PARP Inhibitor in Epithelial Ovarian Cancer: Comparison
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Ovarian cancer is one of the most common gynecologic cancers and has the highest mortality rate of any other cancer of the female reproductive system. Epithelial ovarian cancer (EOC) accounts for approximately 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery accompanied by pre- or postoperative platinum-based chemotherapy. Nevertheless, up to 80% of the patients relapse within the following 12–18 months from the completion of the treatment and then receive first-line chemotherapy depending on platinum sensitivity. Mutations in BRCA1/2 genes are the most significant molecular aberrations in EOC and serve as prognostic and predictive biomarkers. Poly ADP-ribose polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality.

  • ovarian cancer
  • BRCA mutations
  • PARP inhibitors
  • immune checkpoint inhibitors

1. PARP Inhibitors

PARP inhibitors have transformed the treatment landscape of patients with EOC. PARPs are a family of 17 nucleoproteins. Among them, PARP-1 is the best characterised and accounts for approximately 90% of the total PARP activity. PARPs are characterised by a common catalytic site that transfers an ADP-ribose group on a specific acceptor protein using NAD+ as a cofactor. Polymerisation of ADP-ribose (PARylation) is crucial for the important functions of PARP enzymes in the DNA damage response and nucleosome remodeling (Figure 1) [1]. Activation of PARPs occurs through DNA binding via zinc fingers. PARP-1, -2, and -3 are integral in the DNA damage response system by activating response pathways and facilitating repair. Unrepaired SSB or a damaged base can block the replication forks, resulting in fork collapse and DSB.
Figure 1. The cycle of poly ADP-ribose (PAR) metabolism “PARylation”.
Poly ADP-ribose polymerase (PARP) binds the damaged DNA, becomes active, and catalyses the formation of PAR polymers on a variety of protein acceptors, including itself. Electrostatic repulsion between the newly formed polymer and DNA causes the release of PARP, thereby inactivating it. The poly (ADP-ribose) glycohydrolase (PARG) enzyme degrades the PAR, thereby allowing for PARP to once again bind to damaged DNA and initiate “PARylation”.
PARP inhibitors have changed the therapeutic strategy of patients with BRCA-related EOC. These agents have many similarities, but at the same time, notable differences, which are based on the differences between their chemical structural features [2]. All of the PARP inhibitors that were developed in EOC are PARP-1 and PARP-2 inhibitors, while olaparib and rucaparib additionally inhibit PARP-3. Furthermore, rucaparib inhibits tankyrase-1, which is another member of the PARP family. Currently, novel agents are in clinical development. Alterations in BRCA genes may also be the result of either somatic mutations or epigenetic silencing in sporadic EOC, which extends the activity of PARP inhibitors to a greater subset of sporadic EOC patients with HR deficiency. It has not yet been clarified whether the biological effects of harbouring somatic BRCA mutations, a phenomenon termed as BRCAness, is identical to their germline counterparts. However, there are reports of patients with somatic BRCA mutations who achieved longer progression-free survival (PFS) than wild-type cohorts, similar to the population with germline BRCA mutations. Nevertheless, OS was not affected significantly [3].
It is well recognised that when mutations occur within DNA repair pathways, there is an increased risk of malignant transformation and chemotherapy resistance. Much research has focused on protecting cells from DNA damage and/or restoring DNA repair function. However, emerging data suggest that the concept of synthetic lethality may be a particularly attractive therapeutic approach. Within this concept, the potential of PARP inhibitors therapy in EOC was highlighted by preclinical studies and clinical trials, demonstrating their superior efficacy over traditional chemotherapies. PARP inhibitors have greater specificity and fewer off-target side effects than chemotherapy or radiotherapy and can lead to more favorable clinical outcomes. They were found to have a minimal toxic impact on normal cells with functional HR.
A serious concern for the use of PARP inhibitors is the development of acquired drug resistance and de novo malignancies. A better understanding of how different PARP inhibitors are activated to perform overlapping and non-overlapping functions is warranted. Equally, it is important to know how PAR and NAD+ levels are modulated to alter specific biological events toward cellular survival or death. That would potentially result in the design of novel PARP inhibitors that are more specific and tumour-selective and also in the development of better strategies using reliable predictive biomarkers for the treatment with PARP inhibitors. Finally, there is a huge need to identify on which occasions we can re-sensitise recalcitrant tumour cells to PARP activity inhibition.

