher incidences of hematologic toxicity have been observed with niraparib, which is consistent with its pharmacologic properties as niraparib has higher PARP trapping potency relative to olaparib and rucaparib [65, 66]. As discussed above in Section 2.2, individualized starting dose of niraparib was evaluated prospectively in 35% of patients in the PRIMA trial. Results showed improved safety and tolerability of niraparib [42].

3.2.4 Off-target effects

Hypertension and hypertensive crisis have been reported among patients who were treated with niraparib. Grade ≥ 3 hypertension occurred in 5–9% of patients across treatment settings. Niraparib’s pharmacological inhibition of the dopamine transporter, norepinephrine transporter, and serotonin transporter, demonstrated in an in vitro pharmacology screen may explain its unique effects on pulse rate and blood pressure. As such, blood pressure and heart rate monitoring weekly for the first 2 months, then monthly for the first year of treatment, and periodically thereafter is recommended [47, 48].

Posterior reversible encephalopathy syndrome (PRES) is a rare, reversible, neurological disorder that presents with symptoms including seizure, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. PRES was observed in 0.1% of 2165 patients treated with niraparib in clinical trials and post-marketing reports. If PRES is suspected, discontinue niraparib and specific symptoms associated with PRES shall be treated [47, 48].

3.2.5 Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)

MDS/AML occurred in patients treated with PARPi with incidences ranging from 0.2%−1.7% in ovarian cancer clinical trials setting and some cases were fatal [21, 44, 47, 48, 51, 54, 55]. In a pharmacovigilance analysis of the FDA Adverse Events Reporting System (FAERS) database, a total of 319 cases of PARPi-associated MDS/AML were identified from the period of quarter (Q)4, 2014 to Q1, 2020. Death or other life-threatening outcomes were reported in 49% of cases [67]. The duration of PARPi treatment varied from 1 month to >10 years. In all cases, patients had received previous platinum-based chemotherapy and/or other DNA damaging agents including radiation [21, 44, 47, 48, 51, 54, 55].

The mechanism of PARPi associated with MDS/AML remains unclear [67]. It is recommended to not start PARPi therapy until patients have recovered from hematological toxicity caused by prior chemotherapy (≤ grade 1). For prolonged hematologic toxicities >4 weeks, patient shall be referred to a hematologist for further evaluation. If MDS/AML is confirmed, discontinue PARPi permanently [21, 44, 47, 48, 51, 55].

4. General recommendations for patient selection for front-line maintenance PARPi treatment

For decades the initial therapeutic approach for patients with EOC relied on surgery followed by platinum-based chemotherapy [68]. Surgery allows confirmation of the diagnosis, as well as staging of the disease. The main goal of the primary debulking surgery (PDS), which plays a cardinal role in the overall management of advanced EOC (stages III and IV), is to obtain an optimal cytoreduction defined as complete resection of all visible tumors [69]. When complete cytoreduction is not attainable, either due to an extensive disease burden or to poor performance status, the patients are treated first with neoadjuvant platinum-based chemotherapy [70, 71]. This strategy usually encompasses the administration of three cycles of chemotherapy and upon response to the systemic treatment, the interval debulking surgery (IDS) is performed. After surgery, chemotherapy is continued for up to six cycles. When PDS is considered appropriate, intravenous platinum and taxane regimen every 21 days for six cycles represent the adjuvant treatment [72]. However, the timing of surgical intervention in relation to systemic treatment (neoadjuvant vs. adjuvant) is still an unsettled matter.

Since 2011, in the first line setting, the addition of the vascular endothelial growth factor inhibitor (VEGFi), bevacizumab to chemotherapy following debulking surgery has become SOC given the positive results relative to PFS benefit demonstrated in two randomized phase III trials, GOG-0218 and ICON7 [49, 50]. However, the addition of bevacizumab is currently recommended in a subgroup of patients with poor prognosis, namely patients with stage III and residual disease after surgery or stage IV based on a post hoc overall survival analysis.

With the advent of PARPis in the clinic, the paradigm for the treatment of EOC has undergone remarkable changes. To assist health care providers, clinical practice guidelines have been updated to support the decision-making process and to ensure consistency of treatment is aligned with current best evidence-based medicine. In addition to this practice, we also strongly advocate as a primary principle, that sound clinical judgment (e.g., concern relative to treatment-associated toxicity, performance status, and other comorbidities) and patient preference should be also considered. This mindset is extremely important especially when the risk-benefit profile of treatment in a subset of patients has not been clearly established and, therefore, other management options are available.

