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

From 2005, ovarian cancer (OC) has become the second main gynecological cause of cancer-related deaths in China, replacing uterine cancer [1]. According to the GLOBOCAN Global Cancer Statistics, the number of new OC cases in China was 313,959, with a related mortality rate of 2.1% (207,252 patients) in 2020 [2]. It is expected that the incidence of OC in China will continue to rise during the next decade to a higher rate than that predicted globally [3]. In particular, advanced OC has a recurrence rate as high as 80%, with resistance to chemotherapy being a limiting factor for the success rates of relapsed OC treatments [4].

Maintenance treatment (MT) with poly (ADP-ribose) polymerase (PARP) inhibitors is a novel option for patients with OC who had previously received platinum-based chemotherapy treatment to decrease the rates of recurrence or relapse [5, 6]. Recently, trials and real-world studies found that olaparib with and without bevacizumab was an effective and safe MT for patients with OC [7‐12].

Niraparib is a potent selective PARP-1/2 inhibitor with excellent bioavailability when administered orally and is up to 100 times more active against these enzymes than other PARP family members [13]. It was approved in the EU and USA in 2017 [14, 15], and in China in 2019 [16] for MT of recurrent OC. However, in several clinical trials, which analyzed outcomes of niraparib for patients with advanced OC (NOVA, QUADRA, PRIMA, NORA, and PRIME), treatment-emergent adverse events (TEAEs) were reported in 99% of the patients with 51–74% being grade ≥ 3 [17]. It is noteworthy that niraparib increased the progression-free survival (PFS) times significantly compared with placebo [18‐21] as well as eliciting clinically relevant activity in heavily pretreated OC patients [22] irrespective of their homologous recombination deficiency (HRD) status [23]. In addition, the dosage of niraparib as an individualized starting dose (ISD) was determined by the patient’s baseline bodyweight and platelet count. If a patient’s platelet count was < 150,000/μL or their bodyweight was < 77 kg, they received a daily dose of 200 mg. For other patients, the daily dose was 300 mg. Considering that the majority of Chinese patients have a bodyweight < 77 kg, we were particularly interested in the present study to investigate whether it was more beneficial for Chinese patients to have treatment initiated at 200 mg/day compared with 100 mg/day. We also aimed to determine whether reducing the dosage of niraparib from 200 to 100 mg, following ISD dosing principles, affected treatment efficacy [24].

To the best of our knowledge, after niraparib was covered by Chinese health insurance from 2021, multicenter studies on Chinese real-world experience with niraparib as first-line MT for OC have not been thoroughly investigated. The present large-scale observational study used real-world data to assess the efficacy and safety profile of niraparib as first-line MT in patients with newly diagnosed advanced OC, to investigate the clinical benefits associated with prolonged niraparib treatment, and to evaluate the relationship between different doses of niraparib and PFS of patients who were given a reduced dosage due to the occurrence of TEAEs.

Several Chinese phase 3 clinical trials have confirmed that niraparib MT for recurrent OC produced significantly prolonged PFS times compared with placebo [18, 20]. However, compared with randomized clinical trials, real-world studies are less restrictive and have broader enrollment criteria, with the patients more relevant to clinical practice. Until the end of 2021, niraparib was not covered by Chinese medical insurance. From 2021, niraparib as second-line MT was covered by Chinese medical insurance, and then first-line MT was covered by 2022. Therefore, niraparib has not been regularly administered until healthcare reimbursement, resulting in our multicenter data patient cohort being not as large as expected. At the time of the data cut-off, 131 patients remained free of disease progression, which explains why our data maturity was 36.2% (95% CI 23.4–36.5%) and the duration of follow-up differed considerably compared with other studies resulting in a not-reached median PFS (95% CI 23.8–NE). However, in the present study, niraparib as MT for OC patients within 12 weeks of completion of first-line chemotherapy regimens produced overall PFS rates of 87.4%, 75.9%, 63.6%, 56.1%, and 51.8% at 6, 12, 18, 24, and 30 months, respectively, after initiation of treatment for the entire cohort. A similar PFS rate at 18 months of 62% for niraparib plus bevacizumab MT has been published recently [26].

LASSO regression analysis revealed that the factors influencing prolonged PFS times included age, germline BRCA mutation status, and cytoreductive surgery outcomes. HRD-positive patients and BRCA mutation cases had superior PFS rates, respectively, compared with HRD-negative and BRCAwt patients, which confirms that BRCA status and HRD positivity are factors influencing the effectiveness of niraparib therapy in patients with advanced OC [27]. It is noteworthy that niraparib in contrast to other PARP inhibitors (e.g. olaparib) was approved in the EU and USA for first-line MT of OC, regardless of patient HRD status [23].

Also, the cytoreductive surgery outcome status has been described as being a major factor for PFS times when niraparib MT was used for advanced OC patients [28]. With regard to age, previous trials found that it was not a limiting factor for PFS times of OC patients receiving niraparib MT [29, 30], but a real-world study on olaparib MT for OC patients noted that the clinical benefit regarding median PFS times was different in older, compared with younger, patients. Selection in RCTs prefers older patients with a good performance status without other major health issues, but in real-life unselected frail older patients represent a significantly larger proportion than in the cohorts enrolled in randomized controlled trials [31].

The initial dose given to most patients in the present study was 200 mg/day, which produced the best clinical results. After 3 months from the initiation of treatment, some patients chose to discontinue or take a reduced dose due to TEAEs or personal choice. However, an average 200 mg dose led to somewhat higher PFS rates at 18 months with even lower rates of grade 3/4 TEAEs, indicating that a standard dose of 200 mg was efficient and safe, while switching to 100 mg might be necessary, mainly for cases with distinct TEAE susceptibilities, without essentially lessening the long term efficacy of treatment as reported in the PRIME study [20]. According to a meta-analysis of recent trials, patients taking niraparib were at a higher risk of developing nausea, fatigue, anemia, platelet count decreases, vomiting, neutrophil count decreases, headache, constipation, and insomnia of any grade, as well as at a higher risk for grade 3 or 4 fatigue [32], all findings that are in good agreement with those of the present study. The percentages of dose reduction (23.6%) and treatment discontinuation (5.5%) in our study were lower than the 70.9% and 12.0% previously observed [19], and 59.9% and 4% [18] reported in other studies, but similar to the 16.7% and 5.6% in the Chinese real-world study of Ni and colleagues that used only 200 mg doses [33]. This may be due to the low number of patients taking 300 mg in the present study.

The significant effectiveness and manageable safety of niraparib in the registration trials have been confirmed in this real-world study despite the more complex treatment and status of the patients in clinal practice. For Chinese OC patients, it is important to use an ISD strategy of niraparib. The clinical predictive model established in this database needs more data to become more mature and unequivocally verified.