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Original research
Effects of niraparib dose reduction on short-term outcomes in ovarian cancer patients
  1. Matteo Bruno1,
  2. Adriana Ionelia Apostol1,
  3. Serena Maria Boccia1,
  4. Carolina Maria Sassu1,
  5. Sara Lardino1,
  6. Camilla Culcasi1,
  7. Domenica Lorusso1,2,
  8. Giovanni Scambia1,2,
  9. Anna Fagotti1,2 and
  10. Claudia Marchetti1,2
    1. 1Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
    2. 2Dipartimento Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
    1. Correspondence to Professor Anna Fagotti, Dipartimento Scienze della Salute della Donna e del Bambino, Policlinico Universitario Agostino Gemelli, Rome, Italy; anna.fagotti{at}policlinicogemelli.it

    Abstract

    Objectives Despite the individualized starting dose for maintenance therapy in ovarian cancer, the niraparib dose reduction rate remains high. The aim of this study was to evaluate the impact of niraparib dose reduction on progression-free survival in newly diagnosed primary advanced ovarian cancer and recurrent ovarian cancer patients. We also aimed to compare the reduction rates and the safety of niraparib on primary and relapse groups, and identify which factors may predict dose reduction.

    Methods Patients with primary or recurrent ovarian cancer in maintenance who received niraparib between 2019 and 2022 were retrospectively evaluated. Niraparib dosing was based on individualized starting dose of 300 or 200 mg/day. The impact of niraparib dose reductions was focused on patients treated with 200 or 100 mg in both groups. Reduction rates, adverse events and predictive factors of reduction were assessed in each study group. The primary endpoint was progression-free survival in primary and relapse groups; the secondary endpoints were the reduction rates, the safety and tolerability of niraparib in both groups.

    Results Of 215 patients identified, 124 (57.7%) primary and 91 (42.3%) recurrent ovarian cancer patients were included. The majority of patients started niraparib at 200 mg/day (92.7% primary and 80.2% relapse group); dose reductions from 300 or 200 mg/day to 200 or 100 mg/day occurred more frequently within cycles 1–3 (67% primary and 45% relapse group, p=0.001). Grade≥3 adverse events were lower in the relapse group (54.8% primary and 35.1% relapse, p=0.001). In both groups, dose modifications over the treatment did not significantly impair median progression-free survival. Univariate and multivariate analysis demonstrated that weight and platinum-doublets were possible risk factors for dose reduction.

    Conclusions Niraparib dose reduction occurs in almost half of patients within cycles 1–3, although it is significantly more common in the first-line setting. Survival outcomes seem not to be impaired by dose reduction.

    • Ovarian Cancer
    • Gynecology
    • Carcinoma, Ovarian Epithelial
    • Medical Oncology

    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

    https://doi.org/10.1136/ijgc-2024-005363

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      WHAT IS ALREADY KNOWN ON THIS TOPIC

      • Previous randomized clinical trials have introduced the individualized starting dose of niraparib in maintenance therapy in ovarian cancer; however, the niraparib dose reduction rate remains high. There are few studies investigating the impact of niraparib dose reduction on prognosis in a real-life scenario.

      WHAT THIS STUDY ADDS

      • Our analysis showed that in primary and recurrence maintenance therapy for ovarian cancer, niraparib dose reductions tend to occur early during treatment, without impacting progression-free survival, preserving the outcome and safety of dose-reduced patients. Weight and previous double platinum-based treatment may help to predict dose reductions.

      HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

      • These results provide additional information for personalized management of maintenance therapy in primary or recurrent ovarian cancer and monitoring of follow-up of patients on poly (ADP-ribose) polymerase inhibitors (PARPi).

