Time-Trend Analysis and Risk Factors for Niraparib-Induced Nausea and Vomiting in Ovarian Cancer: A Prospective Study
Article information
Abstract
Purpose
Nausea and vomiting are major non-hematological adverse events associated with niraparib maintenance therapy. This study aimed to investigate the time-trend patterns of niraparib-induced nausea and vomiting (NINV) and the associated risk factors in patients with ovarian cancer.
Materials and Methods
In this prospective study, we enrolled patients with stage III-IV epithelial ovarian cancer who received niraparib as frontline maintenance therapy. The clinicopathological characteristics and time-trend patterns of patients with NINV were collected through in-person surveys and electronic medical records from the National Cancer Center.
Results
Of 53 patients, 50 (94.3%) were diagnosed with high-grade serous ovarian carcinoma. BRCA mutations and homologous recombination deficiency (HRD) were identified in 23 (43.4%) and 32 (60.4%) patients, respectively. Thirty-one patients (58.5%) had NINV. Time-trend analyses revealed that the first peak intensity of NINV was reached at 3 h post-dose, and the second peak intensity was reached at 11 hour post-dose. NINV significantly decreased from week 1 to weeks 8 and 12. In multivariate analyses of risk factors for NINV, HRD-positive tumors (p < 0.001) and prior experience of chemotherapy-induced nausea and vomiting (p=0.004) were associated with the occurrence of NINV.
Conclusion
Pre-emptive treatment with antiemetics is required to manage early-phase NINV during niraparib maintenance therapy in patients with risk factors. Additional larger studies are needed to confirm these findings and to develop optimal preventive strategies for NINV.
Introduction
Ovarian cancer is one of the most common and deadliest gynecological cancers worldwide, with 324,398 new cases and 206,839 deaths as of 2022 [1]. In Korea, ovarian cancer accounts for 2.8% and 3.9% of all new cancer diagnoses and cancer-related deaths, respectively, and ranked eighth in both cancer incidence and mortality in 2019 [2]. Due to the absence of disease-specific symptoms and effective screening tools, most patients with ovarian cancer are diagnosed at an advanced stage. The standard treatment for advanced epithelial ovarian cancer is cytoreductive surgery followed by adjuvant chemotherapy [3,4]. Furthermore, the recent introduction of poly(ADP-ribose) polymerase (PARP) inhibitors has significantly improved the survival outcomes of patients with newly diagnosed advanced ovarian cancer [5-7].
Frontline maintenance therapy with niraparib is recommended for patients with advanced, high-grade serous, or endometrioid ovarian cancer who achieve either a complete or partial response to platinum-based chemotherapy, regardless of their homologous recombination deficiency (HRD) status [8]. Niraparib is administered orally once a day, and its peak concentration occurs 4-6 hours after consumption [9]. Niraparib has been reported to significantly increase progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer [10,11]. However, nausea and vomiting are major non-hematological adverse events associated with niraparib maintenance therapy [12,13]. The incidence rates of niraparib-induced nausea and vomiting (NINV) have been reported to be 57.4% and 22.3% in patients with newly diagnosed advanced ovarian cancer, and 73.6% and 34.3% in those with platinum-sensitive recurrent ovarian cancer [7,14]. Furthermore, grade 3 or higher NINV was observed in 2.0% of patients with newly diagnosed advanced ovarian cancer and 4.9% in those with platinum-sensitive recurrent ovarian cancer, further highlighting the need for effective management strategies.
Therefore, this study aimed to investigate the time-trend patterns of NINV and its associated risk factors in patients with ovarian cancer who received frontline niraparib maintenance therapy.
Materials and Methods
1. Study design
This study was designed as a single-center prospective study at the National Cancer Center, Korea. Patients were eligible for inclusion if they met the following criteria: (1) age > 18 years at the time of diagnosis, (2) underwent cytoreductive surgery followed by platinum-based chemotherapy as a first-line treatment and showed a complete or partial response to chemotherapy, (3) had pathologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III or IV epithelial ovarian cancer, and (4) were treated with niraparib as a frontline maintenance therapy initiated between November 2023 and June 2024. Patients with a body weight of < 77 kg or platelet count of < 150×103/L at baseline received 200 mg niraparib once daily. The remaining patients received niraparib 300 mg. The dates and reasons for dose interruption or reduction were documented. Patients with incomplete medical records, those with incomplete survey responses, or those who withdrew from the survey were excluded from the study.