1.1. Olaparib

Olaparib is an inhibitor of PARP-1, PARP-2, and PARP-3 that was first licenced by the FDA for the treatment of patients with advanced EOC and known or suspected BRCA mutations, such as the fourth line of treatment back in 2014 [4]. At the same time, olaparib was licenced by EMA as monotherapy in relapsed BRCA mutated high-grade EOC with previous complete or partial response to platinum-based chemotherapy. This was supported by a phase II clinical trial, which compared olaparib to a placebo [5]. This study showed statistically significant higher PFS of 11.2 months in olaparib maintenance therapy, over 4.3 in placebo (hazard ratio [HR] 0.18; 95% confidence interval [CI] 0.10–0.31; p < 0.0001). In the same study, adverse events were described in relation to olaparib. These included nausea, fatigue, anemia, and neutropenia in a grade of equal or more than 3 in 2%, 7%, 5%, and 4%, respectively, over 0%, 3%, 1%, and 1% in the placebo group. Vomiting, taste alteration, and anorexia were also described. Multiple studies were performed on the use of olaparib in various scenarios. The SOLO1 study (NCT01844986) attempted to assess the role of maintenance olaparib in patients with ovarian cancer and germline BRCA mutations after frontline chemotherapy. The subsequent SOLO2 study (NCT01874353) investigated the use of maintenance olaparib in a similar population after two or more lines of chemotherapy. The primary endpoint was PFS, which was higher in the olaparib group with 19.1 months over 5.5 months in the placebo group (HR 0.30; 95% CI 0.22–0.41; p < 0.0001). The results of the SOLO2 study confirmed the findings with an impressive 30.2 months over 5.5 months of progression free survival in the olaparib group over the placebo group, respectively (HR 0.25; 95% CI 0.18–0.35, p < 0.0001) [6]. In the SOLO 3 study (NCT02282020), olaparib was compared as monotherapy to single-agent chemotherapy. This was a phase III randomised study in patients with recurrent EOC, with germline BRCA mutations that failed in two or more lines of treatment. Additionally, pooled data of 273 patients in two phase I and four phase II studies, where olaparib was used in women with relapsed disease, showed a 36% objective response rate and a 7.4-month median duration when olaparib was given after three or more lines of chemotherapy [7]. The use of PARP inhibitors is not limited to the BRCA mutated EOC. In 2018, olaparib and talazoparib obtained approval for HER2 negative, BRCA1 or BRCA2 mutated, locally advanced, or metastatic breast cancer. As far as the EOC is concerned, approximately one-third of the patients develop ascites throughout the course of the disease. Even though the treatment of the underlying disease is expected to resolve the ascites, the development of chemoresistant disease results in intractable ascites. The increased fluid production from both the tumour cells and tumour-free peritoneum, combined with compromised draining due to obstructed lymphatics, results in ascites’ buildup. Vascular endothelial growth factor (VEGF) has been shown to play a role in the formation of malignant ascites by increasing vascular permeability. Therefore, inhibition of VEGF can prevent ascites accumulation. At the same time, PARP1 plays a role in angiogenesis and can decrease VEGF expression. Inhibition of PARP1 and PARP1 knockouts has shown a decrease in induction of the transcription factor HIF-1α, which upregulates VEGF expression. It would be interesting to formulate olaparib and/or talazoparib in a nanoparticle delivery system, which would allow the drug to be administered intraperitoneally. Therefore, it might be estimated in the future whether the intraperitoneal delivery of olaparib and/or talazoparib could potentially decrease VEGF expression in the peritoneum and subsequently decrease the production of fluid.