      Introduction

      Epithelial ovarian cancer has a poor prognosis; this disease typically presents at an advanced stage with a reported 5-year overall survival rate of about 10–30%.1 Standard treatment for newly diagnosed advanced ovarian cancer is cytoreductive surgery and platinum-based chemotherapy. Despite an initially positive response rate, 70–80% of these patients develop recurrence within 2 years after completion of first-line chemotherapy.2 Patients who relapse have a poor prognosis, with a median secondary progression free-survival which decreases with each relapse.3 In the last decade, clinical trials have focused on the strategy of poly (ADP-ribose) polymerase inhibitors (PARPi) maintenance treatment to increase the chemotherapy-free interval.4–11

      The use in clinical practice of PARPi has increased the treatment options for newly diagnosed or recurrent high-grade serous ovarian cancer. Niraparib was approved in 2017 as maintenance treatment of recurrent ovarian cancer after complete/partial response to platinum-based chemotherapy and an individualized starting dose from 300 to 200 mg has been introduced into daily oncological practice, with equal benefit in terms of progression free-survival and overall survival.12–14

      However, the niraparib dose reduction rates remain high; more than half of patients are supposed to reduce the dose during treatment.15–19 Dose reduction usually occurs early, with most patients reaching their adjusted dose level at the end of month 3 of treatment.15–19 Moreover, whether treatment-emergent adverse events occur more commonly in a specific patient setting and the impact of niraparib dose reduction during treatment on progression free-survival and overall survival has rarely been investigated, particularly outside randomized clinical trials.

      Methods

      Inclusion Criteria

      This was a retrospective, single-center, cohort study. The present study was approved by the Institutional Review Board (IRB) of Policlinico Agostino Gemelli IRCCS (ID 6356). All patients with histologically confirmed primary high-grade serous ovarian cancer, fallopian tubes (International Federation of Gynecology and Obstetrics (FIGO) stage III-IV), or platinum-sensitive recurrent epithelial type treated with niraparib between 2019 and 2022 were included. All patients achieved a partial response or complete response to platinum-based chemotherapy according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1).20 Exclusion criteria were: previous PARPi treatment, use of PARPi as part of an experimental protocol, and patients who continued therapy at another center.

      Data Collection and Procedures

      Patients’ data were retrieved from the Research Electronic Data Capture (RedCap) institutional database. We identified a primary (patients with primary advanced ovarian cancer) and a relapse (patients with recurrent ovarian cancer) group. The starting dose of niraparib was an individualized starting dose based on: weight < or ≥ 77 kg, platelet count < or ≥ 150 000/µL.15 Patients received oral niraparib 300 or 200 mg once daily continuously. Dose reductions to 200 or 100 mg once daily were done as required and according to dose modification guidelines. Safety monitoring was done weekly during the first 28 days and then every 4 weeks. RECIST (version 1.1) tumor assessment via total-body CT was required to evaluate disease progression. After treatment was discontinued, follow-up was performed every 12 weeks for tumor assessments and safety monitoring for the first 2 years.

      The severity of the toxic effects was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). All adverse events were recorded for each patient from the first day until the end of the treatment visit. This real-life study investigated in a large population, as the primary endpoint, whether niraparib dose reduction during treatment impacts progression-free survival in the primary and relapse groups; the secondary endpoints were to compare the reduction rates and the safety and tolerability of niraparib on the primary and relapse groups, and to identify which factors may have an impact on niraparib dose reduction.

      Statistical Analysis

      Standard descriptive statistics were used to evaluate the distribution of each variable. Continuous variables were reported as median and range, and categorical variables as frequency and percentage; chi-square or t-test were used to compare categorical or numerical variables. The logistic regression model was employed to analyze the data relative to clinical variables as predictors of dose reduction in each group. Progression-free survival was defined as the time elapsed between the start of niraparib treatment and documentation of progressive/recurrent disease or the date of last follow-up. Medians and life tables were computed using the product limit estimate by the Kaplan–Meier method and the log-rank test was employed to assess the statistical significance. For both primary and relapse groups, survival analysis was focused on patients treated with 200 or 100 mg: dose reductions that occurred before the fourth maintenance cycle were considered in the lower dose group; this was done to avoid selection bias and to censure any progression that would occur before the optimal individualized dose is reached. We excluded a dosage of 300 mg from the survival analysis due to the low number of patients and consequently of events.

