Safety assessments and clinical features of PARP inhibitors from real-world data of Japanese patients with ovarian cancer

doi:10.21203/rs.3.rs-3129590/v1

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Safety assessments and clinical features of PARP inhibitors from real-world data of Japanese patients with ovarian cancer

https://doi.org/10.21203/rs.3.rs-3129590/v1

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Background

Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib and niraparib, have been increasingly used in ovarian cancer treatment. However, the real-world safety data of these drugs in Japanese patients and the predictability of treatment interruptions are limited.

Methods

This retrospective study included 181 patients with ovarian cancer who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Patient characteristics, treatment history, and hematological data trends were compared, and the predictability of treatment interruptions based on blood sampling data was examined.

Results

Regarding patient backgrounds, the olaparib group had higher proportions of patients with serous carcinoma, BRCA positivity, homologous recombination deficiency, and those receiving maintenance therapy after recurrence treatment than the niraparib group. Regarding toxicity properties, the most common reasons for discontinuation in the olaparib group were anemia, fatigue, and nausea, while discontinuation was primarily due to thrombocytopenia in the niraparib group. Thrombocytopenia caused by niraparib treatment occurred earlier than anemia caused by olaparib treatment. Patients with a low body mass index or who had undergone several previous treatment regimens were more likely to discontinue treatment due to adverse effects within the first 3 months. Although we analyzed blood collection data, predicting treatment interruptions due to blood toxicity using blood data was challenging.

Conclusions

In this study, we revealed the characteristics of patients and the timing of interruptions for each drug, highlighting the importance of carefully managing adverse effects, particularly during the early treatment stages.

Ovarian cancer

PARP inhibitors

olaparib

niraparib

adverse effects

Ovarian cancer is the third most common gynecologic malignancy and was the second leading cause of death from gynecologic cancer worldwide in 2020[1]. Epithelial ovarian cancer constitutes most ovarian malignancies, with most cases diagnosed at an advanced stage. The 5-year survival rate for ovarian cancer is approximately 30%. Despite achieving an approximately 80% response rate with standard treatment of optimal debulking surgery and platinum-based chemotherapy, most patients experience recurrence and disease progression within 2 y, leading to multiple recurrences and the development of platinum-resistant ovarian cancer[2][3]. Therefore, extending the progression-free period and improving the 5-year survival rate are urgent challenges.

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a significant breakthrough in managing advanced ovarian cancer in recent years[4]. PARP is an enzyme crucial for repairing single-strand DNA breaks. PARP inhibitors are a class of drugs that block PARP enzyme activity, causing the accumulation of single-strand breaks, which eventually turn into double-strand breaks (DSBs). DSBs can be repaired by a homologous recombination repair (HRR) pathway. However, in cancer cells with BRCA mutations or homologous recombination deficiency (HRD), the HRR pathway is already impaired. Thus, when PARP inhibitors are used to treat these cells, they further compromise DNA repair mechanisms by blocking the repair of single-strand breaks. This creates a state of synthetic lethality, as the combined effect of the impaired HRR pathway and PARP inhibition induces excessive DNA damage, causing cancer cell death [5].

In Japan, olaparib has received approval for various maintenance treatments, including platinum-sensitive relapsed ovarian cancer in 2018[6] [7], BRCA mutations following remission of first-line platinum chemotherapy in 2019[8], and HRD in combination with bevacizumab after remission of first-line platinum chemotherapy in 2020[9]. Conversely, niraparib was approved for maintenance treatment of platinum-sensitive relapsed ovarian cancer in 2020[10], maintenance treatment following remission of first-line platinum chemotherapy in 2020[11], and monotherapy treatment of HRD and platinum-sensitive relapsed ovarian cancer after third or more chemotherapy sessions in 2020[12] .

