Peripheral Neuropathy Potentially Associated to Poly (ADP-Ribose) Polymerase Inhibitors: An Analysis of the Eudravigilance Database

Poly (ADP-Ribose) polymerase inhibitors (PARPi) have emerged as a targeted therapy in cancer treatment with promising results in various types of cancer. This work aims to investigate the profile of adverse drug reactions (ADRs) associated with PARPi through the reports provided by the Eudravigilance (EV) database. We also intend to analyze the potential association of peripheral neuropathy to PARPi. Data on individual case safety reports (ICSRs) were obtained by accessing the European spontaneous reporting system via the EV website. A total of 12,762 ICSRs were collected from the EV database. Serious cases of nervous system disorders were analyzed providing strong evidence that peripheral neuropathy was reported in a higher frequency in patients treated with niraparib. Most cases reported a not recovered/not resolved outcome and involved drug withdrawal. However, several studies suggest that PARPi attenuate chemotherapy-induced painful neuropathy. Unexpected ADRs such as peripheral neuropathy may also occur, mostly in patients taking niraparib. Further pharmacovigilance studies should be conducted in this area to clarify with more precision the toxicity profile of these drugs.


Introduction
Poly (ADP-Ribose) polymerase inhibitors (PARPi) are a type of targeted anti-cancer therapy. Several theories have emerged to describe the precise mechanism of action by which PARPi induce their anti-cancer activity, although a consensus is yet to be reached [1]. In this context, two of the most described methods rely on inhibition of the PARP enzyme and on the "PARP trapping" concept, PARP1 being the main target [2,3]. PARP1 are considered the most abundant isoform and are recognized by their role in DNA repair processes. Recent evidence highlights their role in several cell processes, ranging from cell proliferation to cell death [4]. Other isoforms such as PARP2, PARP3, and PARP5 are described in the literature. PARP2, PARP3, and PARP5 isoenzymes share some of the physiological functions of PARP1 [5][6][7].
Over the last decade, the U.S. Food and Drug Agency (FDA) and European Medicines Agency (EMA) have already approved four PARPi, namely: olaparib, niraparib, rucaparib and talazoparib. Olaparib was the first PARPi to be developed, approved in 2014 by FDA and EMA [8]. Briefly, the approved clinical indications focus on the maintenance therapy

Data Source
Data on individual case safety reports (ICSRs) were retrieved from the website of suspected ADRs of the EV database by accessing www.adrreports.eu (accessed on 8 March 2023). The EV is a system for managing and analyzing ICSRs of suspected ADRs related to medicines which have been authorized or are being studied in clinical trials in the European Economic Area (EEA) [36,37].

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In the EV database, by using the line listing function, we selected all ICSRs with a PARPi as suspected drug and reported from the date of marketing authorization granted by EMA for each PARPi to 1 March 2023. In this context, the marketing authorization dates were the following: 16 3.7%). In this context, a statistically significant difference was found between sex and the PARPi used (p < 0.00001). A high number of ICSRs were considered "Not specified" in terms of age group (N = 5474, 42.9%), followed by 3670 (28.8%) cases for the age group 18-64 years and 3455 (27%) cases for the age group 65-85 years. In addition, healthcare professionals reported many of the cases (N = 9921, 77.7%) and most ICSRs came from the Non-European Economic Area (N = 9120, 71.5%). Regarding the individual cases reported by SOC, "General disorders and administration site conditions" and "Investigations" were the most described with 4468 and 4292 ICSRs, respectively. Additionally, a high prevalence of "Blood and lymphatic disorders" and "Gastrointestinal disorders" was noticed. Concerning the seriousness of the reported cases, a high percentage was classified as a serious case (10,814, 84.7%) when compared to non-serious cases (N = 1948, 15.3%). In this sense, a statistically significant difference (p < 0.00001) was found between seriousness and the drugs in study. These results are presented in Table 1. Figure 1 presents the contribution of each studied category (gender, age group, reporter group, region, and seriousness) to the total of ICSRs analyzed. a Pearson's Chi-Square test was used to verify a possible relationship between these variables with a statistical significance level of 5% (p < 0.05). b 10 most reported ADRs were analyzed.

Least Reported SOCs
The least reported SOCs presented in Table 1 were analyzed from 1 January 2022 to 31 December 2022. Considering the SOC "Respiratory, thoracic and mediastinal disorders", no statistically significant difference was found between the different PARPi (p-value = 0.25796). However, considering the other SOCs, "Injury, poisoning and procedural complications", "Nervous system disorders", "Psychiatric disorders", and "Skin and subcutaneous tissue disorders", a statistically significant difference was found between PARPi, concerning the SOCs mentioned. Regarding the SOC "Injury, poisoning and procedural complications", off-label use, product dose omission issue, product dose omission in error, contusion, and fall were the main safety issues reported considering all PARPi. Regarding the SOC "Nervous system disorders", headache, peripheral neuropathy, dizziness, taste disorder, and hypoaesthesia were the main reported symptoms considering all PARPi. These results, as well as the main safety issues reported for each mentioned SOC, are presented in Table 2. Figure 2 presents the distribution of the total serious ICSRs reported for each PARPi vs. serious ICSRs reported for some selected SOCs (least reported SOCs), only in the year of 2022 (from 1 January 2022 to 31 December 2022).
All columns highlighted represent the total number of serious ICSRs according to the SOC studied. All suspected ADRs reports in which PARPi were not described as the only suspected drug were excluded. All columns highlighted represent the total number of serious ICSRs according the SOC studied. All suspected ADRs reports in which PARPi were not described as only suspected drug were excluded.