1.2. Niraparib

Niraparib is an orally administrated, selective PARP-1 and PARP-2 inhibitor. Its main activity is via synthetic lethality in tumours with loss of PTEN and BRCA1 or BRCA2 function [8]. Niraparib was used in clinical studies in patients with recurrent platinum-sensitive EOC, irrespectively of the presence of BRCA mutations or HR deficiencies. These showed improved PFS, especially though in patients with BRCA mutations. Based on the double-blind, placebo-controlled, international, phase III ENGOT-OV16/NOVA study (NCT01847274), FDA approved the use of niraparib in maintenance treatment in patients with recurrence of EOC, as long as there was a complete or partial response to platinum-based chemotherapy [9]. The study enrolled 553 patients. Among them, 203 were in the germline BRCA cohort, and 350 patients were in the non-germline BRCA cohort. Patients in the niraparib group had a significantly longer median PFS than those in the placebo group, including 21.0 versus 5.5 months in the gBRCA cohort (HR 0.27; 95% CI 0.17–0.41), as compared with 12.9 months versus 3.8 months in the non-gBRCA cohort for patients who had tumours with HR deficiency (HR 0.38; 95% CI, 0.24–0.59) and 9.3 months versus 3.9 months in the overall non-gBRCA cohort (HR 0.45; 95% CI 0.34–0.61; p < 0.001 for all three comparisons). Severe adverse reactions (grade 3/4) included thrombocytopenia, anaemia, neutropenia, and hypertension in 29%, 25%, 20%, and 9%, respectively. When dose modification was used, most of the hematologic adverse effects were managed [9]. The future looks promising for niraparib, as the PRIMA (NCT02655016), a phase III trial investigating niraparib as a first-line treatment in ovarian cancer, and QUADRA (NCT02354586), a phase II trial investigating the use of niraparib in patients with EOC and multiple lines of treatment are underway [10][11].

1.3. Rucaparib

Rucaparib is a PARP-1, PARP-2 and PARP-3 inhibitor. It has been licenced since 2016 to be used as monotherapy in patients with advanced EOC with either germline or somatic BRCA mutations that have received two or more lines of chemotherapy [12][13]. The activity of rucaparib in the variable genetic environment was investigated in the ARIEL 2 study (NCT01891344) [14]. The population studied were women with high-grade serous or endometrioid EOC, who had received one or more lines of platinum-based chemotherapy, were platinum-sensitive, but suffered a recurrence. Three main groups were identified; one group included patients with BRCA mutations, another had BRCA wild-type and high level of loss of heterozygosity, and lastly, BRCA wild-type genes with a low level of loss of heterozygosity. The median PFS in these groups following treatment was 12.8 (9.0–14.7), 5.7 (5.3–7.6), and 5.2 months (3.6–5.5), respectively. The investigators concluded that patients with BRCA-mutated genes had a significant benefit and that assessment of loss of heterozygosity and BRCA status can be used to predict which patients would benefit most from rucaparib. Another important finding of the ARIEL 2 study was the adverse reaction results. Severe (grade 3) reactions of anaemia, raised transaminases, small intestinal obstruction, and malignant neoplasm progression were identified in 22%, 12%, 5%, and 5%, respectively. The follow-up ARIEL 3 study (NCT01968213) was a double-blind, placebo-controlled, phase III trial that investigated whether rucaparib could be used as maintenance treatment in platinum-sensitive patients [15]. Again, there were three groups. The first group included patients with BRCA-mutated genes; the second included women with defects in the HR pathway, either via BRCA mutation or via high levels of heterozygosity; and the third group included patients with BRCA-mutated genes, BRCA-wild type, and either high, low or indeterminate levels of heterozygosity. The PFS in these groups were 16.6 (HR 0.23; p < 0.0001), 13.6 (HR 0.32; p < 0.0001), and 10.8 months (HR 0.37; p < 0.0001), respectively, whilst the placebo group scored a median PFS of 5.4 months. Severe adverse events were also studied, with notable mentions of anaemia and elevated transaminases with 18.8% and 10.5%, respectively [15]. In the ARIEL4 study (NCT02855944), the efficacy and safety of rucaparib in relapsing EOC in patients with BRCA-mutated genes are being investigated when compared with standard chemotherapy [16]. In the efficacy population (220 patients in the rucaparib group; 105 in the chemotherapy group), the median PFS was 7.4 months (95% CI 7.3–9.1) in the rucaparib group versus 5.7 months (5.5–7.3) in the chemotherapy group (HR 0.64; 95% CI 0.49–0.84; p = 0.0010). Most treatment-mediated adverse events were of grade 1 or 2.