Since eligibility criteria restrict patient enrollment in clinical trials and the adverse effects observed may vary due to racial differences, clinical trial results do not necessarily correspond to real-world practice. Thus, there is growing interest in using real-world data to answer clinical questions unanswerable through clinical trial data[13] [14]. Furthermore, accumulating real-world data may reveal findings unavailable in clinical trials or even overturn clinical trial data. Since maintenance therapy follows an initial treatment, accumulating the clinical data takes time. Olaparib and niraparib have been used for 5 and 2 y, respectively, in Japan. Therefore, we examined the real-world data on the safety of both drugs. Additionally, we assessed whether interruptions could be predicted and whether certain trends existed among patients who interrupted the drugs.

The records of 181 patients with ovarian cancer who received olaparib and/or niraparib treatment at Nagoya University Hospital (Nagoya, Japan) and Aichi Cancer Center Hospital (Nagoya, Japan) from May 2018 to December 2022 were retrospectively reviewed. Both the olaparib and niraparib groups included patients undergoing maintenance treatment for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer after first-line platinum-based chemotherapy and recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer after platinum-based chemotherapy. We investigated the patients’ clinical information, including age, body mass index (BMI), smoking and drinking habits, histological type, BRCA and HRD status, previous chemotherapy regimens, adverse effects, and blood sampling data, at several points. This study was approved by the ethics committee of each institute (Approval No. 2013-0078).

Statistical analyses were performed using GraphPad Prism 9, with the Mann–Whitney U test used for comparisons between both groups. p < 0.05 was considered statistically significant.

Patient characteristics

The olaparib and niraparib groups comprised 131 and 50 patients, respectively (Table 1). The median age was 59 (30–80) in the olaparib group and 50 (23–80) in the niraparib group, while the median BMI was 21.2 (14.2–32.8) in the olaparib group and 21.9 (14.3–30.4) in the niraparib group. There were no differences in smoking habits or diabetes between both groups, but alcohol consumption was higher in the niraparib group (p = 0.01).

Table 1

Patient characteristics
		Olaparib (N = 131)	Niraparib (N = 50)	p value
Age		59 (30–80)	59 (23–80)	0.57
BMI		21.2 (14.2–32.8)	21.9 (14.3–30.4)	0.54
Smoking		14 (10.7%)	8 (16.0%)	0.59
Drinking		9 (6.9%)	10 (20.0%)	0.01
DM		9 (6.9%)	5 (10.0%)	0.53
Histologic subtype
	Serous	115 (87.8%)	32 (64.0%)	< 0.01
	Endometrioid	9 (6.9%)	6 (12.0%)
	Clear	5 (3.8%)	5 (10.0%)
	Carcinosarcoma	0 (0.0%)	1 (2.0%)
	Unknown	2(1.5%)	6 (12.0%)
BRCA status
	Positive	26 (19.8%)	2 (4.0%)	0.01
	Negative	36 (27.5%)	26 (52. 0%)
	Unknown	69 (52.7%)	22 (44. 0%)
HRD
	Positive	19 (14.5%)	4 (8.0%)	0.32
	Negative	2 (1.5%)	12 (24.0%)
	Unknown	110 (83.9%)	33 (66.0%)
BMI, body mass index; DM, diabetes mellitus; HRD, homologous recombination deficiency

The proportion of serous carcinoma was significantly higher in the olaparib group (115/131, 87.8%) compared to the niraparib group (32/50, 64.0%) (p < 0.01). The proportion of BRCA-positive patients was 26/131 (19.8%) in the olaparib group and 2/50 (4.0%) in the niraparib group (p = 0.05), while that of HRD-positive patients was 19/131 (14.5%) in the olaparib group and 4/50 (8.0%) in the niraparib group (p = 0.32). In addition, the BRCA status was unknown for 69/131 (52.7%) patients in the olaparib group and 22/50 (44.0%) patients in the niraparib group. The HRD status was unknown for 110/131 (83.9%) patients in the olaparib group and 33/50 (66.0%) patients in the niraparib group.

