
==== Front
J Gynecol Oncol
J Gynecol Oncol
JGO
Journal of Gynecologic Oncology
2005-0380
2005-0399
Asian Society of Gynecologic Oncology; Korean Society of Gynecologic Oncology; Japan Society of Gynecologic Oncology

39058367
10.3802/jgo.2024.35.e115
Original Article
Ovary
Niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer: final results of a multicenter phase 2 study
https://orcid.org/0000-0002-7417-8595
Itamochi Hiroaki 1
https://orcid.org/0000-0001-9500-9427
Takeshima Nobuhiro 2
https://orcid.org/0000-0002-7750-0623
Hamanishi Junzo 3
https://orcid.org/0000-0002-1903-7001
Hasegawa Kosei 4
https://orcid.org/0000-0002-6589-6480
Matsuura Motoki 5
https://orcid.org/0000-0001-5396-8881
Miura Kiyonori 6
https://orcid.org/0000-0003-4031-8091
Nagao Shoji 7
https://orcid.org/0000-0002-9994-2131
Nakai Hidekatsu 8
https://orcid.org/0000-0003-3135-7398
Tanaka Naotake 9
https://orcid.org/0000-0002-1622-3810
Tokunaga Hideki 1011
https://orcid.org/0000-0003-2526-630X
Nishio Shin 12
https://orcid.org/0000-0002-4189-6187
Watari Hidemichi 13
https://orcid.org/0000-0001-5214-512X
Yokoyama Yoshihito 14
https://orcid.org/0000-0002-6385-6784
Kase Yoichi 15
https://orcid.org/0000-0002-2202-9774
Sumino Shuuji 16
https://orcid.org/0009-0001-8183-9734
Kato Ai 17
https://orcid.org/0000-0002-2252-1830
Suri Ajit 18
https://orcid.org/0000-0002-1435-0779
Yasuoka Toshiaki 19
https://orcid.org/0000-0001-8808-3338
Takehara Kazuhiro 20
1 Department of Clinical Oncology, Iwate Medical University School of Medicine, Yahaba, Japan.
2 Department of Obstetrics and Gynecology, International University of Health and Welfare Hospital, Nasushiobara, Japan.
3 Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
4 Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan.
5 Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo, Japan.
6 Department of Obstetrics and Gynecology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
7 Department of Obstetrics and Gynecology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
8 Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osakasayama, Japan.
9 Department of Gynecology, Chiba Cancer Center, Chiba, Japan.
10 Department of Gynecology, Graduate School of Medicine, Tohoku University, Sendai, Japan.
11 Divison of Obstetrics and Gynecology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
12 Department of Obstetrics and Gynecology, Kurume University School of Medicine, Fukuoka, Japan.
13 Department of Obstetrics and Gynecology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
14 Department of Obstetrics and Gynecology, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan.
15 Clinical Science, Oncology Cell Therapy and Therapeutic Area Unit, Takeda Pharmaceutical Company Limited, Osaka, Japan.
16 Biostatistics, Japan Development Center, Takeda Pharmaceutical Company Limited, Osaka, Japan.
17 Department of Japan Medical Affairs, Japan Oncology Business Unit, Takeda Pharmaceutical Company Limited, Tokyo, Japan.
18 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
19 Department of Obstetrics and Gynecology, Ehime University Graduate School of Medicine, Ehime, Japan.
20 Department of Gynecologic Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan.
Correspondence to Toshiaki Yasuoka. Department of Obstetrics and Gynecology, Ehime University Graduate School of Medicine, Shigenobu Campus, Toon, Ehime 791-0295, Japan. tyasuoka.m.ehimeuniv@gmail.com
9 2024
17 7 2024
35 5 e11513 3 2024
18 6 2024
07 7 2024
© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology
2024
Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective

This study evaluated the long-term safety and efficacy of niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer.

Methods

This was a follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with platinum-sensitive, relapsed ovarian cancer. Participants received niraparib (starting dose 300 mg) once daily in continuous 28-day cycles. The primary endpoint was the incidence of Grade 3 or 4 thrombocytopenia-related events (defined as the overall incidence of the MedDRA Preferred Terms “thrombocytopenia” and “platelet count decreased”) occurring in the 30 days after initial administration of niraparib, and secondary endpoints included evaluation of treatment-emergent adverse events and progression-free survival.