      All statistical tests were performed using the Statistical Product and Service Solutions software (SPSS, version 22.0). Statistical tests were two-sided, and differences were considered significant at the level of p value<0.05.

      Results

      Patients Characteristics

      Online supplemental figure S1 shows the flow chart of patients; 215 patients treated with niraparib maintenance were included in the study period from January 2019 to December 2022: 124 (57.7%) first diagnosis and 91 (42.3%) at relapse. Patients’ characteristics are shown in two groups, according to the timing of treatment (Table 1). All patients received individualized starting doses: the most common niraparib maintenance starting dose in both groups was 200 mg (92.7% primary and 80.2% relapse groups); accordingly, 4.0% of the primary group started with niraparib at 300 mg compared with 14.3% of the relapse group (p=0.023). The use of an initial dose of 100 mg for some patients was due to factors that influence toxicity: Eastern Cooperative Oncology Group (ECOG) (>1), age (>80 years), and weight (<40 kg); this choice was limited to a few cases: four patients in the primary group and five patients in the relapse group.

      Supplemental material

      View this table:
      Table 1

      Baseline characteristics of the primary and relapse groups

      The main differences between the groups were: median weight of the patients at the start of niraparib: 58 kg (range: 40–115) for primary and 62 (range: 40–110) for relapse group (p=0.017), median ECOG (18.5% ECOG 1 for primary and 9.9% for relapse group, p=0.05), carboplatin-based doublet chemotherapy (97.6% for primary and 67.0% for relapse group; p=0.001), and carboplatin doses (499 mg for primary vs 422 for relapse group; p=0.001). Most recurrent ovarian cancer patients had experienced two (69.2%) or more than two (30.8%) prior lines of chemotherapy.

      Survival Analysis

      As of September 2023, the median follow-up for the primary group was 38 months (range: 11–50) and 40 months (range: 14–52) for the relapse group. At the time of the analysis, in the primary group 59 patients (47.6%) were alive without disease, 45 (36.3%) had disease, and there were 20 deaths (16.1%) from disease. Conversely, in the relapse group there were 63 patients (69.2%) alive with disease and 13 (14.3%) deaths from disease. In both groups, progression-free survival was not significantly affected by dose reduction over the treatment.

      In fact, the median progression free-survival or disease-free survival was 27 months for primary group patients treated with niraparib 100 mg and 27 months for those treated with niraparib 200 mg, respectively (p=0.76). Similarly, no difference was found in the recurrent setting related to dose reduction, with 15 months’ median progression free-survival in patients on niraparib 100 mg compared with 16 months in those on niraparib 200 mg (p=0.39) (Figure 1). We did not perform an analysis of the risk of death due to the low number of deaths in the entire cohort.

      Figure 1
      Figure 1

      Progression-free survival in the primary (A) and relapse (B) groups in relation to niraparib dose* reduction. *The analysis does not include patients treated with niraparib 300 mg due to the low number of events.

      Toxicity

      At least one treatment-emergent adverse event was experienced by 95.7% of the primary group and 93.8% of the relapse group. In the primary and relapse groups, grade≥3 adverse events occurred in 68 (54.8%) and 32 (35.1%) patients, respectively (p=0.001). For primary ovarian cancer patients, the most common grade≥3 events were hematological and included neutropenia (n=22, 18%), thrombocytopenia (n=31, 25%), and anemia (n=22, 18%). Also, for recurrent ovarian cancer patients, the most common grade≥3 hematological treatment-emergent adverse events were neutropenia (n=13, 14%), thrombocytopenia (n=20, 22%), and anemia (n=9, 10%). Figure 2 and Online supplemental table S1 summarize the entire grade treatment-emergent adverse events. Treatment discontinuations due to adverse events were 6.5% (8 patients) in the primary and 5.5% (5 patients) in the relapse cohorts, respectively. Among the patients who discontinued, the most significant adverse events were acute myeloid leukaemias (0.8% in the primary group and 2.2% in the relapse group) and one posterior reversible encephalopathy syndrome. Other discontinuation reasons are reported in Online supplemental table S1.