Treatment history

The patients’ treatment history is shown in Table 2. The median observation period was 697 (68–1699) d in the olaparib group and 423 (66–726) d in the niraparib group. The median treatment duration was 190 (14–1667) d in the olaparib group and 203 (5–726) d in the niraparib group. Treatment was discontinued due to adverse effects in 22/131 (16.8%) patients in the olaparib group and 6/50 (12.0%) patients in the niraparib group. The response to the most recent treatment was similar in both groups.

Table 2

Treatment history
		Olaparib (N = 131)	Niraparib (N = 50)	p value
Observation days (days)		697 (68–1699)	423 (66–726)
Duration to the treatment (days)		190 (14–1667)	203 (5–726)
Reason for termination
	PD	63 (48.1%)	29 (58.0%)
	Adverse effect	22 (16.8%)	6 (12.0%)
	Others	2 (0.0%)	1 (2.0%)
Number of previous chemotherapy regimens
	1 ~ 4	114 (87.0%)	49 (98.0%)
	5 ~ 9	13 (9.9%)	1 (2.0%)
	10~	4 (3.1%)	0 (0.0%)
Response to most recent treatment
	CR	62 (47.3%)	27 (54.0%)	0.51
	PR	69 (52.7%)	23 (46.0%)
Maintenance for first-line chemotherapy		31 (23.7%)	28 (56.0%)	< 0.01
Treatment with Bev		18 (13.7%)	-
No surgery		5 (3.8%)	10 (20.0%)	< 0.01
Interruption		68 (51.9%)	32 (64.0%)	0.87
Reason for interruption
	Anemia	33 (48.5%)	8 (25.0%)
	Neutropenia	17 (25.0%)	5 (15.6%)
	Thrombocytopenia	6 (8.8%)	16 (50.0%)
	Fatigue	14 (20.6%)	2 (6.3%)
	Nausea	11 (16.2%)	0 (0.0%)
	Others	8 (11.8%)	7 (21.9%)
CR, complete response; PR, partial response; PD, progressive disease

Furthermore, 31/131 (23.7%) in the olaparib group and 28/50 (56.0%) in the niraparib group received maintenance therapy following first-line chemotherapy. Maintenance therapy in combination with bevacizumab was administered to 18/131 (13.7%) patients in the olaparib group. Additionally, 5/131 (3.8%) patients in the olaparib group and 10/50 (20.0%) patients in the niraparib group were transferred to maintenance therapy without surgery (p < 0.01). Treatment was interrupted in 68/131 (51.9%) patients in the olaparib group and 32/50 (64.0%) patients in the niraparib group (p = 0.87). The most common reason for treatment interruption based on blood data was anemia in 33/68 (48.5%) patients in the olaparib group and thrombocytopenia in 16/32 (50.0%) patients in the niraparib group. In the olaparib group, 20/68 (55.6%) patients interrupted treatment due to fatigue and/or nausea.

The characteristics of cases where treatment was discontinued due to adverse effects in the early treatment stage are shown in Table 3. A total of 13/131 (9.9%) patients in the olaparib group and 5/50 (10.0%) patients in the niraparib group discontinued treatment due to adverse effects within the first 3 months of treatment. The median treatment duration was 43 (14–77) d in the olaparib group and 27 (5–28) d in the niraparib group. The median BMI was 19.9 (14.2–26.5) in the olaparib group and 20.5 (14.3–24.9) in the niraparib group, indicating that both groups had a higher proportion of thin patients compared to the overall population. In both groups, most patients received maintenance therapy after recurrence. The most common reason for early treatment discontinuation was fatigue or vomiting in 8/13 (61.5%) patients in the olaparib group and thrombocytopenia in 3/5 (60.0%) patients in the niraparib group.