Results

Nineteen patients (median age, 62 years; median body weight, 53.9 kg) were enrolled. As previously reported, the incidence of Grade 3 or 4 thrombocytopenia-related events during the first 30 days of treatment was 31.6%. At data cutoff, median (range) treatment exposure was 504.0 (56–1,054) days and mean ± standard deviation dose intensity was 154.4±77.5 mg/day. The most common treatment-emergent adverse events were nausea (n=14, 73.7%), decreased platelet count (n=12, 63.2%), decreased neutrophil count (n=11, 57.9%), anemia, vomiting, and decreased appetite (all n=9, 47.4%). One patient was diagnosed with treatment-related leukemia, which resulted in death. Median (95% confidence interval) progression-free survival was 18.0 (5.6–26.7) months.

Conclusion

Overall, the safety profile of niraparib was considered manageable in this study population of Japanese patients with platinum-sensitive, relapsed ovarian cancer and was consistent with that observed in studies of non-Japanese patients.

Trial Registration

ClinicalTrials.gov Identifier: NCT03759587

Synopsis

We analyzed the long-term safety and efficacy of niraparib in Japanese patients with platinum-sensitive, relapsed ovarian cancer. The safety profile of niraparib was considered manageable in this study population of Japanese patients and was consistent with that observed in studies of non-Japanese patients.

Clinical Trial, Phase II
Poly(ADP-ribose) Polymerase Inhibitors
Ovarian Cancer
Takeda Pharmaceutical Company https://dx.doi.org/10.13039/100008373
==== Body
pmcINTRODUCTION

Ovarian cancer is associated with high morbidity and mortality because it is usually detected at an advanced stage [12]. The incidence of ovarian cancer is steadily increasing in Japan, where late-stage diagnosis is associated with low 5-year overall survival (OS) [3]. Serous carcinoma is the most common type of ovarian cancer [1]. A combination of debulking surgery and platinum therapy is the initial standard treatment and is generally effective at first; however, relapse often occurs [23]. Poly(ADP-ribose) polymerase (PARP) inhibitors have become a treatment option for patients with relapsed ovarian cancer [2]. PARP inhibitors prevent the repair of single-strand DNA breaks by trapping PARP at the site of DNA damage and inhibiting its catalytic activity [4]. PARP inhibition leads to the accumulation of double-strand DNA breaks, which are irreparable in cancer cells with homologous recombination deficiency (HRd), for example, those with deleterious BRCA mutations. In these cells, the accumulation of irreparable double-strand DNA breaks eventually results in cell death. This combined effect of HRd and drug-induced toxicity is called synthetic lethality [4].

Niraparib is an oral, potent, highly selective PARP1 and PARP2 inhibitor [4]. Based on positive results from the phase 3 ENGOT-OV16/NOVA study [5], niraparib was approved in the USA and Europe as maintenance therapy for adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete response (CR) or partial response (PR) to platinum-based chemotherapy. Initially, niraparib was approved for patient groups both with and without germline BRCA (gBRCA) mutations. However, upon request of the US Food and Drug Administration (FDA), GSK restricted the indication of niraparib to only patients with deleterious or suspected deleterious gBRCA mutations [6]. This was based on the FDA’s concerns regarding OS results in the NOVA study, which was a secondary endpoint. In contrast, no labeling restrictions were applied in Japan, Korea, or Europe [7]. AstraZeneca also restricted the indication of another PARP inhibitor, olaparib, to patients with germline and somatic BRCA mutations in this maintenance setting in the USA [8]. These decisions generated clinical uncertainty regarding the use of PARP inhibitors in recurrent ovarian cancer with wild type BRCA. Therefore, more evidence is required to assess the clinical suitability of PARP inhibitors in this setting.

The occurrence of Grade 3 or 4 thrombocytopenia is a major dose-limiting toxicity for niraparib treatment, with baseline platelet count and body weight identified as risk factors [9]. In a post hoc analysis of the NOVA study, the incidence of Grade 3 or 4 thrombocytopenia during the 30 days after the initial dose of niraparib 300 mg once daily was approximately 3-fold greater in patients with a platelet count of <150,000/µL or body weight of <77 kg than in patients with a platelet count of ≥150,000/µL or body weight of ≥77 kg, respectively [9].

A single-arm, phase 2 study (Niraparib-2001) was conducted under agreement with the Japanese regulatory agency (Pharmaceuticals and Medical Devices Agency) to evaluate the safety of niraparib at a starting dose of 300 mg once daily in Japanese patients with platinum-sensitive, relapsed ovarian cancer [10]. Short-term safety data have already been published and showed that the incidence of Grade 3 or 4 thrombocytopenia-related events occurring in the 30 days after the initial administration of niraparib (primary endpoint) was 31.6% (6 of 19 participants) [10]. Here, we report long-term follow-up data for the same Niraparib-2001 study.