1.4. Veliparib

Veliparib is another PARP-1 and PARP-2 inhibitor, which is given orally and is used either in combination chemotherapy or as monotherapy [8]. Its mechanism of action is primarily via PARP inhibition but also acts via sensitising cancer cells to DNA-damaging drugs, such as oxaliplatin, cisplatin, carboplatin, irinotecan, and cyclophosphamide, as well as radiotherapy [17]. There are various data from phase I and II studies on the use of veliparib in monotherapy for EOC with subgroups of BRCA-mutated genes. Notably, the phase II gynaecologic oncology group (GOG) 280 study (NCT01540565) published in 2015 demonstrated an overall response rate of 26% (95% CI 16–38%) [18]. The most common side effects were fatigue, nausea and vomiting, and leukopenia. The combination studies of veliparib with other chemotherapy agents have not been very promising so far. The randomised phase II NCT01306032 trial in EOC patients treated with cyclophosphamide or low dose cyclophosphamide with veliparib was terminated early, as neither overall response rate (11.8% versus 19.4%, respectively) nor median PFS (2.1 versus 2.3 months, respectively; p = 0.68) were improved with the combination [19]. Currently, a phase III GOG 3005 trial (NCT02470585) is investigating the use of veliparib with carboplatin and paclitaxel in high-grade serous EOC or patients with primary peritoneal cancer in a first-line setting [20]. The use of veliparib is not limited to EOC, though. Moreover, veliparib is able to pass through the blood–brain barrier and has shown promising results when used in combination with temozolomide in the treatment of intracranial tumours [21]. This combination, in particular, has proved to be effective in a variety of histologic malignancies such as B-cell lymphoma, lung, pancreatic, EOC, breast, and prostate cancer [22].

1.5. Talazoparib

Talazoparib is a PARP-1 and PARP-2 inhibitor, which is selective against BRCA1, BRCA2, and PTEN mutants. The use of talazoparib in EOC is limited. However, it was the second FDA- and EMA-approved agent for HER2 negative, BRCA-mutated breast cancer. In comparison to veliparib, it seems to have increased radiosensitising capacity and be a more potent PARP inhibitor [23]. In a monotherapy clinical trial (NCT01286987), where effectiveness was studied in over 100 patients with BRCA1/2 mutations and solid tumours, talazoparib was associated with fatigue, anaemia, thrombocytopenia, and nausea [24]. However, it showed an objective response rate of 50% in a subset of BRCA1/2 mutants with high-grade serous EOC. Unfortunately, talazoparib is not currently tested in EOC, but studies regarding its use in metastatic breast cancer are underway.

2. PARP Inhibitor Combination Therapies

PARP inhibitors have increasing indications of being used as monotherapy. However, resistance to PARP inhibitors and attempts to improve their efficacy has driven an attempt to combine PARP inhibitors with other agents [25][26]. Olaparib, for one, is a prime example, as it is being investigated in a randomised, open-label phase II study (NCT01081951) [27]. In this study, patients with recurrent, platinum-sensitive EOC were randomised to either olaparib with paclitaxel and carboplatin, with olaparib maintenance or paclitaxel and carboplatin without any maintenance therapy. The results showed a slight improvement in PFS in the olaparib group of about 2 months—12.2 versus 9.6 months (HR 0.51; 95% CI 0.34–0.77, p = 0.0012). Another combination treatment that has been shown to be effective was olaparib with an anti-angiogenic multikinase inhibitor, cediranib. The median PFS in the combination group was 17.7 months compared to olaparib monotherapy (HR 0.42; p = 0.005) [12][28]. Expectedly, the side effects in the combination group were more common than in the olaparib monotherapy group. This was replicated in other phase I clinical trials of PARP inhibitors and chemotherapeutic agents such as temozolomide, cisplatin, carboplatin, gemcitabine, paclitaxel, or topotecan. These, however, were mainly in the form of myelosuppression [29][30]. Another two studies with promising results were published recently. These were phase I studies of combination therapies of olaparib with the P13K inhibitor BKM123 (NCT0101623349) and the AKT inhibitor AZD5363 (NCT02208375), respectively [31][32]. There are a number of combination studies underway, such as a trial of niraparib and pembrolizumab (TOPACIO study, NCT02657889) and niraparib with bevacizumab (ENGOTOV24/AVANOVA study, NCT02354131) [33][34]. Table 1 depicts the most important clinical trials of PARP inhibitors in EOC.
Table 1. Poly(ADP-ribose) polymerase (PARP) inhibitors trials in EOC.
Combined Treatment (Type and Pathways) Approval Studies/Ref Setting Target PARP Inhibitor
Antiangiogenics

Immunotherapy

PI3K/AKT/mTOR

Wee1

Chemotherapy		 FDA and EMA SOLO1, SOLO2, SOLO3/[6][35][36] EOC with BRCA mutations

