Abstract
Background/Aim: Niraparib dosages can be individualized to reduce the starting dose based on body weight and baseline platelet count. However, even with individualized dosing, scattered cases of ≥Grade 3 hematologic toxicity occur. This study explored markers predictive of serious hematologic toxicity in niraparib therapy. Patients and Methods: This retrospective observational study investigated patients who started niraparib therapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research between December 2020 and March 2022. Associations between hematologic toxicities and serum creatinine ratio (percentage increase in serum creatinine between baseline and after niraparib initiation) were investigated. Results: Out of 50 ovarian cancer patients who initiated niraparib, 45 patients were included in the final analysis. Twenty-three patients (51.1%) developed ≥Grade 3 hematologic toxicity, with neutropenia in 17 (37.8%), anemia in 9 (20.0%), and thrombocytopenia in 4 (8.9%). Patients with Grade 4 hematologic toxicity showed higher serum creatinine ratios than those with ≤Grade 2. Thrombocytopenia ≥Grade 3 occurred only within 2 months of niraparib initiation and was preceded by an increase in serum creatinine in all affected patients. Conclusion: Serum creatinine ratio offers a potential marker for predicting severe hematologic toxicity following niraparib therapy.
Ovarian cancer is one of the most common gynecological cancers, with approximately 314,000 new cases diagnosed and 207,000 deaths worldwide in 2020 (1). Ovarian cancer has few subjective symptoms in the early stages and often remains undetected until already in an advanced state (2, 3). A combination of surgical cytoreduction and chemotherapy is recommended for International Federation of Gynecology and Obstetrics (FIGO) stage II or higher ovarian cancer. The standard chemotherapy is TC, a combination therapy comprising the platinum agent carboplatin and the taxane paclitaxel (4, 5). Ovarian cancer shows a high response rate to chemotherapy, but most patients with advanced disease relapse and the 5-year survival rate for stage III and stage IV disease is poor, at less than 50% (6).
Poly[adenosine diphosphate (ADP)-ribose] polymerase (PARP) inhibitors represent a paradigm shift in treatment strategies for maintenance and recurrence of ovarian cancer. PARP is an enzyme involved in single-strand DNA repair, so inhibition of PARP affects DNA damage repair and results in cell injury (7, 8). Repair genes for double-stranded DNA damage include breast cancer 1 (BRCA1) and BRCA2, and mutations in these genes result in incomplete repair function (8). Genetic mutations other than BRCA1/2 can also cause DNA repair dysfunction and are referred to as homologous recombination deficiency (HRD) (9). The presence of BRCA1/2 gene mutations or HRD increases the likelihood of PARP inhibitor-induced cell death (9). Niraparib is a PARP inhibitor that showed efficacy in late-line treatment of ovarian cancer patients with HRD-positive status in the QUADRA trial (10). In addition, niraparib demonstrated superior progression-free survival (PFS) over placebo in the PRIMA and NOVA trials regardless of BRCA1/2 mutation or HRD status (11, 12). The PRIMA trial showed significantly prolonged PFS with maintenance therapy for newly diagnosed advanced ovarian cancer regardless of HRD status, while a subgroup analysis showed prolonged PFS in the group of patients with HRD-negative status. The NOVA study also showed prolonged PFS with maintenance therapy for platinum-sensitive, recurrent ovarian cancer in a group of patients without germline BRCA mutations (11). Based on these results, niraparib is used for the maintenance treatment of primary or recurrent ovarian cancer for which platinum-based chemotherapy achieved complete or partial response, and for the treatment of HRD-positive status advanced ovarian cancer with three or more prior chemotherapy regimens.
The most frequent adverse events (AEs) in the QUADRA, PRIMA, and NOVA studies were hematologic toxicities such as thrombocytopenia (29.4%, 45.9% and 61.3%), anemia (38.0%, 63.4% and 50.1%), and neutropenia (6.9%, 26.4% and 30.2%), and non-hematologic toxicities such as nausea (56.4%, 57.4% and 73.6%), fatigue (40.0%, 34.7% and 59.4%), headache (11.2%, 26.0% and 25.9%), and insomnia (11.9%, 24.6% and 24.3%, respectively) (10-12). The most common ≥Grade 3 AEs were thrombocytopenia (16.4%, 28.7% and 33.8%), anemia (24.2%, 31.0% and 25.3%), neutropenia (6.3%, 12.8% and 19.6%), hypertension (1.7%, 6.0% and 8.2%) (10-12). Those trials were conducted using a fixed niraparib dose of 300 mg/day (although the PRIMA trial was changed to an individualized dose midstream). However, post-hoc analysis of the NOVA study revealed that factors associated with ≥Grade 3 thrombocytopenia included body weight <77 kg and a baseline platelet count <150,000/μl (13). An individualized dose of 200 mg/day was thus recommended as a starting dose for patients with body weight <77 kg or baseline platelet count <150,000/μl (13). The NORA trial investigated maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using individualized doses and showed prolonged PFS versus placebo (14). Rates of ≥Grade 3 thrombocytopenia, anemia, and neutropenia were 11.3%, 14.7%, and 20.3%, respectively, lower for thrombocytopenia and anemia than in the NOVA study (14). These results suggest that individualized dosing of niraparib offers an effective and safe approach.