MATERIALS AND METHODS

1. Study design

This was a phase 2, multicenter, open-label, single-arm study designed to evaluate the safety and efficacy of niraparib in Japanese patients with relapsed platinum-sensitive ovarian cancer (ClinicalTrials.gov: NCT03759587). The study was conducted at 15 sites in Japan, with data for the final analysis collected between December 28, 2018 and December 6, 2021. Detailed information on the study design and inclusion/exclusion criteria has previously been described [10]. Eligible patients were Japanese women, ≥20 years of age, who were histologically diagnosed with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, for which the histology finding was high-grade (or Grade 3) serous or high-grade predominantly serous, or there was known BRCA1/2 mutation(s). Participants must have completed ≥2 previous lines of platinum-containing therapy, had a CR or PR as per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 lasting ≥6 months in the prior platinum treatment (‘platinum-sensitive’), and a performance status of 0 or 1 on the Eastern Cooperative Oncology Group Performance Status Scale. Patients who had received other PARP inhibitors were excluded from the study.

All patients provided written informed consent to participate in the study. The study was conducted in accordance with ethical principles of the Declaration of Helsinki, the International Council for Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice, and the Institutional Review Board (IRB) regulations. The clinical study protocol, investigator’s brochure, a sample informed consent form, and other study-related documents were reviewed and approved by the local or central IRBs at all study sites. Each investigator conducted the study according to applicable local or regional regulatory requirements and in accordance with the responsibilities listed in the protocol.

2. Treatment

Patients received niraparib 300 mg (3×100 mg hard capsules) once daily orally in continuous 28-day cycles until objective progressive disease, unacceptable toxicity, withdrawal of consent, or study discontinuation. Niraparib dose was reduced and/or interrupted if toxicity of any grade was deemed intolerable for the patient, as previously described [10].

3. Outcomes

The primary endpoint was the incidence of Grade 3 or 4 thrombocytopenia-related events occurring in the 30 days after initial administration of niraparib, defined as the overall incidence of the MedDRA Preferred Terms “thrombocytopenia” and “platelet count decreased.” Secondary safety endpoints were the overall safety of niraparib, including the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs that led to drug dose reduction, interruption, or discontinuation. Secondary efficacy endpoints were progression-free survival (PFS), OS, and overall response rate (ORR), which were assessed by the investigator. PFS was defined as the time from enrollment until the first date of documented disease progression as determined by RECIST version 1.1, clinical criteria, or death by any cause. OS was defined as the time from enrollment to death by any cause. ORR was defined as the proportion of patients with CR or PR, as assessed by the investigator, using RECIST version 1.1.

4. Statistics

Both the full analysis set (efficacy analyses) and safety analysis set included all patients who received ≥1 dose of study drug. The response-evaluable set (ORR analysis) included all patients who received ≥1 dose of study drug and had ≥1 measurable lesion at baseline. The threshold incidence of thrombocytopenia in non-Japanese patients was estimated based on data from the NOVA study [5]. In that study, the incidence of Grade 3 or 4 thrombocytopenia during the 30 days after the initial niraparib dose was 34.6% in patients with a baseline body weight of <77 kg or baseline platelet count of <150,000/µL. The incidence of platelet count decreasing to <50,000/μL (equivalent to or worse than Grade 3 thrombocytopenia) was 46% in patients with a baseline body weight of <58 kg. Therefore, the expected incidence of thrombocytopenia in this study population was 46% because ≥77% of Japanese patients with ovarian cancer had a body weight of ≤59 kg [10]. Based on a threshold incidence of 34.6% and an expected incidence of 46%, 15 patients would provide 76% probability that the point estimate of the incidence of thrombocytopenia would be ≥35%, with which a certain level of evaluation was expected to be achievable. PFS and OS were analyzed using the Kaplan–Meier method to provide quartiles and progression/survival rate at specified points with 2-sided 95% confidence interval (CI). ORR was calculated based on binomial distribution with a 2-sided 95% CI.

RESULTS

1. Study population

In total, 19 patients enrolled in the study and were included in the full and safety analysis sets. Only 5 of these patients were included in the response-evaluable analysis set. Patient demographics and baseline clinical characteristics are shown in Table 1. The median (range) age of patients was 62 (44–79) years and the median (range) body weight was 53.9 (40.8–79.1) kg. Over half of the patients (n=11, 57.9%) had a body weight of <58 kg and 1 patient (5.3%) had a body weight of ≥77 kg.