      Figure 2
      Figure 2

      Treatment-emergent adverse events in the primary and relapse groups. a Hypertransaminasemia, headache, insomnia, arthralgias, myalgias, hypercreatininemia, skin disorders, anxiety, eye disorders. AE, adverse event.

      Dose Reduction

      Dose reduction during niraparib maintenance occurred in 71% (n=88) and 53.8% (n=49) of patients in the primary and relapse groups, respectively (p=0.007). Dose reductions occurred more frequently within cycles 1–3 in the primary group (n=83, 67%) when compared with the relapse group (n=41, 45%) (p=0.001); however, the dose reduction rate in the same time frame exhibits a similar trend for both groups (Online supplemental table S1, Figure 3).

      Figure 3
      Figure 3

      Niraparib dose reduction during the treatment period.

      Predictive Factors of Dose Reduction

      As shown in Table 2, the univariate analysis demonstrated that weight>61 kg (OR: 0.97, 95% CI: 0.95 to 1.00, p=0.05) and mono platinum-based chemotherapy (OR: 0.39, 95% CI: 0.18 to 0.86, p=0.02) were identified as protective factors when compared with weight≤61 kg and double platinum-based chemotherapy, which are consequently identified as risk factors for dose reduction. Despite the limitations of univariate analysis, platelet count at starting therapy, ECOG, and carboplatin dose (calculated in terms of carboplatin mg and carboplatin area under the curve (AUC)) showed no statistically significant impact. On multivariable analysis, weight (OR: 0.56, 95% CI: 0.32 to 0.98, p=0.04) and double platinum-based chemotherapy (OR: 0.41, 95% CI: 0.18 to 0.91, p=0.03) were confirmed as independent risk factors of dose reduction.

      View this table:
      Table 2

      Univariate and multivariate analysis of predictive factors of dose reduction*

      Discussion

      Summary of Main Results

      In our study cohort, niraparib dose reduction, particularly within the first three cycles, occurs more frequently in the primary setting compared with patients with recurrent ovarian cancer. Nonetheless, dose changes throughout treatment did not impact progression free-survival, preserving the outcome of dose-reduced patients, in both populations. Also, the incidence of common adverse events in our cohort is comparable with randomized studies.

      Results in the Context of Published Literature

      The differences in niraparib dose reduction between the primary and relapse groups led us to investigate whether there were factors predictive of dose modifications that may eventually be different according to the disease setting. Other factors analyzed in the literature were: age, race, ECOG, hemoglobin counts, duration of prior chemotherapy, and lines of prior chemotherapy.6 15 18 21 Baseline weight≤61 kg and double platinum-based chemotherapy emerged as predictive factors of toxicity and dose reduction, both in the primary and relapse populations. However, in the recurrent setting a low toxicity does not justify the choice to adopt platinum-based monotherapy, also considering maintenance with niraparib.

      Since the chemotherapy response cannot be foreseen, the most effective combination of chemotherapeutics has to be used in case of relapses, considering previous therapies and the patient’s clinical conditions. In our cohort, carboplatin dose is not a predictor of dose reduction; however, for future research it would be more consistent to calculate dosage according to carboplatin AUC instead of carboplatin mg, as several factors (including weight) have an impact and may be confounding factors (higher carboplatin mg dosing in patients that weight more, which is also linked to potentially lower niraparib toxicity).

      To our knowledge, published data on the impact of dose reduction of PARPi therapy on outcomes are limited. In studies on olaparib, the overall response rate appeared higher for patients receiving 300 or 400 mg twice daily compared with 200 mg twice daily, but this analysis by Mateo et al22 was based on a small number of patients. Conversely, Francis et al23 reported that olaparib dose reduction for adverse events during the first 12 weeks did not impact on progression free-survival and overall survival. In studies on niraparib, an interim analysis of the PRIMA study18 showed that for homologous recombination proficient (HRp) patients, starting niraparib at 300 mg/day prolonged the median progression-free survival by 2.8 months while starting at 200 mg/day prolonged median progression-free survival by only 0.1 months. However, the PRIMA trial was not designed with the intent of studying different starting doses and the lower dose has only been tested in a limited number of subjects; therefore, this study lacks the necessary statistical power to allow any firm conclusions to be drawn regarding the 200–300 mg starting dose.12 13