2. Outcome measures
The time-trend pattern of NINV was investigated during patient visits to the National Cancer Center, Korea, between November 2023 and August 2024. The survey forms are shown in S1 Fig. The survey consisted of a detailed hourly rate of NINV, documenting its severity over 24 hours. The intensity of NINV was based on the nausea and vomiting criteria specified in the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0 [15,16]. According to CTCAE, grade 1 nausea is defined as “loss of appetite without alteration in eating habits,” grade 2 as “oral intake decreased without significant weight loss, dehydration or malnutrition,” and grade 3 as “inadequate oral caloric or fluid intake.”
Additionally, the intensity scale used in this study ranged from 0 to 10 and was categorized as follows: grade 1 NINV was assigned scores from 0 to 3, grade 2 NINV from 3 to 6, and grade 3 NINV was categorized by scores from 7 to 10, based on a previous study [17]. The survey was conducted four times at 1 week, 4 weeks, 8 weeks, and 12 weeks after niraparib initiation.
Patient demographic, clinicopathological, and treatment data were retrieved by reviewing electronic medical records. Variables related to niraparib therapy, such as BRCA mutations, HRD status, initiation date of treatment, daily dosage schedules, doses administered, and comprehensive toxicity profiles, were documented. Additional data included records of adverse events and medical interventions employed to reduce hematological and non-hematological toxicities, including the use of antiemetics, dose adjustments, and interruptions.
3. Statistical analysis
Patients were categorized into two groups based on their NINV grades: no NINV (grade 0) and mild-to-severe NINV (grade 1-3). Categorical variables were analyzed using Fisher’s exact test or the chi-squared test and are summarized as the number of events and their respective proportions. Continuous variables were analyzed using the Kruskal-Wallis test or Wilcoxon rank-sum test and are summarized as medians and their respective ranges. Univariate and multivariate logistic regression analyses were performed to identify factors that potentially affect the frequency and intensity of NINV in patients undergoing niraparib maintenance therapy. Additionally, a two-tailed t test was performed to demonstrate the change in NINV intensity during niraparib maintenance therapy. Statistical analyses were performed using Python ver. 3.11.5. Statistical significance was assessed using a two-tailed t test, with a p-value of < 0.05.
Results
1. Patient characteristics
A total of 53 patients were enrolled in this study (Fig. 1), of whom 31 (58.5%) experienced any-grade NINV. Three patients (5.7%) had grade 3 NINV, which resolved within 8 weeks (S2 Fig.).
Flow diagram. FIGO, International Federation of Gynecology and Obstetrics.
The baseline demographic and clinicopathological characteristics of the patients are summarized in Table 1. The median age of the patients was 54 years (range, 34 to 70 years), and 50 patients (94.3%) were diagnosed with high-grade serous carcinoma. Thirty-one patients (58.5%) had FIGO stage 4 ovarian cancer. Thirty-three patients (62.3%) received neoadjuvant chemotherapy. Forty patients (75.5%) had no residual tumors. Twenty patients (37.7%) experienced chemotherapy-induced nausea and vomiting (CINV) during previous platinum-based chemotherapy. Thirty-two patients (60.4%) tested positive for HRD.
Baseline patient characteristics categorized by grade of niraparib-induced nausea and vomiting
2. Time-trend analysis
The patient-reported intensity of NINV in patients with grade 1-3 (n=31) is shown in Fig. 2. Patients were orally administered niraparib at various times between 6 PM and 12 AM: 1 patient at 6-8 PM (3.2%), 20 patients at 8-10 PM (64.5%), nine patients at 10 PM-12 AM (29.0%), and one patient at 12-2 AM (3.2%).
Hourly pattern of niraparib-induced nausea and vomiting (NINV) intensity over 12 weeks in patients with Common Terminology Criteria for Adverse Events grade 1-3 nausea and vomiting and a swimmer plot of the patient drug administration schedule. LPV, likely pathologic variant; PV, pathologic variant.