Table 1 Demographics and baseline clinical characteristics

Characteristics	Safety population (n=19)	
Age (yr)	62 (44–79)	
Age category (yr)		
	18–64	11 (57.9)	
	65–74	6 (31.6)	
	≥75	2 (10.5)	
Body weight (kg)	53.9 (40.8–79.1)	
	<58	11 (57.9)	
	≥58 and <77	7 (36.8)	
	≥77	1 (5.3)	
	Mean ± standard deviation	57.5±10.45	
Time from initial diagnosis (yr)	3.35 (1.2–19.6)	
Primary tumor site		
	Ovarian	10 (52.6)	
	Primary peritoneal	5 (26.3)	
	Fallopian tube	4 (21.1)	
ECOG status		
	0	17 (89.5)	
	1	2 (10.5)	
Cancer stage at initial diagnosis		
	IC	1 (5.3)	
	IIC	1 (5.3)	
	IIIB	2 (10.5)	
	IIIC	10 (52.6)	
	IV	4 (21.1)	
	Unknown	1 (5.3)	
Time to progression after penultimate platinum therapy		
	6–12 mo	5 (26.3)	
	>12 mo	14 (73.7)	
Best response to most recent platinum therapy		
	CR	9 (47.4)	
	PR	10 (52.6)	
Time from last platinum therapy to first dose of niraparib (days)	42.0 (14–65)	
Histological subtype		
	Serous	19 (100.0)	
Tumor grade		
	High-grade	19 (100.0)	
Values are presented as median (min–max) or number (%) unless otherwise indicated. Table adapted from Takehara et al. [10].

CR, complete response; ECOG, Eastern Cooperative Oncology Group; PR, partial response.

Most patients (94.7%) received an initial dose of niraparib 300 mg; however, a dose reduction was required by most patients in later cycles. At the beginning of cycle 2, 5 patients (26.3%) received niraparib 300 mg, 11 patients (57.9%) received niraparib 200 mg, and 3 patients (15.8%) received niraparib 100 mg. By cycle 27, all remaining patients (n=6) received a reduced dose of niraparib: 1 patient (16.7%) received niraparib 200 mg and 5 patients (83.3%) received niraparib 100 mg. At data cutoff, all remaining patients (n=3) received niraparib 100 mg; 16 patients had discontinued treatment either owing to progressive disease (n=10), an adverse event (n=5), or patient withdrawal (n=1). The median (range) overall treatment exposure was 504.0 (56–1,054) days and the mean ± standard deviation dose intensity was 154.4±77.5 mg/day.

2. Safety endpoints

Table 2 shows an overview of TEAEs. Five patients (26.3%) discontinued niraparib treatment owing to TEAEs and most patients required dose reduction, interruption, or modification owing to TEAEs (each n=16, 84.2%). All TEAEs of Grade 3 or 4 toxicity are shown in Table 3. The incidence of Grade 3 or 4 thrombocytopenia-related events was 31.6% (n=6) [10]. One patient (5.3%) reported thrombocytopenia, which was graded 4 in severity. Grade 3 or 4 events of decreased platelet count were reported in 4 patients (26.3%) and 1 patient (21.1%), respectively.

Table 2 Overview of TEAEs (safety analysis set)

Adverse events	Niraparib 300 mg (n=19)	
No. of events	Patients	
TEAEs	351	19 (100.0)	
	Treatment-related	254	19 (100.0)	
	Grade ≥3	35	14 (73.7)	
	Treatment-related, grade ≥3	31	11 (57.9)	
	Toxicity			
		Grade 1	229	0 (0.0)	
		Grade 2	87	5 (26.3)	
		Grade 3	30	10 (52.6)	
		Grade 4	5	4 (21.1)	
		Grade 5	0	0 (0.0)	
	Leading to study drug discontinuation	6	5 (26.3)	
	Leading to study drug dose reduction	47	16 (84.2)	
	Leading to study drug interruption	86	16 (84.2)	
	Leading to study drug modification	90	16 (84.2)	
Serious TEAEs	4	4 (21.1)	
	Not treatment-related	1	1 (5.3)	
	Treatment-related	3	3 (15.8)	
	Leading to study drug discontinuation	2	2 (10.5)	
	Leading to death	0	0 (0.0)	
Values are presented as number (%) of patients unless otherwise indicated. TEAEs were defined as adverse events that occurred after administration of the first dose of study drug and are shown by MedDRA System Organ Class and Preferred Term.

MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event.

Table 3 TEAEs observed in ≥10% of patients and all TEAEs of Grade ≥3 (safety analysis set)

System Organ Class and Preferred Term	Niraparib 300 mg (n=19)	
TEAEs	Grade ≥3 TEAEs	
Any TEAE	19 (100.0)	14 (73.7)	
Blood and lymphatic system disorders	10 (52.6)	6 (31.6)	
	Anemia	9 (47.4)	6 (31.6)	
	Neutropenia	3 (15.8)	1 (5.3)	
	Leukopenia	2 (10.5)	1 (5.3)	
	Thrombocytopenia	1 (5.3)	1 (5.3)	
Cardiac disorders	3 (15.8)	-	
	Palpitations	3 (15.8)	-	
Gastrointestinal disorders	18 (94.7)	1 (5.3)	
	Nausea	14 (73.7)	-	
	Vomiting	9 (47.4)	-	
	Stomatitis	5 (26.3)	-	
	Abdominal pain upper	4 (21.1)	-	
	Abdominal pain	3 (15.8)	-	
	Constipation	2 (10.5)	-	
	Dental caries	2 (10.5)	1 (5.3)	
	Diarrhea	2 (10.5)	-	
General disorders and administration site conditions	10 (52.6)	-	
	Malaise	5 (26.3)	-	
	Fatigue	2 (10.5)	-	
	Pyrexia	2 (10.5)	-	
Hepatobiliary disorders	2 (10.5)	1 (5.3)	
	Bile duct stone	1 (5.3)	1 (5.3)	
Immune system disorders	4 (21.1)	-	
	Contrast media allergy	4 (21.1)	-	
Infections and infestations	10 (52.6)	-	
	Nasopharyngitis	6 (31.6)	-	
	Upper respiratory tract infection	2 (10.5)	-	
Investigations	15 (78.9)	8 (42.1)	
	Platelet count decreased	12 (63.2)	5 (26.3)	
	Neutrophil count decreased	11 (57.9)	6 (31.6)	
	White blood cell count decreased	7 (36.8)	3 (15.8)	
	Blood creatinine increased	3 (15.8)	-	
	Alanine aminotransferase increased	1 (5.3)	1 (5.3)	
Metabolism and nutrition disorders	9 (47.4)	1 (5.3)	
	Decreased appetite	9 (47.4)	-	
	Hypokalemia	1 (5.3)	1 (5.3)	
Musculoskeletal and connective tissue disorders	9 (47.4)	-	
	Back pain	4 (21.1)	-	
	Arthralgia	3 (15.8)	-	
	Muscle spams	2 (10.5)	-	
	Pain in extremity	2 (10.5)	-	
Neoplasms benign, malignant, and unspecified*	1 (5.3)	1 (5.3)	
	Leukemia	1 (5.3)	1 (5.3)	
Nervous system disorders	9 (47.4)	-	
	Headache	7 (36.8)	-	
Psychiatric disorders	2 (10.5)	-	
	Insomnia	2 (10.5)	-	
Reproductive system and breast disorders	2 (10.5)	-	
Respiratory, thoracic, and mediastinal disorders	5 (26.3)	-	
	Dyspnea	2 (10.5)	-	
	Oropharyngeal discomfort	2 (10.5)	-	
Skin and subcutaneous tissue disorders	8 (42.1)	-	
	Pruritus	2 (10.5)	-	
	Rash	2 (10.5)	-	
Vascular disorders	1 (5.3)	1 (5.3)	
	Hypertension	1 (5.3)	1 (5.3)	
Values are presented as number (%) of patients. TEAEs were defined as adverse events that occurred after administration of the first dose of study drug and are shown by MedDRA System Organ Class and Preferred Term. TEAEs occurring in <10% of patients are also included in the ‘TEAEs’ column if they are presented in the ‘Grade ≥3 TEAEs’ column.

MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event.

*Includes cysts and polyps.

All 19 patients reported ≥1 TEAE during the study, including 10 patients (52.6%) who experienced a Grade 3 event and 4 patients (21.1%) who experienced a Grade 4 event (Table 2). The most common TEAEs were nausea (n=14, 73.7%), decreased platelet count (n=12, 63.2%), decreased neutrophil count (n=11, 57.9%), anemia, vomiting, and decreased appetite (all n=9, 47.4%) (Table 3). There were 4 (21.1%) serious TEAEs in the study, which were bile duct stone, leukemia, pneumonia, and thrombocytopenia (all n=1, 5.3%).

