A real-world disproportionality analysis of Rucaparib: Post-marketing Pharmacovigilance Data

As one of the third most common gynecologic malignancy in the world, ovarian cancer remains an almost uniformly fatal disease, because more than 70% of patients will relapse within the first 5 years [1‐3]. Studies have reported that treatment with Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors (PARPis) is one of the latest achievements in the study of recurrent ovarian cancer [4, 5]. Rucaparib has been proved to be a selective inhibitor of PARP enzymes such as PARP-1 and PARP-2, which can induce synthetic lethality in cancer cells. It can exert efficacy both in BRCA-mutated patients who can not tolerate further platinum-based chemotherapy and those who respond (completely or partially) to platinum-based chemotherapy independent of the BRCA status [6].

It has been reported that rucaparib induced an overall response rate of 54% and a median duration of response of 9.2 months in relapsed, platinum-sensitive high-grade ovarian carcinoma patients [7]. In an ARIEL 3 study, patients with recurrent platinum-sensitive ovarian cancer who had at least 2 prior lines of chemotherapy and had a complete or partial response to the last platinum-based treatment were randomized to receive rucaparib or placebo maintenance. The median progression-free survival (PFS) for patients with BRCA-mutant carcinomas was 16.6 months in the rucaparib group and 5.4 months in the placebo group (hazard ratio [HR], 0.23; 95% CI, 0.16–0.34; P < 0.0001) [8]. In the instructions issued by FDA in 2022, it has been approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Rucaparib is nowadays widely used for the maintenance therapy for patients with recurrent ovarian cancer with BRCA1 and BRCA2 mutations, and metastatic breast cancer, prostate cancer or pancreatic cancer [9‐12].

The product description of rucaparib and its early evaluation of post-marketing safety indicated that the most common adverse drug reactions (ADRs) were fatigue, vomiting, diarrhea, nausea, constipation, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation, anemia, thrombocytopenia, neutropenia, rash, abdominal pain, and dyspnea, etc. With the increasing use of rucaparib, some infrequent adverse events (AEs) begin to occur, such as intestinal obstruction, vertigo, dehydration and photosensitivity, etc. Although some safety studies on rucaparib have been reported in several clinical trials and meta-analyses, or systematic reviews [13‐16], systematic research on AE signals related to rucaparib based on large international and real-world databases is still lacking.

As a free and open spontaneous reporting system, the Food and Drug Administration Adverse Event Reporting System (FAERS) is now widely used to evaluate the post-marketing safety of drugs. In the present study, the data mining of FAERS is used to detect and analyze the signals of rucaparib-related AEs from the first quarter of 2017 to the second quarter of 2022, so as to explore the situation and general rules of AEs and provide reference for its rational use in clinic.

Among the AEs of rucaparib, risk of grade 3–4 were relatively high and grade 3 AEs have been observed in 75% patients [25, 26]. In 58.6% and 9.8% of patients, rucaparib was interrupted and discontinued, respectively and 45.9% of patients were reduced the dose because of treatment-related AEs [27]. A pharmacovigilance approach was used in our study for exploring the relationship between rucaparib and its AEs, so as to evaluate its post-marketing safety. Compared with men (4.49%), women (95.51%) were more likely to occur AEs, which was because rucaparib was mainly used to treat ovarian cancer and breast cancer. When the dose of rucaparib is 600 mg bid, the common AEs are fatigue (12.9%), thrombocytopenia (18.8%), neutropenia (27.1%), anemia (11.8%) and nausea (7.1%), which are included in the drug description, and our research results also confirm it [28, 29].

One of the most common AEs of rucaparib is hematologic toxicity. Among the hematological AEs, anemia was the most frequently reported PARPi-induced AE in a real world study [30], and it could be associated with symptoms that affect patient quality of life (e.g. light-headedness and fatigue). In addition to anemia, other common hematotoxicity of rucaparib include thrombocytopenia, and neutropenia [29, 31]. For grade 2 or higher thrombocytopenia/decreased platelet count, rucaparib is recommended to be interrupted and resumed at a lower dose upon recovery to grade 1 or better. Heparin use is also one of the risk factors for thrombocytopenia, which will be concerned in clinic. For patients with asymptomatic neutropenia/decreased neutrophil count, rucaparib can usually be continued without dose modification. Antibiotic prophylaxis should be initiated in patients with grade 4 afebrile neutropenia, and rucaparib should be remain in use until recovery with a lower dose [32].

As a significant AE of rucaparib, blood creatinine abnormal was reported with signal strength being ROR 10.94 (6.33–18.91), PRR 10.93 (116.11), IC 2.56 (1.76) and EBGM 10.83 (6.27), respectively, in our results. In patients treated with rucaparib, elevated serum creatinine level has been observed. This AE may be due to the inhibition of tubule transporters MATE1, MATE2-K and OCT-2, which resulting in reduced creatinine secretion in proximal tubules [33]. To reduce the risk, renal function monitoring and effective management can be carried out in rucaparib therapy for intervention. Management with dose reduction or treatment delay is necessary.