Analysis of ICSRs-Peripheral Neuropathy
A detailed analysis of peripheral neuropathy serious cases was performed from January 2022 to 31 December 2022 for the inhibitors olaparib, niraparib, and rucaparib total of 100 cases were considered, with a high prevalence (99.0%) in female sex. In te of age group, 40 ICSRs (40.0%) do not refer to the age group, followed by 33 (33.0%) ca in elderly (64-85 years), and 24 (24.0%) cases in adults (18-64 years). Concerning outcome, most cases reported a not recovered/not resolved outcome (N = 47, 47.0%) all of them indicated the seriousness criteria "other medically important informatio However, the high percentage of the cases reported as "unknown" should be highligh (N = 44, 44.0%). Drug withdrawal was the most frequent action taken (N = 52, 52.0%) addition, most ICSRs reported only one nervous ADRs (N = 49, 49.0%), considering 1 overall (nervous and non-nervous) ADRs reported. For concomitant medicines, the jority of ICSRs do not contain any information in this field (N = 69, 69.0%). These res are mentioned in Table 3.

Analysis of ICSRs-Peripheral Neuropathy
A detailed analysis of peripheral neuropathy serious cases was performed from 1 January 2022 to 31 December 2022 for the inhibitors olaparib, niraparib, and rucaparib. A total of 100 cases were considered, with a high prevalence (99.0%) in female sex. In terms of age group, 40 ICSRs (40.0%) do not refer to the age group, followed by 33 (33.0%) cases in elderly (64-85 years), and 24 (24.0%) cases in adults (18-64 years). Concerning the outcome, most cases reported a not recovered/not resolved outcome (N = 47, 47.0%) and all of them indicated the seriousness criteria "other medically important information". However, the high percentage of the cases reported as "unknown" should be highlighted (N = 44, 44.0%). Drug withdrawal was the most frequent action taken (N = 52, 52.0%). In addition, most ICSRs reported only one nervous ADRs (N = 49, 49.0%), considering 1295 overall (nervous and non-nervous) ADRs reported. For concomitant medicines, the majority of ICSRs do not contain any information in this field (N = 69, 69.0%). These results are mentioned in Table 3.