A clinical report from the United States using niraparib at 200 mg/day showed that the incidence of ≥Grade 3 thrombocytopenia was 3% (15). A clinical report from China using niraparib at 200 mg/day showed that rates of ≥Grade 3 thrombocytopenia, anemia, and leukopenia were 11.6%, 7.0%, and 9.3%, respectively (16). The frequency of ≥Grade 3 hematologic toxicity was lower with the individualized dose than with the fixed dose of 300 mg/day. However, in clinical practice, cases of sudden-onset hematologic toxicity requiring blood transfusion or emergency hospitalization have been encountered, and hematologic toxicity represents an adverse effect that should be considered in the treatment of niraparib.
In addition to baseline weight and platelet count, decreased creatinine clearance has been reported to be a possible risk factor for niraparib-induced thrombocytopenia (17). However, niraparib does not require dose adjustment in patients with renal impairment (18). Therefore, in this study, we hypothesized that elevated serum creatinine, and not renal impairment, might be associated with niraparib-induced hematologic toxicity.
Patients and Methods
Study design and participants. This retrospective cohort study used data from a single center. Eligibility criteria included patients who received niraparib for ovarian cancer at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research between December 2020 and March 2022. Patients were excluded if they met any of the following criteria within 30 days of niraparib initiation: i) use of other PARP inhibitors; ii) discontinuation of treatment; or iii) no measurements of serum creatinine. The observation period for eligible patients was from the start of treatment until September 30, 2022, or discontinuation of niraparib treatment.
The initial dose of niraparib was 300 mg/day if the patient weighed ≥77 kg and had a platelet count of ≥150,000/μl, and 200 mg/day if the patient weighed less ≤77 kg or had a platelet count of ≤150,000/μl. Initial visits were made at intervals of 7-14 days, and treatment was continued at intervals of 14-28 days thereafter at the discretion of the attending physician. Supportive medications prescribed were domperidone and metoclopramide for nausea and calcium channel blockers and angiotensin II receptor blockers for hypertension. Blood samples were collected on the day the patient arrived at the hospital. The study protocol was approved by the Clinical Research Ethics Review Committee of the Hospital (approval no. 2022-GB-043) and was conducted in accordance with the Declaration of Helsinki.
Data collection. The following clinical data were obtained from electronic medical records for patients who received niraparib. Patient data included age, weight, Eastern Cooperative Oncology Group (ECOG) performance status, tumor site, FIGO stage at diagnosis, treatment line, presence of BRCA mutation, and HRD status. In addition, treatment data included surgical history, niraparib dosage, AEs, changes in dosing schedule due to AEs, serum creatinine, neutrophils, hemoglobin, platelets, and history of blood transfusions. Baseline serum creatinine was the mean of three values before niraparib initiation. The rate of increase in serum creatinine (serum creatinine ratio) was assessed as the ratio of the highest value within 30 days of niraparib initiation to the baseline value. The serum creatinine ratio for reduced dose was assessed as the ratio of serum creatinine at baseline and within 30 days after resuming treatment. Non-hematologic toxicity as an AE was evaluated by a physician or pharmacist who met with the patient on the day of the visit. AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE version 5).
Statistical analysis. Statistical analysis was performed between two or three groups using serum creatinine ratio as a continuous variable. The Mann-Whitney U-test was used for comparisons between two groups, and Dunnett’s multiple comparison test was used for comparisons between three groups. All significance levels were set to 5%. For statistical analysis, SPSS version 24.0 software (SPSS, Chicago, IL, USA) was used.
