Abstract
Lessons Learned
Pharmacokinetics characteristics of niraparib in Chinese patients were similar to those in white patients.
Niraparib could be well tolerated by Chinese patients, and adverse events were manageable in this study.
Population pharmacokinetics analysis indicated that baseline body weight had a modest impact on pharmacokinetics parameters of niraparib; however, it was not considered clinically important.
Background
This randomized, open‐label, single‐arm, phase I study was designed to investigate the pharmacokinetics (PK) and safety of niraparib in Chinese patients with epithelial ovarian cancer.
Methods
Eligible patients were randomized in a 1:1:1 ratio to receive 100, 200, or 300 mg of niraparib once daily. PK parameters were analyzed after single and multiple dose administrations.
Results
Thirty‐six Chinese patients were enrolled in total. Niraparib was rapidly absorbed after administration, and median time‐to‐peak (Tmax) was 3 hours. The long terminal elimination half‐life (T1/2 ∼ 35 hours) supports once‐daily dosing regimen. The exposure to niraparib showed linear and dose‐proportional pharmacokinetics, whereas other PK parameters such as Tmax, T1/2, and accumulation ratio were dose independent. Population PK analysis indicated that there was no effect of race on niraparib PK parameters, whereas baseline body weight had a modest impact on niraparib exposure. Grade 3/4 treatment‐emergent adverse events (TEAEs; reported in ≥10% of patients) included platelet count decreased (a total of five patients who were all from the 300‐mg group) and neutrophil count decreased. The TEAEs were manageable after dose modification.
Conclusion
The PK profile of niraparib in Chinese patients is consistent with that in white patients. Niraparib is safe and well tolerated in Chinese patients with ovarian cancer.
Discussion
Niraparib, a highly selective poly(ADP‐ribose) polymerase (PARP)‐1/‐2 inhibitor, is approved by the U.S. Food and Drug Administration 1 as a maintenance therapy in platinum‐sensitive, recurrent ovarian cancer 2, 3, 4, 5. However, no studies on the PK and safety profile of niraparib in the Chinese population have been conducted.
This study was designed to investigate the PK and safety characteristics of niraparib in Chinese patients with epithelial ovarian cancer and to determine any ethnic diversity between Chinese and white patients.
The maximum serum concentration (Cmax) and area under the plasma concentration curve (AUC) increased dose‐proportionally at doses from 100 to 300 mg once daily (Table 1). Comparison of the PK parameters of niraparib between Chinese and white patients demonstrated similar distributions. A population PK analysis of niraparib in Chinese and white patients was performed using data (including 144 white and 36 Chinese patients) from the PN001 study, the NOVA study, and the present study. Results showed that there was no effect of race on niraparib AUC and a negligible effect on Cmax and that the Cmax and AUC of niraparib slightly increased as the baseline body weight decreased (Fig. 1).
Table 1.
Summary of pharmacokinetic parameters (Cmax and AUC0–24h) for niraparib after a single‐dose administration
| Dose | Cmax, nM, Geometric mean [coefficient of variation] (patients, n) | AUC0–24h, hours × nM, Geometric mean [coefficient of variation] (patients, n) | T1/2, hours, Geometric mean | ||||
|---|---|---|---|---|---|---|---|
| Chinese | Whitea | Chinese | Whitea | Chinese | Whitea | ||
| 100 mg | 958 [33.1%] (12) | 926 [57.6%] (5) | 11,231 [27.6%] (12) | 10,216 [46.8%] (5) | 36.3 | 36.8 | |
| 200 mg | 1,834 [22.4%] (12) | 1,577 [69.8%] (6) | 21,727 [27.4%] (12) | 17,683 [82.7%] (6) | 31.1 | 32.8 | |
| 300 mg | 3,214 [26.0%] (12) | 2,232 [39.9%] (10) | 40,234 [22.8%] (12) | 25,411 [38.4%] (10) | 34.3 | 36.2 | |
From Reference 2.
Abbreviations: AUC0–24h, areas under serum concentration‐time curve from 0 to 24 hours; Cmax, maximum serum concentration.