For newly diagnosed patients, testing for BRCA mutation (germline/somatic) is strongly recommended, given that systemic therapeutic options are available in frontline setting. Maintenance use of olaparib for 2 years as first-line management approach should be the SOC for all patients with BRCA1/2 mutation in newly diagnosed advanced EOC after a response to chemotherapy based on SOLO-1 trial results. As mentioned in the 5-year follow-up analysis of SOLO-1, olaparib recipients had doubled the median PFS compared to those treated with placebo [46].

If BRCA mutation (germline/somatic) results are negative, HRD test should be considered to identify a subgroup of women who are BRCA wild type but derive greater clinical benefit from a PARPi. In the presence of positive HRD score after CR or PR to front-line platinum-based chemotherapy, maintenance use of niraparib for 3 years or olaparib in combination with bevacizumab are available options based on PRIMA and PAOLA-1 study, respectively. Both studies enrolled newly diagnosed EOC patients, regardless of their BRCA status.

PRIMA trial enrolled high-risk patients, that is, 35% of patients had stage IV [42] and 45% of patients had visible disease after PDS or IDS [73]. Among patients with HRD and BRCA wild type, the median PFS was 19.6 months in the niraparib group vs. 8.2 months in the placebo group (HR = 0.50; 95% CI 0.31–0.83) [42].

In PAOLA-1 trial, the median PFS was 28.1 months vs. 16.6 months, respectively, for HRD-positive BRCA wild-type. Due to that fact that PAOLA-1 study design did not have olaparib maintenance only arm, the value of adding bevacizumab remains uncertain [41].

Patients with HRR-proficient tumors have poorer prognosis. Nonetheless, for woman whose tumor is found to be HRR proficient (HRD negative), PARPi monotherapy can still be offered, despite the diminished clinical benefit seen among this cohort of women based on PRIMA trial results. [74] In HRD-negative patients, niraparib demonstrated a modest yet statistically significant improvement in median PFS 8.1 months vs. 5.4 months, with niraparib versus placebo (HR 0.68, CI 95% 0.49–0.94). Conversely, in PAOLA-1 study, olaparib plus bevacizumab did not show a significant improvement in PFS in HRD-negative patients [41].

Therefore, bevacizumab monotherapy regimen upfront after induction with chemotherapy may be considered a valid strategy in patients with HRD negative tumors considering specific clinical characteristics (e.g., pleural effusions or ascites) with the option to administer a PARPi in later lines upon recurrence. It has been noted, however, that this approach will need to demonstrate a subsequent response to platinum to guarantee PARPis sensitivity. Indeed, the American Society of Clinical Oncology (ASCO) guideline supports the use of PARPis in all patients with advanced EOC in the front-line maintenance setting regardless of HRD status. Based on the current label, only niraparib is approved in the first-line maintenance treatment setting regardless of biomarker status. In this scenario, bevacizumab could be postponed to later line for the treatment of women with both platinum-sensitive and platinum-resistant diseases [75].

Lastly, given that patients enrolled in these studies excluded women who previously received PARPi, no data are currently available on the efficacy of retreatment with PARPi after progression. Hence, up to this point, the recommendation advises against PARP inhibitor retreatment in advance EOC [75]. Needless to say, this area of research is becoming the highest unmet need in ovarian cancer due to the increasing patient population receiving first-line PARPis.

5. Conclusion

The main objective of this chapter was to highlight the recent contribution brought by the approval of PARPis for the treatment of advanced EOC. The PARPis clinical development underscored the value of the “bench to bedside framework” which translates basic biological knowledge into medical therapeutic application.

Initially developed as maintenance therapy in patients with complete or partial response after platinum-based chemotherapy in a recurrent setting, PARPi is now approved in multiple settings including as a frontline management strategy. However, the use of these novel agents early in the disease trajectory exposes new therapeutic challenges associated with PARPi-resistance which clinically leads to treatment failure. As a result, uncovering the molecular mechanisms linked to acquired and intrinsic resistance to PARPi is an active area of research. Overall increased drug efflux (which leads to reduced intracellular drug concentrations), restoration of HRR repair (re-expression of functional proteins involved in HRR or somatic reversion mutations in either BRCA1 or BRCA2), and aberrations in PARP signaling are the common pathways involved in PARPi-resistance [76]. A detailed elucidation of these molecular events would be essential for the design of new therapeutic strategies to prevent/overcome resistance. Currently, several hypotheses within clinical trials (targeted combination intervention) are under investigation with the aim to re-sensitize and enhance ovarian cancer cells to PARPis, while optimizing tolerability and quality of life. The hope is that there will be a continuous improvement in targeted therapies leading to an extension of overall survival and an effective curability of this disease.

Conflict of interest

Nicola Di Santo is employed by Pfizer, Inc. and has an ownership interest (including stocks); Yin Wong is employed by GSK, plc and has an ownership interest (including stocks).