Results
Patient characteristics. Between December 2020 and March 2022, a total of 50 ovarian cancer patients initiated niraparib and 45 were analyzed (Figure 1). Patient characteristics are shown in Table I. Median age was 60 years (range=38-86 years), median body weight was 48.7 kg (range=36.1-80.9 kg) and 44 (97.8%) patients were in FIGO stage III/IV. BRCA wild-type and mutants were detected in 20 (44.4%) and 2 (4.5%) patients, respectively. HRD positive and negative statuses were detected in 5 (11.1%) and 16 (35.5%) patients, respectively. Among the 45 patients, 41 patients (91.1%) underwent primary or interval debulking surgery, 44 patients (97.8%) received maintenance therapy, and 44 patients (97.8%) started niraparib at 200 mg/day. Niraparib dose reduction, treatment interruption and treatment discontinuation due to AEs occurred in 18 (40.0%), 28 (62.2%), and 4 patients (8.9%), respectively.
Patient flow chart and reasons for exclusion. This study included patients who started niraparib between December 2020 and March 2022. Exclusion criteria were: i) use of other PARP inhibitors; ii) discontinuation of treatment; and iii) no serum creatinine measured within 30 days of niraparib initiation.
Patient characteristics.
Adverse events. A total of 41 patients (91.1%) developed hematologic toxicity, with anemia in 82.2%, neutropenia in 80.0%, and thrombocytopenia in 73.3%. Of these, 23 patients (51.1%) had ≥Grade 3 hematologic toxicity, with anemia in 20.0%, neutropenia in 37.8%, and thrombocytopenia in 8.9%. In addition, 33 patients (73.3%) had ≥Grade 1 non-hematologic toxicities, including nausea in 46.7%, fatigue in 44.4%, hypertension in 28.9%, headache in 15.6%, insomnia in 15.6% and pneumonia in 2.2%. Of these, 4 patients (8.9%) developed ≥Grade 3 non-hematologic toxicity, including nausea in 4.4% and hypertension in 4.4% (Table II).
The incidence of adverse events.
Relationship between adverse events and serum creatinine ratio. All 45 eligible patients showed elevated serum creatinine within 30 days of niraparib initiation. Higher serum creatinine ratio before and after niraparib initiation tended to be associated with worse grade of hematologic toxicity (Grade 0-2: median=1.23, range=1.05-1.62; Grade 3: median=1.28, range=1.13-1.47; Grade 4: median=1.45, range=1.30-1.57) (Figure 2). A comparison of serum creatinine ratios for each AE is shown in Table III. Serum creatinine ratio tended to be higher in patients with ≥Grade 3 anemia, thrombocytopenia, and transfusions.
Relationship between hematologic adverse events and serum creatinine ratio. Serum creatinine ratio increased with niraparib according to the grade of hematologic adverse events. The vertical axis shows the ratio of serum creatinine before and within 30 days after niraparib initiation. For hematologic adverse events, the worst grades of neutropenia, anemia, and thrombocytopenia were used in each case and compared. The grade of adverse events was evaluated using CTCAE version 5. Serum creatinine ratios were compared between hematologic adverse events ≤Grade 2 and Grade 3, and between ≤Grade 2 and Grade 4, using Dunnett’s multiple comparison test.
Comparison of serum creatinine ratios for each adverse event.
Timing of ≥Grade 3 hematologic toxicities. The timings of ≥Grade 3 hematologic toxicities are shown in Figure 3. Thrombocytopenia ≥Grade 3 occurred within 2 months of niraparib initiation and did not occur after 3 months. Neutropenia was most common at 2 months and continued to occur in 15% of patients at 10 months. Anemia began 2 months after niraparib administration and continued to occur in 15% of patients at 10 months.
Timing of ≥Grade 3 hematologic adverse events. Percentage of ≥Grade 3 hematologic adverse events during the 10-month observation period. Hematologic adverse events are listed for neutropenia, anemia, and thrombocytopenia. If ≥Grade 3 hematologic adverse events continued over a month, only the time of onset was counted.
Time series of serum creatinine and platelet counts. Serum creatinine and platelet counts are shown for four cases in which ≥Grade 3 thrombocytopenia occurred (Figure 4). Case 1 was a 69-year-old woman receiving niraparib at 200 mg/day, case 2 was a 70-year-old woman receiving niraparib at 200 mg/day, case 3 was an 84-year-old woman receiving niraparib at 200 mg/day, and case 4 was a 66-year-old woman receiving niraparib at 200 mg/day. All four patients started maintenance treatment with primary platinum-based chemotherapy. In all cases, the increase in serum creatinine preceded ≥Grade 3 thrombocytopenia. In case 1, serum creatinine increased to 0.8 mg/ml (serum creatinine ratio=1.44) on day 29 of niraparib treatment, and thrombocytopenia Grade 4 occurred on day 43. In case 2, serum creatinine increased to 0.82 mg/ml (serum creatinine ratio=1.57) on day 15 of niraparib treatment, and thrombocytopenia Grade 4 occurred on day 21. In case 3, serum creatinine increased to 0.96 mg/ml (serum creatinine ratio=1.27) on day 24 after niraparib administration, and thrombocytopenia Grade 3 occurred the same day. In case 4, serum creatinine increased to 1.04 mg/ml (serum creatinine ratio=1.46) on day 8 of niraparib treatment, and thrombocytopenia Grade 4 occurred on day 22.