      Baseline weight as a predictive factor for the reduction in the main toxicities in niraparib maintenance is in line with several previous studies6 18 24–26; interestingly, the median weight of our population in the primary group was 58 kg, according to other studies.25 26 Despite individualized starting dose being largely utilized in daily practice, dose reductions are reported in roughly 50–65% of cases (Online supplemental table S2). In line with the published literature, dose reduction occurred within the first three cycles in 45–70% of our patient population and, consequently, many women reached a stable dose of niraparib 100 mg/day.21–23 Whether or not this ‘low’ dose might hamper survival outcomes has been addressed in the explorative analysis of randomized trials.17 Our survival analysis in a real-life setting confirms that there is a comparable risk of recurrence for patients on 100 mg/day versus 200 mg/day for both the primary and relapse groups.

      Interestingly, although patients in the first-line setting were significantly more likely to reduce the starting dose, with an overall reduction rate higher than in the recurrent setting (71% vs 53.8%; Online supplemental table S1, Figure 3), we observed that reductions occured mainly in the first three cycles in both groups and remained within the range 4–7.8% in subsequent cycles. A higher trend in dose reduction in primary ovarian cancer patients receiving PARPi maintenance compared with the relapse group has already been suggested from randomized clinical trials; 75.9% and 66.5% of patients undergoing niraparib fixed dose required a dose adjustment, in the PRIMA and NOVA trials, respectively (Online supplemental table S2).

      We report a higher reduction rate of niraparib individualized starting dose in the primary group compared with randomized studies in which an individualized starting dose was applied (71% in our primary group, 61.5% in PRIMA and 40.4% in PRIME); although stratifying differences regarding merely grade≥3 treatment-emergent adverse events; those differences are comparable to these studies (Online supplemental table S2). Nevertheless, it is important to underline that patients in the real world are often more fragile than those enrolled in clinical trials25 26 and this might justify our higher reported reduction compared with randomized control trials. Finally, it might also be thought that the aggressiveness of cytoreductive surgery can somehow have an impact on the frailty of treated patients.

      Strengths and Weaknesses

      In this study we confirm the importance of flexible-reduction management of niraparib in daily, real-life oncology practice in a larger series of patients than in randomized clinical trials. Moreover, we investigated the frequency of dose reduction in different patient settings (primary vs relapse groups), searching for modifiable predictive factors of dose reduction. Finally, our results report a short-term efficacy and safety in progression-free survival of patients undergoing niraparib dose reduction, which represents a safety signal that this might deserve further analysis with long-term follow-up of lower dosages.

      Nonetheless, some limitations of the present study should be considered. First, its retrospective design may have increased selection bias. Second, the follow-up times were not long enough to establish long-term overall survival outcomes. Third, the absence of homologous recombination deficiency (HRD) status (except for BRCA1/BRCA2 mutation) may have affected the interpretation of the findings and led to the exclusion of HRD status in determining a progression free-survival correlation. Furthermore, the study was carried out in a single center.

      Implications for Practice and Future Research

      In the light of these data, prospective studies on niraparib de-escalation from the commencement of treatment should be performed. However, studies in vivo13 27 28 of the differing distribution of niraparib dosages have shown that the human bioavailability of niraparib at the starting dose of 300 mg is around 72.5% but also that the inter-subject variability in niraparib pharmacokinetic parameters is consistent. Moreover, the steady-state plasma concentrations of niraparib fluctuate between 0.6 and 0.8 µg/mL every 24 hours at a dose of 200 mg, resulting in lower plasma fluctuations when compared with a 300 mg dose.13 27 28 Therefore, a dosage that is acceptable for one patient may be excessive for another and vice versa. At the present time, with the scarce knowledge available, it appears more realistic to personalize the dose according to the patient’s needs and characteristics (ie, weight, platelets count) with flexible reduction management to avoid preventable toxicity.