TEAEs leading to niraparib dose reduction, interruption, or discontinuation are shown in Table 4. The most common TEAEs leading to dose reduction or interruption were decreased platelet count (reduction: n=9, 47.4%; interruption: n=10, 52.6%), decreased neutrophil count (both n=6, 31.6%), and anemia (reduction: n=4, 21.1%; interruption: n=7, 36.8%). TEAEs leading to discontinuation of study drug were anemia (n=2, 10.5%), thrombocytopenia, decreased platelet count, decreased neutrophil count, and leukemia (all n=1, 5.3%).

Table 4 TEAEs leading to study drug dose reduction, interruption, or discontinuation (safety analysis set)

System Organ Class and Preferred Term	Niraparib 300 mg (n=19)	
Leading to dose reduction in ≥10% of patients	Leading to dose interruption in ≥10% of patients	Leading to discontinuation in all patients	
Any TEAE	16 (84.2)	16 (84.2)	5 (26.3)	
Blood and lymphatic system disorders	4 (21.1)	7 (36.8)	3 (15.8)	
	Anemia	4 (21.1)	7 (36.8)	2 (10.5)	
	Thrombocytopenia	1 (5.3)	1 (5.3)	1 (5.3)	
Cardiac disorders	2 (10.5)	2 (10.5)	-	
Gastrointestinal disorders	3 (15.8)	3 (15.8)	-	
	Nausea	3 (15.8)	3 (15.8)	-	
	Vomiting	2 (10.5)	2 (10.5)	-	
General disorders and administration site conditions	2 (10.5)	2 (10.5)	-	
	Malaise	2 (10.5)	2 (10.5)	-	
Infections and infestations	-	2 (10.5)	-	
Investigations	12 (63.2)	12 (63.2)	2 (10.5)	
	Platelet count decreased	9 (47.4)	10 (52.6)	1 (5.3)	
	Neutrophil count decreased	6 (31.6)	6 (31.6)	1 (5.3)	
	White blood cell decreased	2 (10.5)	3 (15.8)	-	
Metabolism and nutrition disorders	2 (10.5)	1 (5.3)	-	
	Decreased appetite	2 (10.5)	1 (5.3)	-	
Neoplasms benign, malignant, and unspecified*	-	-	1 (5.3)	
	Leukemia	-	-	1 (5.3)	
Nervous system disorders	2 (10.5)	2 (10.5)	-	
Values are presented as number (%) of patients. TEAEs were defined as adverse events that occurred after administration of the first dose of study drug and are shown by MedDRA System Organ Class and Preferred Term. TEAEs occurring in <10% of patients are also included in the ‘Leading to dose reduction in ≥10% of patients’ and ‘Leading to dose interruption in ≥10% of patients’ if they are presented in the ‘Leading to discontinuation in all patients’ column.

MedDRA, Medical Dictionary for Regulatory Activities; TEAE, treatment-emergent adverse event.

*Includes cysts and polyps.

There were no on-treatment deaths reported during the study. There was one case of leukemia that was deemed treatment-related by the investigator and led to the patient’s death. The patient was a 45-year-old woman with relapsed ovarian cancer, who had a medical history of bilateral salpingo-oophorectomy, omentectomy, and total hysterectomy. She also had a history of paroxysmal supraventricular tachycardia due to Wolff-Parkinson-White syndrome. The patient had previously received 3 lines of chemotherapy (paclitaxel + carboplatin). During the study, she received niraparib treatment for 504 days before discontinuing treatment owing to thrombocytopenia (Grade 4). She was diagnosed with leukemia 25 days after discontinuation of niraparib and died 27 days after the leukemia diagnosis.

3. Efficacy endpoints

The full analysis set (n=19) was used to determine PFS and OS. Median (95% CI) follow-up for PFS and OS was 32.3 (32.1–not evaluable) and 33.1 (32.9–34.1) months, respectively. Median (95% CI) PFS was 18.0 (5.6–26.7) months (Fig. 1). Median OS was not reached; however, the estimated proportion of patients who survived was 100% at 12 months and 78.9% at 24 months (Fig. 2). For ORR, none of the 5 patients in the response-evaluable analysis set had a response: 4 patients had stable disease and 1 patient had progressive disease.

Fig. 1 Kaplan–Meier plot of PFS in the full analysis set.

PFS, progression-free survival.

Fig. 2 Kaplan–Meier plot of OS in the full analysis set.