Figure 1.
Forest plot of covariate effects on niraparib steady‐state Cmax and AUC. (A): Covariate effects on niraparib steady‐state Cmax. (B): Covariate effects on niraparib steady‐state AUC. For all covariate scenarios, all other covariates were maintained at values for the reference patient (69.35 kg body weight, white, taking niraparib in the fasted state; median 300 mg once daily typical steady‐state Cmax from typical values of parameters = 1,309 ng/mL). Numbers in the right panel represent median [95% CI].
Abbreviations: AUC, area under the concentration‐time curve; CI, confidence interval; Cmax, maximum concentration.
Similar to the results in white patients, the major adverse events occurred in the hematologic system and digestive system 6. No new safety issues were found in the current study. Previously, the NOVA study suggested that patients with baseline body weight <77 kg who received a starting dose of 300 mg once daily were subject to a higher incidence of TEAEs and may benefit from a starting dose of 200 mg once daily without compromising efficacy 7. It is worth noting that the baseline body weight of Chinese patients in the 300‐mg group ranged from 38.4 to 63.0 kg, which was significantly lower than 77 kg, thus explaining the fact that 200 mg once daily was the most common dosage after dose modification. The lower baseline body weight also caused slightly higher drug exposure when compared with white patients (Table 1).
In conclusion, the PK profile of niraparib in Chinese patients was consistent with that in white patients. Niraparib demonstrated an expected safety profile and was well tolerated in Chinese patients with ovarian cancer.
Trial Information
- Disease
Ovarian cancer
- Stage of Disease/Treatment
Metastatic/advanced
- Prior Therapy
Two prior regimens
- Type of Study – 1
Phase I
- Type of Study – 2
PK and safety
- Primary Endpoint
Pharmacokinetics
- Secondary Endpoint
Safety
- Investigator's Analysis
Drug tolerable, efficacy indeterminant
Drug Information
- Drug 1
- Generic/Working Name
Niraparib/ZL‐2306
- Trade Name
ZEJULA
- Company Name
Zai Lab Co., Ltd.
- Drug Type
Small molecule
- Drug Class
PARP
- Dose
100, 200, 300 mg once daily
- Route
Oral (p.o.)
- Schedule of Administration
- Patients were randomized into designated dose groups (100 mg, 200 mg, 300 mg). To investigate the pharmacokinetic profile of a single dose of niraparib, each patient was observed for 7 days without further administration of niraparib. From the 8th day, the patients started to consecutively take the prescribed dose of niraparib once daily. One cycle of treatment was defined as 28 days of continuous administration (the first cycle including a 7‐day washout period after a single dose administration).
Patient Characteristics
- Number of Patients, Male
0
- Number of Patients, Female
36
- Stage
FIGO stage III or IV
- Age
Median (range): 53.5 (43–74)
- Number of Prior Systemic Therapies
Median (range): 1 (1–2)
- Performance Status: ECOG
-
0 — 15
1 — 21
2 — 0
3 — 0
Unknown — 0
- Other
Patients’ characteristics are shown in Table 2.
Table 2.