Table 3

The characteristics of patients who discontinued treatment due to adverse effects within the first 3 months of treatment
		Olaparib (N = 131)	Niraparib (N = 50)
Discontinued cases		13 (9.9%)	5 (10.0%)
Duration to the treatment(days)		56 (14–154)	27 (5–28)
BMI		20.1 (14.2–29.5)	20.5 (14.3–24.9)
Smoking		1 (7.7%)	1 (20.0%)
Drinking		0 (0.0%)	0 (0.0%)
DM		1 (7.7%)	0 (0.0%)
Number of previous chemotherapy regimens		2 (1–6)	2 (1–3)
Response to most recent treatment
	CR	9 (69.2%)	1 (20.0%)
	PR	4 (30.8%)	4 (80.0%)
Maintenance for first-line chemotherapy		3 (23.1%)	1 (20.0%)
Reason for termination
	Anemia	2 (15.4%)	0 (0.0%)
	Neutropenia	1 (7.7%)	0 (0.0%)
	Thrombocytopenia	0 (0.0%)	3 (60.0%)
	Fatigue, Vomiting	8 (61.5%)	1 (20.0%)
	Dysgeusia	1 (7.7%)	1 (20.0%)
	Interstitial pneumonia	1 (7.7%)	0 (0.0%)
BMI, body mass index; DM, diabetes mellitus; CR, complete response; PR, partial response

Hematological data trends

The trends of blood hemoglobin and platelet levels, which were the most common causes of treatment interruption based on blood data, in the olaparib and niraparib groups, respectively, are shown in Fig. 1a. In the olaparib group, there were 30 cases of initial treatment interruption due to anemia after the start of treatment. Among these, 22/30 (73.3%) were interrupted within 4–12 weeks of treatment. Conversely, there were 16 cases of initial treatment interruption due to thrombocytopenia in the niraparib group (Fig. 1b). Among these, 15/16 (93.8%) were interrupted within 8 weeks of treatment. Interruptions due to thrombocytopenia in the niraparib group tended to occur earlier than interruptions due to anemia in the olaparib group. As described above, the timing of interruptions showed certain trends and characteristics for each drug.

Prediction of interruption

Predicting adverse effects in patients would enhance treatment management and ensure safe administration of the drug, leading to successful completion of the treatment. We hypothesized that the degree of adverse effects during chemotherapy might correlate with that during maintenance therapy using consecutive PARP inhibitors. Therefore, to predict treatment interruption due to hematological adverse effcts, blood collection data before treatment and after chemotherapy were investigated. Specifically, we compared the blood collection data at the initial visit and at the start of olaparib/niraparib treatment and the rate of change between the groups with and without interruption. The results for interruption due to anemia in the olaparib group are shown in Fig. 2a. No significant differences existed between both groups, and predicting interruption due to anemia from the blood data at the initial visit or the start of treatment was challenging. The results for interruption due to thrombocytopenia in the niraparib group are shown in Fig. 2b. No significant differences existed between both groups, and predicting interruption due to thrombocytopenia from the blood data at the initial visit or the start of treatment was challenging. Both olaparib-induced interruption due to anemia and niraparib-induced interruption due to thrombocytopenia were difficult to predict from the blood data.

Due to the high recurrence rate and low survival rate of ovarian cancer, as well as the limited availability of drugs other than chemotherapy in the past, the emergence of PARP inhibitors has brought hope for ovarian cancer treatment[15]. We aimed to explore the real-world data of olaparib and niraparib in Japan, as both agents target the same pathways but are used differently. Olaparib is primarily used as a single agent in maintenance therapy after first-line chemotherapy for BRCA-positive patients, based on the SOLO-1 study[8], and in combination with bevacizumab for HRD patients, based on the PAOLA-1 study[9]. Conversely, niraparib can be used regardless of biomarkers, based on the PRIMA study[11]. BRCA mutations and HRD are frequently observed in high-grade serous ovarian carcinoma[16], suggesting that the niraparib group may have had fewer patients with serous carcinoma, BRCA-positive status, and HRD. The complete response rate after the most recent platinum-based chemotherapy was 47.3% in the olaparib group and 54.0% in the niraparib group. When limited to patients receiving maintenance therapy after first-line chemotherapy, the rate was 93.5% in the olaparib group and 60.7% in the niraparib group, similar to prior studies[8] [9] [11].