Time series of serum creatinine and platelet counts. Platelets and serum creatinine in four patients with ≥Grade 3 thrombocytopenia. The horizontal axis indicates the number of days after niraparib administration. The range of ≥Grade 3 thrombocytopenia is shown in gray.
Change in serum creatinine ratio with niraparib dose. Niraparib dose reductions occurred in 18 patients, of whom 17 (94.4%) underwent a reduction from 200 mg/day to 100 mg/day and 1 patient (5.6%) from 300 mg/day to 200 mg/day. Serum creatinine ratio from baseline before treatment initiation tended to decrease with niraparib dose reduction (Figure 5). Median serum creatinine ratio showed no significant difference before niraparib dose reduction (1.27; interquartile range=1.21-1.37) and after (1.22; interquartile range=1.17-1.31; p=0.189).
Comparison of increased serum creatinine between initial dose and reduction dose. The vertical axis expresses values as a ratio of serum creatinine. Initial dose is expressed as the ratio of serum creatinine before niraparib initiation to serum creatinine within 30 days after niraparib initiation. Reduced doses are expressed as the ratio of serum creatinine at baseline and within 30 days after resuming treatment at a reduced dose. Dose reductions were seen in 18 patients, with 17 patients reduced to 200 mg and one to 300 mg. Serum creatinine ratios were compared using the Mann-Whitney U-test.
Discussion
Even when niraparib therapy was initiated at individualized doses, nearly half of the patients developed hematologic toxicity ≥Grade 3, indicating that hematologic toxicity is also a problem in clinical practice. In addition, patients with Grade 4 hematologic toxicity showed a greater increase in serum creatinine than those with ≤Grade 2. Hematologic toxicities showed differences in timing of onset, with thrombocytopenia ≥Grade 3 occurring only within 2 months of niraparib initiation. This leads us to believe that thrombocytopenia is the adverse event requiring the most attention in the early stages of administration. In addition, thrombocytopenia ≥Grade 3 occurred 0-14 days after serum creatinine ratio was most elevated. These results suggest that serum creatinine ratio is associated with hematologic toxicity in niraparib therapy.
Niraparib has been shown to represent a substrate for the multidrug and toxin extrusion protein (MATE) 1 and MATE 2-K transporters in the kidney (18). MATE 1/2-K are transporters that eject creatinine and other substances from the renal tubules into the urine (19). Niraparib has been reported to cause increases in serum creatinine, suggesting that this may be related to inhibition of MATE 1/2-K transporters and dopamine norepinephrine transporter (17, 20). Serum creatinine elevations with PARP inhibitors, including niraparib, are often reversible and rarely pose a clinical problem (20-22). This may be because the increase in serum creatinine with PARP inhibitors represents an apparent increase in creatinine due to inhibition of the transporter and may not reflect actual declines in renal function (23). In vitro, inhibition of MATE 1/2-K uptake reportedly becomes stronger with increasing concentrations of tyrosine kinase inhibitors (24, 25). In other words, we believe that the higher the blood concentration of niraparib, the stronger the inhibition of MATE 1/2-K. Serum creatinine ratio was significantly higher in patients who developed Grade 4 hematologic toxicity compared to that of patients who developed ≤Grade 2 in the present study. Niraparib is also reportedly associated with blood concentration and AEs (22). From these considerations, we believe that serum creatinine ratio may reflect blood concentrations of niraparib. In addition, a trend was seen toward a lower percentage increase in serum creatinine with reductions in niraparib dose. This suggests that reductions in blood concentration of niraparib correlated with reductions in the serum creatinine ratio.
The incidence of hematologic toxicity in this study tended to be higher than in previous reports. Body weight has been described as a risk factor for thrombocytopenia, potentially due to the fact that many patients in this study were small (median body weight of 48.7 kg). In fact, median body weight in the QUADRA study (conducted mainly in Europe and the United States and reporting on actual clinical practice in the United States) was 70 kg, while median body weight in the NORA study (conducted in China, also in East Asia) was 61.0 kg (10, 14, 15). Median body weight in actual clinical practice in China was 50.5 kg, close to the patient population in the present study (16). Although the incidence of hematologic toxicity was higher in the present study, the shorter median follow-up (2 months) in the Chinese clinical report may have contributed to a lower incidence of AEs.