Over the treatment course, the intensity of NINV continuously decreased (Fig. 2). When comparing weeks 1 and 12, the intensity of NINV showed a significant decrease at 12 AM (mean difference, 2.129; p=0.022), 6 AM (1.452; p=0.023), 8 AM (1.984; p=0.003), and 10 AM (1.339; p=0.020) (S3 Table).
3. Logistic regression analysis
Table 2 presents the results of univariate and multivariate analyses. In univariate analysis, younger age at diagnosis (odds ratio [OR], 6.101; 95% confidence interval [CI], 2.816 to 13.516; p < 0.001), lower FIGO stage (OR, 3.825; 95% CI, 1.128 to 12.975; p=0.031), positive HRD status (OR, 70.320; 95% CI, 12.072 to 409.91; p < 0.001), and presence of CINV in previous chemotherapy (OR, 11.159; 95% CI, 2.458 to 50.572; p=0.002) were associated with a high frequency of NINV development (Table 2). In multivariate analysis, age at diagnosis, FIGO stage, HRD status, and history of CINV in previous chemotherapy were adjusted. After adjusting for these variables, positive HRD status (adjusted OR, 40.71; 95% CI, 5.978 to 132.89; p < 0.001) and presence of CINV in previous chemotherapy (OR, 9.534; 95% CI, 2.050 to 44.312; p=0.004) were confirmed as risk factors for NINV development.
Univariate and multivariate logistic regression analyses of baseline and treatment-related factors for niraparib-induced nausea and vomiting
4. Treatment-related outcomes
There were no significant differences in the proportion of patients experiencing dose reduction, drug discontinuation, or hematological and non-hematological toxicities, except for nausea and vomiting, between the two groups (Table 3).
Adverse event management in patients receiving niraparib by grades of niraparib-induced nausea and vomiting
Discussion
To the best of our knowledge, the current study is the first to demonstrate the time-trend pattern of NINV intensity in patients with advanced epithelial ovarian cancer who received niraparib as a frontline maintenance therapy. We observed that NINV intensity peaked within 8 hours of niraparib intake, which decreased over time within the 12-week period. Furthermore, positive HRD status and a history of CINV from platinum-based chemotherapy were identified as risk factors for NINV.
In this study, 31 patients (58.5%) had any-grade NINV throughout the 12 weeks following initiation of niraparib maintenance therapy. The incidence of any-grade NINV in our study was comparable to that in previous randomized controlled trials, with 57.4% (278/484) in the PRIMA trial and 44.7% (114/255) in the PRIME trial, indicating similar baseline characteristics across studies [7,18].
The highest intensity of NINV was maintained within the first 8 hours of niraparib administration, suggesting the need for time-sensitive and appropriate medical interventions. This observation may be linked to the time required to reach the peak plasma concentration of niraparib. A maximal plasma concentration of 494 ng/mL for the tablet form of niraparib is reached after 4 hours after administration and during an 8-hour fast state [9]. The sustained high-intensity NINV between 4 and 8 hours after drug intake could be explained by the patients’ reported food intake time in the morning. High-fat meals after niraparib administration were reported to numerically increase the time to reach the maximal concentration of niraparib, from 3.5 hours in the fasted state to 8 hours in the high-fat meal state, because of its delayed effect on the gastric absorption of the drug [19,20]. This delay in initial absorption could explain the increase in NINV intensity after 4-8 hours of niraparib consumption, as most patients (93.5%, n=29/31) were administered niraparib between 8 PM and 12 AM.
In time-trend analysis, NINV intensity declined as the treatment continued. This overall decrease could be explained by the high frequency of dose modifications during niraparib maintenance therapy. This finding is consistent with that of a previous study in which 80% of patients with platinum-sensitive ovarian cancer underwent niraparib dose modification. Patients reported significantly reduced rates of hematological toxicity without deterioration in PFS [21]. In this study, 34 patients (64.2%) underwent dose reductions from 200 mg to 100 mg daily, and 20 patients (45.3%) underwent dose interruptions ranging from 1 to 8 weeks. Active dose adjustment of niraparib is performed to manage early-phase high-intensity NINV and improve treatment adherence.