In this study, there were differences in adverse effects between the olaparib group and the niraparib group. Despite sharing the same pharmacological mechanism, the toxicity profile is different for both agents[17] [18]. The differences in adverse effects of these agents could be attributed to dosage schedule, half-life, drug interactions, and metabolism[19]. In this study, Grade 3 or 4 adverse reactions in the olaparib group included anemia (25.2%), neutropenia (14.5%), thrombocytopenia (3.8%), and fatigue/nausea (15.3%), occurring more frequently than in previous studies [6] [7] [8] [9]. This discrepancy might be because the Japanese have a lower BMI than Westerners. Conversely, Grade 3 or 4 adverse reactions in the niraparib group comprised anemia (14.0%), neutropenia (10.0%), thrombocytopenia (32.0%), and fatigue/nausea (6.0%), respectively, with these results either being the same or less frequent than in previous studies[10] [11] [20]. This may be because the starting dose for niraparib was individualized based on body weight and platelet count. Previous studies started with a fixed dose of 300 mg, and the NOVA trial results led to the individualization of the initial dose according to body weight and platelet count. Moreover, recently published data from the NORA trial confirmed that dose individualization is associated with improved hematologic toxicity[21].

Thrombocytopenia is a peculiar toxicity observed in niraparib treatment, and we showed that niraparib-induced thrombocytopenia occurs earlier than olaparib-induced anemia. Furthermore, there were three cases where platelet levels did not recover after treatment interruption, leading to the discontinuation of the drug. This finding suggests that niraparib-induced thrombocytopenia may be more robust than olaparib-induced anemia. Among patients who discontinued treatment due to adverse effects, 59% in the olaparib group and 100% in the niraparib group discontinued within the first 3 months of treatment. It was considered that thin patients with several previous regimens should be managed with particular attention to adverse effects early in the treatment. Furthermore, careful long-term management of adverse effects is crucial, especially when treated with olaparib.

While there have been many reports on the adverse effects of PARP inhibitor therapy[22] [23], no reports describing their predictability exist. This is the first study on the predictability of interruptions in PARP inhibitor therapy using blood collection data. However, the blood toxicity of both agents was difficult to predict using blood collection data. Generally, hematological adverse events associated with PARP inhibitors are frequent but transient, occurring during the first months of therapy, and are often resolved with dose reduction. We also observed hematological adverse events in the later treatment stages, especially in the olaparib group, and rare complications such as myelodysplastic syndrome and acute myeloid leukemia[24]. Thus, regular blood tests should be conducted even after the initial months of treatment.

In conclusion, we examined the real-world data on the safety of olaparib and niraparib, as well as the predictability of intake interruption based on blood sampling data. Patient backgrounds and toxicity profiles differed between the olaparib and niraparib groups. However, predicting the blood toxicity of both agents using blood collection data was challenging. This study revealed the characteristics of the patients and the timing of interruption for each drug and highlighted the importance of carefully managing adverse effects, particularly during the early treatment stages.

Acknowledgements

We express the highest appreciation to the entire staff of the Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, and Department of Gynecology, Aichi Cancer Center. This work was supported by JSPS KAKENHI Grant Number 21H03075 and the Princess Takamatsu Cancer Research Fund (No. 20-25237), Moreover, this study was also supported by Program for Tokai Pathway to Global Excellence (T-GEx) FY2021 and for Promoting the Enhancement of Research Universities as young researcher units for the advancement of new and undeveloped fields at Nagoya University. Furthermore, we thank Enago (https://www.enago.jp/) for English language editing of this manuscript.

Data availability statements

All data generated or analyzed during this study are included in this published article.

Contributions

All authors contributed to the study conception and design. Data collection and analysis were performed by R.U., E.W., and A.Y. The first draft of the manuscript was written by R.U. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics declarations

Competing interests

The authors declare no competing interests.

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Safety assessments and clinical features of PARP inhibitors from real-world data of Japanese patients with ovarian cancer

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Abstract

Background

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Introduction

Patients and Methods

Results

Patient characteristics

Treatment history

Hematological data trends

Prediction of interruption

Discussion

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