In this study, the onset of hematologic toxicity tended to be either acute (occurring within 2 months) or delayed (occurring continuously after the third month). Thrombocytopenia ≥Grade 3 did not occur after the third month. This is consistent with the results of a retrospective safety analysis of the ENGOT-OV16/NOVA study by Berek et al., which showed that the incidence of hematologic toxicities decreased after the fourth month of niraparib treatment, particularly thrombocytopenia, which occurred in less than 1% of patients (13). In practice, acute and rapid hematologic toxicity is often a problem. In this study, four cases showed ≥Grade 3 or thrombocytopenia, all of which occurred acutely within 2 months. Care is therefore required regarding rapid-onset hematologic toxicity, particularly thrombocytopenia, within 2-3 months of niraparib initiation. In addition, elevations in serum creatinine were highest at 0-14 days before the onset of ≥Grade 3 thrombocytopenia. This suggests that early detection of serious hematologic toxicity may be possible by frequent visits every 1-2 weeks for patients with high serum creatinine ratios that may reflect blood concentration.
The cohort in the present study was only 50 patients. However, few previous studies of niraparib have examined hematologic toxicity. Key findings from the 50 patients in this study were that: a) serum creatinine ratio may be associated with serious hematologic toxicity, and b) increases in serum creatinine ratio preceding serious hematologic toxicity are important findings in the management of niraparib AE. Secondly, niraparib blood concentration was not measured in this study. The results of this study suggest that serum creatinine ratio is related to blood concentrations of niraparib, and that severe hematologic toxicity may occur. Future studies will resolve our hypothesis by measuring blood concentrations. The results of this study are thus important for further studies.
Patients who developed severe hematologic toxicity in this study tended to have higher serum creatinine ratios. This may be related to serum creatinine ratios in relation to niraparib blood concentration. Hematologic toxicity was biphasic, as acute or delayed, and severe thrombocytopenia was more common in the acute phase within 2 months. Furthermore, severe thrombocytopenia in the acute phase occurred within 0-14 days of the highest serum creatinine ratio. We therefore recommend that blood samples be drawn every 1-2 weeks after niraparib initiation to follow-up serum creatinine ratios, and that patients with high ratios continue to have blood samples drawn every 1-2 weeks for up to 2 months. The serum creatinine ratio in niraparib therapy has been shown to offer a potential marker for predicting serious hematologic toxicity.
Conclusion
Even at individualized doses of niraparib, the high incidence of hematologic toxicity was found to be clinically problematic. Predicting severe hematologic toxicity with niraparib and managing treatment with an appropriate dosing schedule is an important issue. Serum creatinine ratio may be related to niraparib blood concentration and offers a potential marker for predicting severe hematologic toxicity following niraparib therapy.
Acknowledgements
The Authors would like to thank the participating patients, their family members, and all researchers in this study.
Footnotes
Authors’ Contributions
Koki Hashimoto: Conceptualization, data curation, formal analysis, investigation, methodology, project administration, supervision, investigation, visualization, writing original draft, and review and editing. Kazuyoshi Kawakami: Conceptualization, methodology, project administration, review and editing. Takashi Yokokawa: Conceptualization, methodology, review and editing. Naoki Shibata: Methodology, review and editing. Azusa Soejima: Methodology, review and editing. Takahito Sugisaki: Review and editing. Yuka Mori: Review and editing. Hisanori Shimizu: Review and editing. Mayu Yunokawa: Conceptualization, review and editing. Hiroyuki Kanao: Review and editing. Masakazu Yamaguchi: Project administration, supervision, review and editing.
Conflicts of Interest
K. Hashimoto received lecture fees from Takeda Pharmaceutical Co., Ltd. T. Yokokawa received lecture fees from AstraZeneca Co., Ltd. N. Shibata received lecture fees from Chugai Pharmaceutical Co., Ltd. M. Yunokawa received lecture fees from Takeda Pharmaceutical Co., Ltd., AstraZeneca Co., Ltd., and Chugai Pharmaceutical Co., Ltd. M. Yamaguchi received lecture fees from Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Celltrion Healthcare Co., Ltd., and Nippon Kayaku Co., Ltd.
- Received June 29, 2023.
- Revision received August 2, 2023.
- Accepted August 3, 2023.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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