Although myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) are rarely observed in patients receiving rucaparib treatment in Phase II (Study 10 and ARIEL 2) and Phase III (ARIEL 3) studies, they are still potentially fatal AEs [7, 27]. MDS and AML are heterogeneous diseases characterized by highly unstable chromosomes, with a variety of potential molecular abnormalities, which are generally believed to be caused by the mechanism of wrong DNA damage repair [34]. PARPis can increase the risk of MDS and AML through DNA damaging reactions, because it can lead to acquired mutations with clonal hematopoiesis in the circulatory system. Furthermore, PARPis may cause off-target epigenetic changes through potential clonal hematopoietic transformations, which can also result in MDS and AML [35]. Our study observed that rucaparib-related bone marrow disorder had a signal strength with ROR 8.81 (4.39–17.67), PRR 8.80 (54.91), IC 2.06 (1.04) and EBGM 8.74 (4.36), respectively. The risk of AEs with MDS/AML usually emerged after long-term treatment, suggesting that caution should be taken when prescribing long-term rucaparib [35]. It is reported that the use of anti-cancer drugs, including alkylating agents, topoisomerase inhibitors, platinum drugs and bevacizumab, will significantly increase the risk of MDS/AML. Therefore, when using rucaparib, it is necessary to avoid the combined use of the above anti-cancer drugs [36].

In the label of rucaparib, rash is one of the ADR reported in ≥ 20% of patients including blister, blood blister, dermatitis, dermatitis contact, eczema, genital rash, palmar-plantar erythrodysaesthesia syndrome, skin lesion, skin exfoliation and urticaria. Our study showed some other related AEs such as nail discolouration, hair growth abnormal, solar dermatitis and onychomadesis. Among them solar dermatitis should be noticed, because this AE had significant signal strength in the skin and subcutaneous tissue disorders of rucaparib in our study. Evaluation of phototoxicity induced by rucaparib has demonstrated that rucaparib can trigger photosensitivity reactions. This phototoxicity can be attributed to photosensitized damage towards main cellular biomolecules (lipids, proteins and DNA) [37].

It is noteworthy that in our analysis, we also found 21 new and unexpected AEs that not mentioned in the drug description including intestinal obstruction, ascites, gastrooesophageal reflux disease, glomerular filtration rate decreased, blood iron decreased, dehydration and hypersomnia. The results of an international, multicenter, open-label phase 2 trial showed that 204 patients who received rucaparib had serious AEs including small intestinal obstruction (10 [5%] of 204 patients), malignant neoplasm progression (10 [5%]), and anaemia (9 [4%]). Grade 1–2 and grade 3 about dehydration was 4.9% (10/204) and 2.9% (6/204), respectively in the same study [7]. Gastrointestinal disorders are the common AEs of rucaparib in our study, including nausea (n = 2,003), vomiting (n = 698), diarrhoea (n = 685) and constipation (n = 670),which are in line with results in the clinical trial [7]. Gastroesophageal reflux has been reported to be causally associated with adiposity, diabetes, smoking and high caffeine consumption, even major depressive disorder [38, 39]. Ascites may be an important AE caused by rucaparib with ROR 6.75 (5.24–8.69), PRR 6.70 (294.25), IC 2.59 (2.21) and EBGM 6.66 (5.17), respectively, which deserves the attention of clinicians. In a study evaluating the pharmacokinetics and safety of rucaparib in patients with advanced solid tumors, the most common treatment-emergent adverse events (TEAEs) observed at the SOC level were gastrointestinal disorders (18.8%), including abdominal pain, ascites, and nausea [40]. Due to the relatively recent introduction of rucaparib, its safety needs to be supported by big data analysis of real-world self-reported AEs.

In terms of the occurrence time of rucaparib-related AEs, our research showed most of them occurred in the early stage of treatment, which was consistent with the results reported [8]. The majority of the AEs occurred within the first 1 month (n = 1,291, 65.60%), 2 months (n = 171, 8.69%) and 3 months (n = 112, 5.69%) after rucaparib treatment, with 12 days of the median onset time. Besides, the WSP test in our study revealed that all rucaparib-associated AEs in SOC level had an early failure type profile, suggesting that the risk of rucaparib-associated AEs increased at an earlier stage of treatment and then gradually decreased over time. But the risk of some fetal AEs including MDS and AML usually emerged after long-term treatment [35]. Therefore, in future clinical studies, rucaparib related AEs required a longer follow-up time for further observation.

Because FAERS database reporting used in our study is voluntary, some of the AE reports may be arbitrary, biased, underreporting, or have incomplete content, etc. which will also affect the results. In addition, although oral administration is convenient and shows favorable compliance with the majority of patients, it may be affected by numerous factors, including food, metabolic enzymes and transporters. These interactions may be associated with serious AEs or may reduce the treatment efficacy of rucaparib, which need continuous attention. Because FAERS data does not grade AEs, only serious and non-serious outcomes caused by AEs were reported. Therefore, we are unable to provide grade classification on each AE. In the data analysis, unmeasured multiple confounding factors including potential DDI, drug combinations and patient comorbidities that may affect AEs were not included. Further research is needed in the future.

Based on the FAERS database, we assessed the post-marketing safety profiles of rucaparib. Common AEs of anaemia, thrombocytopenia, nausea, blood creatinine increase, and AST/ALT increase were detected. Of note, 21 new and unexpected significant AEs that off-label were also found in the present study. Rucaparib-associated AEs in SOC level had an early failure type profile, suggesting that the risk of rucaparib-associated AEs increased at an earlier stage of treatment and then gradually decreased over time. Our study provides important support for clinical safety studies of rucaparib.