      The suggestion that primary ovarian cancer patients on niraparib individualized starting dose may have more dose reductions due to platinum-based chemotherapy combination compared with the mono-platinum of the relapse group is a new finding that has yet to be highlighted and merits further investigation. In this regard, single-agent carboplatin in the recurrent setting could be an option, although still not proven. Otherwise, a reduction in the number of cycles of chemotherapy to reduce PARPi-related toxicities could be an option. At present, no data support this hypothesis. However, the N-PLUS/NOGGO-ov53/ENGOT-ov62 (ClinicalTrials.gov Identifier: NCT05460000) study is currently ongoing to investigate whether progression-free survival in patients receiving three cycles of chemotherapy followed by maintenance with niraparib is not inferior to six cycles of chemotherapy followed by niraparib in advanced HRD high-grade ovarian cancer patients with no disease at the end of primary surgery. Therefore, this trial will also inform about the toxicity profile of PARPi after chemotherapy de-escalation.

      Conclusions

      The efficacy and manageable safety of niraparib individualized starting dose were confirmed in the present study despite the more complex status of epithelial ovarian cancer patients in clinical practice. In both the primary and relapse settings, niraparib dose reduction tends to occur early but dose changes throughout treatment did not impact progression-free survival, preserving the outcome of dose-reduced patients. The combination of weight and double platinum-based chemotherapy might help to predict dose reduction and to tailor the work-up and follow-up of patients on PARPi. These results could provide important information for personalizing the oncological management of maintenance therapy in primary or recurrent ovarian cancer patients.

      Data availability statement

      All data relevant to the study are included in the article or uploaded as supplementary information.

      Ethics statements

      Patient consent for publication

      Ethics approval

      This study involves human participants and was approved by Comitato Etico Territoriale Lazio Area 3, Fondazione Policlinico A. Gemelli (IRCCSID: 6356). Participants gave informed consent to participate in the study before taking part.