OS, overall survival.

DISCUSSION

This was the long-term follow-up analysis of a phase 2 study that evaluated the safety of niraparib in Japanese patients with platinum-sensitive, relapsed ovarian cancer [10]. As previously reported, the primary endpoint of incidence of Grade 3 or 4 thrombocytopenia-related events occurring in the 30 days after initial administration of niraparib was 31.6% [10]. This incidence is similar to that seen in non-Japanese patients in the NOVA study for the overall population (28.9%) and for patients with a body weight of <77 kg (34.6%), but lower than the incidence for patients with a body weight of <58 kg (45.0%) [5]. Given that the mean body weight of patients in this study was lower than in the NOVA study (57.5 vs 69.7 kg), the difference in thrombocytopenia-related events may be related to dose modification, because by the beginning of cycle 2, 14 patients (73.7%) were receiving a reduced niraparib dose (200 or 100 mg). Mean dose intensity in this long-term follow-up was 154.4 mg/day, compared with 192 mg/day in the primary analysis [10]. Although in most cases, the niraparib dose was reduced to 200 or 100 mg/day by the beginning of cycle 4, most patients were then able to maintain treatment at the reduced dose. The post hoc analysis of the NOVA study showed that after dose modification, the most commonly administered dose was 200 mg and efficacy was not compromised once patients reached their individual optimal dose (200 or 100 mg) [9].

Overall, the safety profile of niraparib in this study was considered manageable and consistent with results from previous clinical trials in non-Japanese patients [5101112]. The most common TEAEs of Grades 3 or 4 toxicity were anemia, decreased platelet count, decreased neutrophil count, and decreased white blood cell count. The occurrence of these hematology disorders and changes in these hematology values are expected over the course of niraparib treatment, as observed with other PARP inhibitors [1314]. One patient developed leukemia during the long-term follow-up period, which was deemed related to niraparib treatment by the investigator and resulted in the patient’s death. Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) were reported in the NOVA trial, in which AML or MDS occurred in 14 of 367 patients (3.8%) who received niraparib (10 [7.4%] mutated gBRCA, 4 [1.7%] wild type gBRCA) versus 3 of 179 (1.7%) patients who received placebo (2 [3.1%] mutated gBRCA, 1 [0.9%] wild type gBRCA) [15]. These patients had all received previous chemotherapy with DNA-damaging agents. In previous studies, PARP inhibitors have been associated with development of AML or MDS in patients in the first-line setting [16]. Niraparib should be discontinued if MDS or AML is confirmed [6].

In this study, niraparib efficacy was assessed by PFS, OS, and ORR. The median PFS was 18.0 months, with at least 4 of the 19 patients remaining progression-free for approximately 2.5 years. Median OS was not reached at data cutoff; however, the estimated proportion of patients who survived was 100% at 12 months and 78.9% at 24 months. In the NOVA study, the median OS with niraparib was 40.9 months versus 38.1 months with placebo in the cohort with mutated gBRCA (hazard ratio [HR]=0.85; 95% CI=0.61–1.20). In the cohort with wild type gBRCA, the median OS was 31.0 and 34.8 months, respectively (HR=1.06; 95% CI=0.81–1.37) [15]. There were no responders in the response-evaluable analysis set of this study, but stable disease was recorded for 4 of the 5 patients.

In the USA, based on final OS results from the NOVA study, the niraparib indication has been restricted to patients with deleterious or suspected deleterious gBRCA mutations [6]. However, because OS was a secondary endpoint, the NOVA study was not powered to demonstrate OS, nor was it designed to control for the number, type, and timing of subsequent treatments post-progression. Furthermore, in the NOVA long-term follow-up, no new safety signals or toxicity (such as hematologic events, MDS or AML, or cardiovascular events) were identified as contributing to the OS results of the cohort with wild type gBRCA [17]. In Japan, Korea, Taiwan and the EU, the indications remain unchanged [7]. Overall, data suggest that niraparib has a favorable benefit–risk profile in second-line or later maintenance therapy. The primary endpoint of the NOVA study was PFS, for which a statistically significant benefit of niraparib was demonstrated for cohorts with and without gBRCA mutation [5]. These results were supported by several secondary endpoints, including time to first subsequent therapy, time to second subsequent therapy, and time from initial study randomization to second disease progression or death from any cause. Additionally, a phase 3 randomized controlled trial designed to evaluate the efficacy and safety of niraparib in patients with platinum-sensitive relapsed ovarian cancer in Chinese patients (NORA study) reported a numerically longer median OS in the overall population regardless of gBRCA mutation status [18]. In the USA, a possible positive effect of niraparib on OS was reported in a real-world study using the Flatiron Health database to compare niraparib and active surveillance in a patient population with wild type gBRCA similar to that of the NOVA study [19]. In Japan, an ongoing observational study (UMIN Clinical Trial Registry: JGOG3031) will provide real-world data on the safety and efficacy of niraparib in a maintenance setting in Japanese patients with ovarian cancer.