Patients’ demographics and baseline disease characteristics
| Variables | Niraparib 100 mg once daily (n = 12) | Niraparib 200 mg once daily (n = 12) | Niraparib 300 mg once daily (n = 12) | Overall (n = 36) |
|---|---|---|---|---|
| Age, years | ||||
| Mean (SD) | 57.4 (7.79) | 52.2 (7.32) | 57.8 (9.55) | 55.8 (8.45) |
| Median | 58.5 | 49.5 | 54.5 | 53.5 |
| Minimum, maximum | 48, 74 | 43, 64 | 46, 72 | 43, 74 |
| Weight, kg | ||||
| Mean (SD) | 61.35 (8.57) | 65.20 (11.26) | 55.69 (7.56) | 60.75 (9.83) |
| Median | 62.25 | 64.00 | 58.00 | 61.50 |
| Minimum, maximum | 48.0, 75.3 | 50.0, 93.0 | 38.4, 63.0 | 38.4, 93.0 |
| BMI, kg/m2 | ||||
| Mean (SD) | 24.55 (3.63) | 24.87 (3.47) | 22.72 (3.23) | 24.04 (3.48) |
| Median | 24.49 | 25.01 | 22.81 | 24.06 |
| Minimum, maximum | 19.59, 32.31 | 19.78, 32.95 | 16.40, 27.78 | 16.40, 32.95 |
| ECOG performance status, n (%) | ||||
| 0 | 6 (50.0) | 5 (41.7) | 4 (33.3) | 15 (41.7) |
| 1 | 6 (50.0) | 7 (58.3) | 8 (66.7) | 21 (58.3) |
| Site of primary tumor, n (%) | ||||
| Ovary | 11 (91.7) | 12 (100.0) | 11 (91.7) | 34 (94.4) |
| Fallopian tubes | 1 (8.3) | 0 | 1 (8.3) | 2 (5.6) |
| Histological subtype, n (%) | ||||
| High‐grade serious ovarian cancer | 10 (83.3) | 11 (91.7) | 11 (91.7) | 32 (88.9) |
| Others | 2 (16.7) | 1 (8.3) | 1 (8.3) | 4 (11.1) |
| BRCA mutations, n (%) | ||||
| Positive for a deleterious mutation genetic variant | 6 (50.0) | 6 (50.0) | 2 (16.7) | 14 (38.9) |
| Suspected deleterious genetic variant | 0 | 0 | 1 (8.3) | 1 (2.8) |
| Favor polymorphism | 1 (8.3) | 1 (8.3) | 1 (8.3) | 3 (8.3) |
| Genetic variant of uncertain significance | 0 | 0 | 1 (8.3) | 1 (2.8) |
| No mutation or benign polymorphism | 3 (25.0) | 2 (16.7) | 1 (8.3) | 6 (16.7) |
| Not performed | 2 (16.7) | 3 (25.0) | 6 (50.0) | 11 (30.6) |
| No. of lines of previous chemotherapy, n (%) | ||||
| 1 | 8 (66.7) | 8 (66.7) | 9 (75.0) | 25 (69.4) |
| 2 | 4 (33.3) | 4 (33.3) | 3 (25.0) | 11 (30.6) |
Abbreviations: BMI, body mass index; ECOG, Eastern Cooperative Oncology Group.
Primary Assessment Method
- Title
Total patient population
- Number of Patients Screened
42
- Number of Patients Enrolled
36
- Number of Patients Evaluable for Toxicity
36
- Number of Patients Evaluated for Efficacy
0
- Evaluation Method
RECIST 1.1
- Response Assessment OTHER
n = 0
- Outcome Notes
Efficacy of niraparib was assessed by investigators for treatment decision making. The efficacy data were not collected in this study.
Adverse Events
| All Dose Levels, All Cycles | |||||||
|---|---|---|---|---|---|---|---|
| Name | NC/NA | 1 | 2 | 3 | 4 | 5 | All grades |
| Neutrophil count decreased | 47% | 6% | 36% | 11% | 0% | 0% | 53% |
| White blood cell decreased | 50% | 17% | 33% | 0% | 0% | 0% | 50% |
| Nausea | 61% | 25% | 14% | 0% | 0% | 0% | 39% |
| Platelet count decreased | 67% | 11% | 8% | 6% | 8% | 0% | 33% |
| Anemia | 70% | 8% | 14% | 8% | 0% | 0% | 30% |
| Fatigue | 72% | 22% | 6% | 0% | 0% | 0% | 28% |
| Vomiting | 72% | 17% | 8% | 3% | 0% | 0% | 28% |
| Alanine aminotransferase increased | 75% | 22% | 3% | 0% | 0% | 0% | 25% |
| Insomnia | 78% | 14% | 8% | 0% | 0% | 0% | 22% |
| Anorexia | 78% | 14% | 8% | 0% | 0% | 0% | 22% |
Incidence of treatment‐emergent adverse events reported in ≥20% patients.