HER2-negative BRCA-mutated breast cancer

Metastatic pancreatic cancer with germline BRCA mutations

Prostate cancer		 PARP-1, -2 and -3 Olaparib
Antiangiogenics

Immunotherapy		 FDA ENGOTOV16/NOVA, PRIMA, QUADRA/[9][10][11] Platinum-sensitive EOC with BRCA mutations PARP-1 and -2 Niraparib
Immunotherapy FDA and EMA ARIEL2, ARIEL 3, ARIEL 4/[14][15][16] Monotherapy in advanced EOC with germline or somatic BRCA mutations PARP-1, -2 and -3 and tankyrase-1 Rucaparib
Chemotherapy

Radiotherapy		 No NCT01540565/[18] EOC with BRCA mutations PARP-1 and -2 Veliparib
Immunotherapy

Chemotherapy		 No NCT01286987/[24] HER2-negative breast cancer PARP-1 and -2 Talazoparib

3. Mechanisms of PARP Inhibitors Resistance

Acquired resistance to PARP inhibitors is common, involving multiple mechanisms, including increased drug efflux, decreased PARP trapping, reestablishing replication fork stability (fork protection), and re-activation of HR. Among them, fork protection mechanism and restoration of HR mechanism are the two main mechanisms for PARP inhibitors resistance. In PARP inhibitors-resistant but BRCA-mutant ovarian cancer cells, both fork protection functions of BRCA1/2 and HR are sequentially bypassed, and cells become increasingly dependent on ataxia telangiectasia and Rad3-related kinase (ATR) for recruitment of RAD51 onto DSB and stalled forks. As such, one mechanism of PARP inhibitor-mediated cytotoxicity is via dysregulation of replication fork reversal and/or restart. Therefore, stabilisation of replication forks may result in PARP inhibitor resistance. Fork remodelling is controlled by several chromatin remodelling proteins. The HR function is restored by secondary reversion mutations of BRCA1, BRCA2, and RAD51 isoforms [37][38]. In patients with germline BRCA-mutated ovarian and breast cancer, secondary mutations that restore functional BRCA2 protein can be induced by exposure to cisplatin or PARP inhibitors [39][40].
p53-binding protein 1 (53BP1) is a chromatin-binding protein 1 that regulates DNA repair primarily by limiting long-range 5′–3′ nucleolytic digestion of DNA ends. The protection of DNA ends by the 53BP1-dependent pathway promotes physiological or pathological DSB repair by NHEJ. This is based on the fact that 53BP1 is involved in several NHEJ-driven biological processes. Among them are included the immunoglobulin class switching, the fusion of dysfunctional telomeres, and the chromosome aberrations caused by the exposure of BRCA1-deficient cells to PARP inhibitors.
The loss of 53BP1 reverses the cell and organismal lethality associated with mutations in BRCA1. Loss of 53BP1 in BRCA1-deficient cells restores, to some degree, HR in a manner that depends on the activation of end resection. This interaction points to a unique antagonism between BRCA1 and 53BP1. Overall, initiating end resection is a key decision point in DSB repair pathway choice that affects the therapeutic efficacy of PARP inhibitors.
The recent detection of shieldin illustrates the difficulties involved in HR restoration during the development of PARP inhibitors’ resistance. Restored HR is newly contributed to the shieldin complex. Shieldin was recognised as a four-submits ssDNA-binding complex comprising REV7, c20orf196 (SHLD1), FAM35a (SHLD2), and FLJ26957 (SHLD3) [41]. It was shown to accumulate at the DSB site and attach to ssDNA to prevent DSB resection and accelerate NHEJ. Consequently, loss of shieldin hinders NHEJ and assists resistance to PARP inhibition in BRCA1 knock out cells due to restored HR [41][42]. This is additional evidence that shieldin acts in the same pathway as 53BP1.
Many other genes involved in HR, e.g., BRCA1, BRCA2, RAD51, and MRE11, are also involved in fork protection. Nonetheless, the process of resistance happening through the restoration of HR and fork protection is contradictory [43][44][45][46]. Deactivation of MUS81 or loss of PTIP in BRCA-mutant cells restores fork protection but has no impact on HR. In addition, overexpression of miR-493–5p also did not restore HR [46]. As measured by RAD51 focus formation, restoration of HR is shown to be acquired before restoration of fork protection in a panel of isogenic olaparib-resistant BRCA1 mutant ovarian cancer cells [43]. This suggests that restoration of HR and fork protection are not connected to the mechanisms of PARP inhibitors’ resistance. Therefore, both restored HR and fork protection that should be taken into consideration when thinking of PARP inhibitors therapies as single agents as well as in combination to sustain therapeutic benefit.

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