In this study, multivariate analysis demonstrated that positive HRD status was associated with a high frequency of NINV occurrence. Increased incidence of nausea and vomiting in patients with HRD might be explained as follows. PARP inhibitors primarily target PARP1, but they also have off-target effects through kinase inhibition pathways [22]. Niraparib and rucaparib exhibit broader kinase polypharmacology than olaparib, indicating that their off-target effects may contribute to a higher incidence of NINV [23]. Secondly, serotonin release and NK1 receptor activation which are well-known mediators of CINV might increase in patients with HRD because of increased DNA damage due to synthetic lethality [24]. Thirdly, high adherence to niraparib of HRD patients could be another factor of increased NINV. A study highlighted that 26% of the non-adherent patients were HRD-positive, suggesting continued usage of niraparib as a cause of increased NINV in HRD-positive patients [12]. Further research would be required to confirm the current explanations.
A previous study showed that the antitumor efficacy of PARP inhibitors was linked to the presence of early and serious adverse events and that the patient group with high hematological toxicity had higher rates of PFS (30 vs. 20 weeks, p=0.047) [25]. The PAOLA trial demonstrated that the survival benefit of PARP inhibitors was higher in the HRD-positive group (37.2 vs. 17.7 months; hazard ratio [HR], 0.33; 95% CI, 0.25 to 0.45; p < 0.001) than the HRD negative group (16.6 vs. 16.2 months; HR, 1.00; 95% CI, 0.75 to 1.35; p < 0.001) [26]. Given that HRD-positive patients show a better response to PARP inhibitors and are likely to favor PARP inhibitor therapy in the future, it is crucial to proactively manage the high frequency of NINV in these patients during treatment.
Previous experiences with CINV from adjuvant platinum-based treatments were also associated with the subsequent occurrence of NINV in this study. One explanation might be related to their similar pharmacokinetics involving neurotransmitter activation. Paclitaxel and carboplatin can activate neurotransmitter receptors in the area postrema of the brain or stimulate vagal afferents near the enterochromaffin cells in the intestine [27]. Niraparib also increases neurotransmitter levels with inotropic effects, including the inhibition of neuronal dopamine, norepinephrine, and serotonin transporters [28]. These drugs activate similar neurotransmitter pathways, which explains why patients with prior CINV are likely to experience similar levels of nausea and vomiting when taking PARP inhibitors.
This study has certain limitations that must be addressed. The data may be prone to recall bias because hourly NINV timetables were collected from patients after a certain duration, which is inevitable in a survey study. To enhance the accuracy of data, it is advisable to conduct a study in which patients report NINV contemporaneously with the occurrence of symptoms. However, this study has definitive merit as it is the first to evaluate the pattern of nausea and vomiting after niraparib, a PARP inhibitor, on an hourly basis within a single day.
In conclusion, this study showed that NINV reached a peak intensity within 8 hours of niraparib intake. The study also observed an overall decreasing pattern in NINV intensity over 12 weeks. A positive HRD status and the presence of CINV in previous chemotherapy regimens were related to a higher occurrence of NINV. Based on these results, a preemptive antiemetic strategy during niraparib maintenance therapy could improve patient treatment adherence.
Electronic Supplementary Material
Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).
Notes
Ethical Statement
This study involved in-person surveys and medical data collection approved by the participants and the Institutional Review Board of the National Cancer Center, Korea. Number: NCC2023-0344. Informed consent was obtained from all participants.
Author Contributions
Conceived and designed the analysis: Jeong YW, Kim DE, Lim MC.
Collected the data: Jeong YW, Kim DE.
Contributed data or analysis tools: Jeong YW, Kim DE, Kim JH, Lim MC.
Performed the analysis: Jeong YW, Kim DE.
Wrote the paper: Jeong YW, Kim DE, Kim JH, Kim SI, Ha HI, Lim MC.
Others (Review & Approval): Jeong YW, Kim DE, Kim SI, Ha HI, Park SY, Lim MC.
Conflict of Interest
Conflict of interest relevant to this article was not reported.
Funding
This research was supported by a grant from the Korean Cancer Survivors Healthcare R&D Project through the National Cancer Center, funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2023-CC140196).