Abbreviation: NC/NA, no change from baseline/no adverse event.
Serious Adverse Events
| Name | Grade | Attribution |
|---|---|---|
| Platelet count decreased | 3 | Probable |
| Vomiting | 3 | Probable |
| Anemia | 3 | Probable |
Assessment, Analysis, and Discussion
- Completion
Study completed
- Investigator's Assessment
Drug tolerable, efficacy indeterminant
Previously, the PN001 study 6 and the NOVA study 7, 8, 9 demonstrated the pharmacokinetic and safety profile of niraparib among white patients. The PN001 study was a phase I dose‐escalation trial that supported the conclusion that niraparib has favorable pharmacological properties and recommended a dose of 300 mg once daily for white patients in the phase II/III setting. The phase III NOVA study extended these results and indicated that patients with baseline body weight of <77 kg or baseline platelets count of <150,000/μL may benefit from an initial dose of 200 mg once daily. Moreover, the PK profile of niraparib shows that it has several advantages over other poly(ADP‐ribose) polymerase (PARP) inhibitors (i.e., olaparib 2, rucaparib 10, and veliparib 11, 12), including higher bioavailability (73%), longer terminal elimination half‐life (T1/2 ∼ 36.4 hours), larger apparent volume of distribution (Vd/F ∼ 1,220 L), and a unique metabolic enzyme (carboxylesterases) 2.
This is the first study on the pharmacokinetics (PK) and safety profile of niraparib in Chinese patients with epithelial ovarian cancer. The study was designed based on the results of the PN001 study and the NOVA study (Fig. 2). The PK parameters after single‐dose administration were obtained on the first week, whereas the steady‐state PK parameters for multiple dose administrations were measured on the 22nd day of the first cycle.
A total of 36 Chinese patients with ovarian cancer were enrolled in this study; their baseline characteristics were comparable to those of the previous phase I study except for the baseline body weight (Table 2). It is not surprising to see that enrolled patients in this study had lower baseline body weight than that in the previous studies as Asians generally have smaller body size than whites. After a single oral administration of 100 mg, 200 mg, or 300 mg of niraparib, the drug was rapidly absorbed into the blood circulation, and the median time‐to‐peak was 2.99–3.05 hours (Fig. 3; Table 3). Within the 100–300 mg dose range, the terminal elimination half‐life (T1/2), apparent clearance, and Vd/F slightly varied with the administered dosage. The average T1/2 in the current study was 35.0 hours, which is quite comparable to that of white patients with ovarian cancer in previous studies (Table 1). Compared with other PARP inhibitors (olaparib 2, rucaparib 10, and veliparib 11, 12), niraparib has a longer T1/2, so that patients only need to take niraparib once daily, which is more convenient for patients and thus may improve long‐term adherence to treatment.
Table 3.
Summary of pharmacokinetic parameters of niraparib after single‐dose and multiple‐dose administration for Chinese patients with ovarian cancer
| PK parameters, unit | Dose group | |||
|---|---|---|---|---|
| 100 mg (n = 12) | 200 mg (n = 12) | 300 mg (n = 12) | ||
| Cmax, nM | GEO Mean (CV%) | 957.41 (31.7) | 1,833.89 (22.4) | 3,214.16 (25.9) |
| Tmax, hours | Median (minimum, maximum) | 3.01 (2.9, 3.1) | 2.99 (2.0, 5.9) | 3.05 (2.9, 6.1) |
| AUC0–24, hours × nM | GEO mean (CV%) | 11,230.89 (27.6) | 21,726.61 (27.4) | 40,233.96 (22.8) |
| T1/2, hours | Mean ± SD | 37.02 ± 7.94 | 31.46 ± 5.35 | 36.45 ± 17.21 |
| Vd/F, L | Mean ± SD | 689.03 ± 220.27 | 636.53 ± 170.88 | 560.63 ± 197.40 |
| CL/F, L/hour | Mean ± SD | 12.98 ± 3.52 | 14.33 ± 4.50 | 11.18 ± 3.34 |
| Css,max, nM | GEO mean (CV%) | 2,373.83 (56.1) | 3,864.89 (21.3) | 6,459.65 (29.3) |
| AUCss, hours × nM | GEO mean (CV%) | 24,869.97 (27.8) | 45,538.20 (31.9) | 86,929.42 (28.6) |
| RAC | GEO mean (CV%) | 2.951 (23.1) | 2.716 (21.9) | 2.641 (29.6) |
Abbreviations: AUC0–24, areas under serum concentration‐time curve from 0 to 24 hours; AUCss, areas under serum concentration‐time curve from 0 to 24 hours at steady state; CL/F, apparent clearance from the plasma; Cmax, maximum serum concentration; Css,max, maximum serum concentration at steady state; GEO, geometric; RAC, accumulation ratio; T1/2, elimination half‐life; Tmax, time to reach Cmax; Vd/F, apparent volume of distribution.