Limitations of this study include a small sample size, a lack of comparator arm, and a lack of biomarker information. The sample size was based on results from a post hoc safety analysis of the NOVA study. The efficacy of niraparib in Japanese patients has been investigated in another phase 2 study with a patient population similar to the primary analysis population in the QUADRA trial [20].

In conclusion, the safety profile of niraparib at a starting dose of 300 mg once daily was considered manageable in this study population of Japanese patients with platinum-sensitive, relapsed ovarian cancer and was consistent with that observed in studies of non-Japanese patients.

ACKNOWLEDGEMENTS

The authors thank the patients, their families and caregivers, and all of the investigators and their team members at each study site. Medical writing support was provided by Cara Kingston, PhD and Jennifer Hung, PhD of Oxford PharmaGenesis, Melbourne, Australia and funded by Takeda Pharmaceutical Company Ltd in accordance with Good Publication Practice (GPP 2022) guidelines (www.ismpp.org/gpp-2022).

Funding: This study was funded by Takeda Pharmaceutical Company Ltd.

Presentation: Content included in this manuscript has been previously presented online at the 64th Annual Congress of the Japan Society of Obstetrics and Gynecology, July 14–16, 2022, Abstract HS-023.

Conflict of Interest: Kosei Hasegawa declares the receipt of research grants from Daiichi Sankyo, Eisai, MSD, and Takeda Pharmaceuticals Company Ltd, honoraria from AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Genmab, Kaken, Kyowa Kirin, MSD, Sanofi, and Takeda Pharmaceuticals Company Ltd, and travel expenses from Regeneron. Kosei Hasegawa is also on the advisory board of Chugai, Eisai, Genmab, MSD, Roche, Sanofi, and Takeda Pharmaceuticals Company Ltd. Shoji Nagao declares the receipt of grants from AstraZeneca, consulting fees from AstraZeneca, and honoraria from AstraZeneca, Chugai, Eisai, MSD, and Takeda Pharmaceuticals Company Ltd. Kazuhiro Takehara declares the receipt of speaker bureaus fees from AstraZeneca, MSD, and Takeda Pharmaceutical Company Ltd, and manuscript writing fees from MSD. Hidekatsu Nakai and Hidemichi Watari declare the receipt of lecture fees from Takeda Pharmaceutical Company Ltd. Shuuji Sumino is an employee of Takeda Pharmaceutical Company Ltd. Yoichi Kase and Ai Kato are employees of, and hold stocks in Takeda Pharmaceutical Company Ltd. Ajit Suri is an employee of Millennium Pharmaceuticals, part of Takeda Pharmaceutical Company Ltd, and holds stocks in Takeda Pharmaceutical Company Ltd. Other authors have no conflict of interest to disclose.

Data Availability: The data sets, including the redacted study protocol, redacted statistical analysis plan, and individual participants’ data supporting the results reported in this article, will be made available within 3 months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.

Author Contributions: Conceptualization: K.Y.

Formal analysis: I.H., 1T.N., H.J., H.K., M.M., M.K., 1N.S., N.H., 2T.N., T.H., 2N.S., W.H., Y.Y., K.Y., S.S., K.A., S.A., Y.T., T.K.

Funding acquisition: K.Y.

Investigation: I.H., 1T.N., H.J., H.K., M.M., M.K., 1N.S., N.H., 2T.N., T.H., 2N.S., W.H., Y.Y., K.Y., S.S., K.A., S.A., Y.T., T.K.

Methodology: K.Y., S.S., S.A.

Resources: K.Y.

Supervision: K.Y.

Validation: K.Y., S.S.

Writing - review & editing: I.H., 1T.N., H.J., H.K., M.M., M.K., 1N.S., N.H., 2T.N., T.H., 2N.S., W.H., Y.Y., K.Y., S.S., K.A., S.A., Y.T., T.K.

1T.N., Nobuhiro Takeshima; 2T.N., Naotake Tanaka

1N.S., Shoji Nagao; 2N.S., Shin Nishio
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