      References

      1. ↵
        1. Trimbos JB,
        2. Vergote I,
        3. Bolis G, et al
        . Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer–Adjuvant ChemoTherapy in Ovarian Neoplasm Trial. J Natl Cancer Inst 2003;95:113–25. doi:10.1093/jnci/95.2.113
        OpenUrlCrossRefPubMedWeb of Science
      2. ↵
        Cancer Stat Facts: Ovarian Cancer. National Cancer Institute: Surveillance, Epidemiology, and End Results Program, Available: https://seer.cancer.gov/statfacts/html/ovary.html
      3. ↵
        1. Alberts DS,
        2. Liu PY,
        3. Wilczynski SP, et al
        . Randomized trial of pegylated liposomal doxorubicin (PLD) plus carboplatin versus carboplatin in platinum-sensitive (PS) patients with recurrent epithelial ovarian or peritoneal carcinoma after failure of initial platinum-based chemotherapy (Southwest Oncology Group Protocol S0200). Gynecol Oncol 2008;108:90–4. doi:10.1016/j.ygyno.2007.08.075
        OpenUrlCrossRefPubMedWeb of Science
      4. ↵
        1. Mirza MR,
        2. Benigno B,
        3. Dørum A, et al
        . Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo results from the phase III ENGOT-OV16/NOVA trial. Gynecol Oncol 2020;159:442–8. doi:10.1016/j.ygyno.2020.09.006
        OpenUrlCrossRefPubMed
      5. ↵
        1. Wu XH,
        2. Zhu JQ,
        3. Yin RT, et al
        . Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind,placebo-controlled phase III trial. Ann Oncol 2021;32:512–21. doi:10.1016/j.annonc.2020.12.018
        OpenUrlCrossRefPubMed
      6. ↵
        1. Matulonis UA,
        2. Monk BJ,
        3. Secord AA, et al
        . Baseline platelet count and body weight as predictors of early dose modification in the QUADRA trial of niraparib monotherapy for the treatment of heavily pretreated (≥4th line), advanced, recurrent high-grade serous ovarian cancer. Gynecol Oncol 2019;154:3. doi:10.1016/j.ygyno.2019.04.017
      7. ↵
        1. González-Martín A,
        2. Pothuri B,
        3. Vergote I, et al
        . Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2019;381:2391–402. doi:10.1056/NEJMoa1910962
        OpenUrlCrossRefPubMed
      8. ↵
        1. Li N,
        2. Zhu J,
        3. Yin R, et al
        . Treatment with niraparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer: a phase 3 randomized clinical trial. JAMA Oncol 2023;9:1230–7. doi:10.1001/jamaoncol.2023.2283
        OpenUrl
      9. ↵
        1. Farmer H,
        2. McCabe N,
        3. Lord CJ, et al
        . Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917–21. doi:10.1038/nature03445
        OpenUrlCrossRefPubMedWeb of Science
      10. ↵
        1. Bryant HE,
        2. Petermann E,
        3. Schultz N, et al
        . PARP is activated at stalled forks to mediate Mre11- dependent replication restart and recombination. EMBO J 2009;28:2601–15. doi:10.1038/emboj.2009.206
        OpenUrlAbstract/FREE Full Text
      11. ↵
        1. Yang Y-G,
        2. Cortes U,
        3. Patnaik S, et al
        . Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but Com- promises the reactivation of stalled replication forks. Oncogene 2004;23:3872–82. doi:10.1038/sj.onc.1207491
        OpenUrlCrossRefPubMedWeb of Science
      12. ↵
        1. GlaxoSmithKline
        . ZEJULA (Niraparib): US prescribing information. 2020. Available: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf [Accessed 9 Nov 2021].
      13. ↵
        1. GlaxoSmithKline
        . ZEJULA (Niraparib): summary of product characteristics. 2020. Available: https://www.ema.europa.eu/en/documents/product-information/zejula-epar-product-information_en. pdf [Accessed 16 Nov 2021].
      14. ↵
        1. GSK
        . GSK provides an update on Zejula (niraparib) US prescribing information. 2022. Available: https://www.gsk.com/en-gb/media/press-releases/gsk-provides-an-update-on-zejula-niraparib-us-prescribing-information
      15. ↵
        1. Berek JS,
        2. Matulonis UA,
        3. Peen U, et al
        . Safety and dose modification for patients receiving niraparib. Ann Oncol 2018;29:1784–92. doi:10.1093/annonc/mdy181
        OpenUrlPubMed
      16. ↵
        1. Mirza MR,
        2. Wu X,
        3. Zhu J, et al
        . Vp7-2022: an ad-hoc interim overall survival results of niraparib with individualized starting dose as maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer (NORA): a double-blind, randomized, placebo-controlled, phase III trial. Ann Oncol 2023;34:124–5. doi:10.1016/j.annonc.2022.11.007
        OpenUrl
      17. ↵
        1. Gonzalez Martin AJ,
        2. Pothuri B,
        3. Vergote IB, et al
        . 530P PRIMA/ENGOT-OV26/GOG-3012 study: updated long-term PFS and safety. Ann Oncol 2022;33:S789. doi:10.1016/j.annonc.2022.07.658
      18. ↵
        1. Mirza MR,
        2. González-Martín A,
        3. Graybill WS, et al
        . Prospective evaluation of the tolerability and efficacy of niraparib dosing based on baseline body weight and platelet count: results from the PRIMA/ENGOT-OV26/GOG-3012 trial. Cancer 2023;129:1846–55. doi:10.1002/cncr.34706
        OpenUrl
      19. ↵
        1. Moore KN,
        2. Secord AA,
        3. Geller MA, et al
        . Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2019;20:636–48. doi:10.1016/S1470-2045(19)30029-4
        OpenUrlCrossRefPubMed
      20. ↵
        1. Eisenhauer EA,
        2. Therasse P,
        3. Bogaerts J, et al
        . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47. doi:10.1016/j.ejca.2008.10.026
        OpenUrlCrossRefPubMedWeb of Science
      21. ↵
        1. Monk BJ,
        2. González-Martin A,
        3. Buckley L, et al
        . Safety and management of niraparib monotherapy in ovarian cancer clinical trials. Int J Gynecol Cancer 2023;33:971–81. doi:10.1136/ijgc-2022-004079
        OpenUrlAbstract/FREE Full Text
      22. ↵
        1. Mateo J,
        2. Moreno V,
        3. Gupta A, et al
        . An adaptive study to determine the optimal dose of the tablet formulation of the PARP inhibitor olaparib. Target Oncol 2016;11:401–15. doi:10.1007/s11523-016-0435-8
        OpenUrl
      23. ↵
        1. Francis KE,
        2. Kim SI,
        3. Friedlander M, et al
        . The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer. Ann Oncol 2022;33:593–601. doi:10.1016/j.annonc.2022.02.222
        OpenUrlCrossRefPubMed
      24. ↵
        1. Gallagher JR,
        2. Heap KJ,
        3. Carroll S, et al
        . Real-world adverse events with niraparib 200 mg/day maintenance therapy in ovarian cancer: a retrospective study. Future Oncol 2019;15:4197–206. doi:10.2217/fon-2019-0471
        OpenUrlCrossRef
      25. ↵
        1. Pagkali A,
        2. Mamais I,
        3. Michalinos A, et al
        . Safety profile of niraparib as maintenance therapy for ovarian cancer: a systematic review and meta-analysis. Curr Oncol 2022;29:321–36. doi:10.3390/curroncol29010029
        OpenUrl
      26. ↵
        1. Zhao M,
        2. Qiu S,
        3. Wu X, et al
        . Efficacy and safety of niraparib as first-line maintenance treatment for patients with advanced ovarian cancer: real-world data from a multicenter study in China. Target Oncol 2023;18:869–83. doi:10.1007/s11523-023-00999-x
        OpenUrl
      27. ↵
        1. van Andel L,
        2. Rosing H,
        3. Zhang Z, et al
        . Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. Cancer Chemother Pharmacol 2018;81:39–46. doi:10.1007/s00280-017-3455-x
        OpenUrl
      28. ↵
        1. Nakai H,
        2. Matsumura N
        . Individualization in the first-line treatment of advanced ovarian cancer based on the mechanism of action of molecularly targeted drugs. Int J Clin Oncol 2022;27:1001–12. doi:10.1007/s10147-022-02163-3
        OpenUrl