The mean Vd/F of niraparib in this study was 628.3 L, which is significantly higher than the reported values of other PARP inhibitors (i.e., olaparib 2, rucaparib 10, and veliparib 11, 12), indicating that it has better tumor tissues penetration as well as increased cytocidal capabilities against cancer cells. The steady‐state accumulation ratios (RAC) in different dose groups remained essentially unchanged (RAC ∼ 2.951 in the 100‐mg group, 2.716 in the 200‐mg group, and 2.641 in the 300‐mg group) after multiple dose administrations. The consistent accumulation ratios resulted in predictable steady‐state drug exposure.
Among the 36 patients who were treated with niraparib, a total of 35 patients reported at least one treatment‐emergent adverse event (TEAE), including 11 (91.7%) patients in the 100‐mg group, 12 (100%) in the 200‐mg group, and 12 (100%) in the 300‐mg group. Although the overall frequency of TEAEs was similar in each dose group, the occurrence and severity of TEAEs were both higher in the 300‐mg group than in the 100‐mg group and the 200‐mg group (Tables 4 and 5). In the study, the most frequent (≥20%) nonhematologic TEAEs included nausea, asthenia, vomiting, alanine aminotransferase increased, insomnia, and decreased appetite, whereas the most frequent (≥20%) hematologic TEAEs included neutrophil count decreased, white blood cell count decreased, platelet count decreased, and anemia (Table 4). Major (reported in ≥5% patients) TEAEs of grade 3/4 included platelet count decreased (13.9%), neutrophil count decreased (11.1%), anemia (8.3%), and gamma glutamyl transferase increased (5.6%). The TEAEs of grade 3/4 in most patients were manageable by drug interruption or dose reduction. With regard to platelet count decreased, it mostly occurred in the first cycle (28 days per cycle) and reversed to baseline level within 1 month's duration of treatment with niraparib (Fig. 4). A retrospective analysis of the NOVA study suggested that patients with baseline body weight <77 kg or platelet count <150 × 109/L have a higher incidence of platelet count decreased when receiving a starting dose of 300 mg once daily 7. The median baseline body weight of Chinese patients in the 300‐mg group was 58 kg (ranging from 38.4 kg to 63.0 kg), which was statistically lower than 77 kg, thus explaining why all five patients reporting platelet count decreased of grade 3/4 were found in the 300‐mg group (Table 5). After drug interruption or dose reduction, all the platelet counts decreased to grade 3/4 were restored to grade 1 or better.
Table 4.