Discussion
PARPi are a novel class of targeted cancer therapies that have shown promising results in various types of oncological pathologies such as ovarian, breast, prostate, and pancreatic cancers [1,39]. Additionally, the literature has highlighted several associations, particularly the combination of these agents with immunotherapy and chemotherapy [31,40,41]. This study intended to investigate spontaneous reports related to the approved PARPi, olaparib, rucaparib, niraparib, and talazoparib, through the analysis of data obtained from EV, to provide an overview of suspected ADRs, with a focus on nervous disorders, particularly peripheral neuropathy.
A total of 12,762 ICSRs were retrieved from the date of marketing authorization granted by EMA to 1 March 2023 for each PARPi. Female patients are the most reported cases by healthcare professionals, especially in the age groups 18-64 years and 65-85 years. This fact can be explained through the approved therapeutic indications for this class of drugs. Olaparib and niraparib were the first two approved PARPi in the European Union market, approved in 2014 and 2017, respectively, and have provided great clinical benefits to ovarian cancer patients [19,42]. In addition, rucaparib was approved in 2018 by EMA and has a beneficial role in this type of cancer [24,43]. In a general way, "General disorders and administration site conditions" is the most reported SOC among PARPi with 4468 ICSRs analyzed. These results are aligned with what has already been described in the Summary of Product Characteristics (SmPC) and by some authors. Fatigue, regardless of the grade, is considered a very common symptom [20][21][22][23] in patients taking these drugs, representing a percentage about 59-69% of patients who experienced it [9,16,24]. PARP1, the main enzymatic target of PARPi, has been implicated in the regulation of circadian metabolic activities and it can be hypothesized that the disruption of these metabolic activities could be the basis for the high frequency of fatigue [44,45]. LaFargue et al. also pointed out investigational toxicities (hypercholesterolemia and increased amounts of serum hepatic enzymes), as well as gastrointestinal and haematological toxicities, as frequent among PARPi [31]. The inhibition of PARP2 may be involved in the development of haematological toxicity as PARP2 has been shown to have a role in the regulation of red blood cell production [44,45]. In addition, nervous, respiratory, psychiatric and skin disorders are considered less common toxicities when compared to the others described [31].
Considering the typology of reported ADRs among PARPi, in more serious cases, it was possible to observe a greater number of ICSRs in patients taking niraparib. Through a detailed analysis, differences in terms of ADRs frequency can be described [46]. For example, in terms of respiratory symptoms, dyspnoea and cough were reported in 79 and 37 ICSRs, respectively. However, interstitial lung disease was reported in 43 ICSRs associated with olaparib [47,48]. It should be noted that this adverse effect is not described in olaparib's SmPC [20]. Some cases of suspected interstitial lung disease have also been described for niraparib, which also does not have this adverse effect described in the SmPC [22]. According to the literature, the mechanism of respiratory toxicities is not well defined. However, preclinical data have described that the activation of PARP enzymes is associated with bronchial hyper-reactivity and airway remodeling [49]. In terms of psychiatric disorders, 155 serious cases of insomnia were reported with the niraparib inhibitor. According to the SmPC, insomnia is considered a very common ADR in patients taking this drug. Additionally, anxiety and depression are considered common reactions [22]. The disparity between niraparib vs. olaparib/rucaparib in terms of psychiatric ADRs may be related to niraparib's pan-neurotransmitter pharmacology [50]. Additionally, headache and dizziness were also mainly reported in patients taking niraparib. These results have already been highlighted in the literature [9,16,24]. However, a definitive link could not be established due to incomplete reporting of all off-target profiles of PARPi [50]. Concerning the suspected ADRs peripheral neuropathy, 87 serious ICSRs were found, in 2022, for niraparib, followed by 11 cases in patients taking rucaparib and 2 cases associated with olaparib. This ADRs is not mentioned in niraparib, rucaparib, or olaparib SmPC's [20][21][22].
The characteristics of those ICSRs that reported peripheral neuropathy were analyzed in more detail for the inhibitors olaparib, niraparib, and rucaparib. The majority of cases were reported in female patients (99.0%) and in adults (18-64 years) and elderly (65-85 years) people (57.0%). Regarding the outcome, although 44.0% of the cases did not contain any information, it was possible to observe that 47.0% of the cases were classified as a not recovered/not resolved outcome. Furthermore, all of them were classified with the seriousness criteria "Other medically important information". Drug withdrawal was the action applied to about half of the cases (52.0%), followed by dose reduction (18.0%). Guo et al. recently conducted a real-world pharmacovigilance study based on suspected ADRs for niraparib reported to the FAERS that described peripheral neuropathy as an unexpected significant ADRs. In this study, 649 cases were reported between 2017 and 2021 [32]. Another recent study using the FAERS database mentioned 362 reports of peripheral neuropathy. In this context, Tian et al. mentioned that the reporting odds ratio (ROR) in signals detections suggested that neurotoxicity might be more frequent in patients treated with niraparib [47]. According to these authors, further investigations are needed in this area. Additionally, mostly preclinical studies suggested that, when compared with conventional chemotherapy, PARPi may help with symptoms related to peripheral neuropathy [51][52][53][54]. However, a meta-analysis performed by Balko et al. showed that PARP inhibition activity does not appear to reduce the risk of developing neuropathy induced by chemotherapy [55]. Considering the above, new pharmacovigilance studies should be conducted to clarify more precisely the toxicity profile of these drugs.
For this study, some strengths and limitations should be considered. The major strength was the access to a large and comprehensive spontaneous reports database on PARPi. We were able to analyze ICSRs from a heterogeneous population, which is usually not considered in the premarketing clinical trials. Despite our best efforts to conduct a sound study and to minimize bias, there are important limitations that need to be acknowledged, namely the lack of crucial information in ICSR, such as outcome, action taken and its results, and concomitant medicines, among others. The phenomenon of underreporting and underestimation of the frequency of ADRs in oncology is also a major problem that needs to be considered [56]. Additionally, this data cannot provide evidence on the causal relationship between ADRs and the suspected drugs.

Conclusions
A retrospective analysis was conducted on data retrieved from the EV database. The spontaneous reporting system represents a useful tool for understanding drug safety data and for better characterization of drug safety profiles. Although PARPi are targeted drugs, several systems/organs may be affected by taking these drugs. Unexpected ADRs may also occur, such as peripheral neuropathy. More high-quality pharmacovigilance studies should be conducted to better understand the PARPi toxicity profile. In this context, new guidelines for healthcare professionals to manage these adverse effects in a real setting may be provided. Funding: This work was partially supported by CICS-UBI, which is financed by national funds from Fundação para a Ciência e a Tecnologia (FCT) and by Fundo Europeu de Desenvolvimento Regional (FEDER) under the scope of PORTUGAL 2020 and Programa Operacional do Centro (CENTRO 2020), with the project reference numbers UIDB/00709/2020 and UIDP/00709/2020.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: All data that the authors extracted from the European Medicines Agency (EMA) pharmacovigilance database called EudraVigilance are publicly available. Pharmacovigilance data from EudraVigilance is publicly available at www.adrreports.eu (accessed on 8 March 2023).

Conflicts of Interest:
The authors declare no conflict of interest.