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      Footnotes

      • X @annafagottimd

      • MB and AIA contributed equally.

      • Presented at The abstract of this article was presented in the Mini-oral Session on Ovarian Cancer during the European Society of Gynaecological Oncology (ESGO) Congress held in Istanbul, Turkey, September 28 to October 1, 2023.

      • Contributors MB, CM, AIA: conceptualization, data curation, methodology, formal analysis, writing original draft. SMB, CMS: data collection, investigation, methodology. MB, CM: methodology, formal and statistical analysis. AIA, SL, CC: data collection, data curation. GS, AF, DL: investigation, validation, supervision. All authors discussed the results; reviewed and revised the manuscript, and approved the final version of the manuscript. CM: guarantor for the overall content.

      • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

      • Competing interests CM is on the consultant/advisory board for Clovis, Pharmamar, GSK, AstraZeneca, and MSD, and received travel accommodation from Pharmamar and Roche. AF reports commercial interests with AstraZeneca, MSD, Johnson & Johnson, and Pharmamar. GS reports research support from MSD and honoraria from Clovis Oncology, and is a consultant for GSK, Tesaro, and Johnson & Johnson. DL is on the consultant/advisory board for Clovis Oncology, Pharmamar, GSK, AstraZeneca, MSD, Genmab, Immunogen, Seagen, Novartis, Oncoinvest, Concept, and Sutro; she reports research support from Clovis Oncology, GSK, MSD, Pharmamar, Genmab, Immunogen, Incyte, Roche, Seagen, and Novartis, and received travel accommodation from AstraZeneca, Clovis Oncology, and GSK.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.