Treatment‐emergent adverse events occurring in at least 20% of patients in any cohort
| Preferred terms | Niraparib 100 mg once daily (n = 12), n (%) | Niraparib 200 mg once daily (n = 12), n (%) | Niraparib 300 mg once daily (n = 12), n (%) | Total (n = 36), n (%) |
|---|---|---|---|---|
| Treatment‐emergent adverse event | 11 (91.7) | 12 (100.0) | 12 (100.0) | 35 (97.2) |
| Neutrophil count decreased | 5 (41.7) | 5 (41.7) | 9 (75.0) | 19 (52.8) |
| White blood cell count decreased | 5 (41.7) | 4 (33.3) | 9 (75.0) | 18 (50.0) |
| Nausea | 1 (8.3) | 4 (33.3) | 9 (75.0) | 14 (38.9) |
| Platelet count decreased | 3 (25.0) | 1 (8.3) | 8 (66.7) | 12 (33.3) |
| Anemia | 1 (8.3) | 2 (16.7) | 8 (66.7) | 11 (30.6) |
| Asthenia | 2 (16.7) | 3 (25.0) | 5 (41.7) | 10 (27.8) |
| Vomiting | 1 (8.3) | 2 (16.7) | 7 (58.3) | 10 (27.8) |
| Alanine aminotransferase increased | 3 (25.0) | 4 (33.3) | 2 (16.7) | 9 (25.0) |
| Insomnia | 2 (16.7) | 3 (25.0) | 3 (25.0) | 8 (22.2) |
| Decreased appetite | 1 (8.3) | 2 (16.7) | 5 (41.7) | 8 (22.2) |
Table 5.
Niraparib‐related grade ≥ 3 treatment‐emergent adverse events in descending order
| Preferred terms | Niraparib 100 mg once daily (n = 12), n (%) | Niraparib 200 mg once daily (n = 12), n (%) | Niraparib 300 mg once daily (n = 12), n (%) | Total (n = 36), n (%) |
|---|---|---|---|---|
| AE of CTCAE grade 3 or above occurred at least once | 5 (41.7) | 2 (16.7) | 7 (58.3) | 14 (38.9) |
| Platelet count decreased | 0 | 0 | 5 (41.7) | 5 (13.9) |
| Neutrophil count decreased | 1 (8.3) | 1 (8.3) | 2 (16.7) | 4 (11.1) |
| Anemia | 0 | 0 | 3 (25.0) | 3 (8.3) |
| Gamma glutamyl transferase increased | 1 (8.3) | 0 | 1 (8.3) | 2 (5.6) |
| Metabolic disorder | 1 (8.3) | 0 | 0 | 1 (2.8) |
| Weight decreased | 1 (8.3) | 0 | 0 | 1 (2.8) |
| Vomiting | 1 (8.3) | 0 | 0 | 1 (2.8) |
| Intestinal obstruction | 1 (8.3) | 0 | 0 | 1 (2.8) |
| Blood pressure increased | 0 | 0 | 1 (8.3) | 1 (2.8) |
| Blood triglycerides increased | 0 | 1 (8.3) | 0 | 1 (2.8) |
| Blood creatine phosphokinase increased | 1 (8.3) | 0 | 0 | 1 (2.8) |
| Hyperlipidemia | 1 (8.3) | 0 | 0 | 1 (2.8) |
Abbreviations: AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events.
During the study period, there was no TEAE‐induced death. A total of five serious adverse events (SAEs) were reported (four in the 300‐mg group, one in the 100‐mg group), which included vomiting (one patient in the 100‐mg group), platelet count decreased (three patients in the 300‐mg group), and anemia (one patient in the 300‐mg group). All five SAEs were considered to be related to the study drug.
Previously, the NOVA study demonstrated that patients in the niraparib group have a significant improvement in progression‐free survival regardless of BRCA mutation status 8. Although efficacy data were not collected in this study because of limited sample size, a phase III study (NORA) is ongoing to evaluate the efficacy of niraparib with a larger sample size in Chinese patients.
In summary, Niraparib was well tolerated in Chinese patients with ovarian cancer, and the TEAEs were manageable after drug interruption or dose reduction. These findings support that there is little ethnic difference in the handling of niraparib.
Disclosures
Ashley Milton: Tesaro (E); Jianmei Hou: Zai Lab (E); Yongjiang Hei: Zai Lab (E, OI). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Figure and Tables
Footnotes
- Sponsor: Zai Lab Co., Ltd.
- Principal Investigators: Xiaohua Wu, Jian Zhang
- IRB Approved: Yes
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