Impact of PARP inhibitors on progression-free survival in platinum-sensitive recurrent epithelial ovarian cancer: a retrospective analysis

Objective

Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib and niraparib have shown promise in extending progression-free survival (PFS) in patients with platinum-sensitive recurrent (PSR) epithelial ovarian cancer. In this retrospective study, we aimed to present our own data on the effect of PARP inhibitors on PFS in recurrent epithelial ovarian cancer.

Methods

82 patients diagnosed with PSR epithelial ovarian, tubal, or primary peritoneal cancer between May 2017 and September 2023 were initially enrolled from our hospital. However, 16 patients had prior exposure to PARP inhibitors during primary treatment, and 11 were lost to follow-up. Consequently, the study focused on 55 eligible patients. PFS was compared between patients receiving PARP inhibitor maintenance therapy and those who did not.

Results

Among the 55 patients with PSR epithelial ovarian cancer, 18 received olaparib as maintenance therapy, 19 received niraparib, and 18 opted for observation. PARP inhibitor therapy significantly extended PFS (mean 24.0 months) compared to observation (mean 9.0 months, p = 0.0005), regardless of BRCA mutation status (HR = 0.20, 95% CI: 0.08–0.50). Subgroup analysis showed no statistical difference between olaparib and niraparib. Additionally, there was no PFS difference based on BRCA mutation status within both PARP inhibitor groups.

Conclusion

Our retrospective study demonstrates that PARP inhibitor maintenance therapy, including olaparib and niraparib, significantly prolongs PFS in patients with PSR epithelial ovarian, tubal, or primary peritoneal cancer, These findings support the broad utilization of PARP inhibitors as a standard maintenance therapy for PSR epithelial ovarian cancer irrespective of BRCA mutation status.

PARP inhibitor maintenance therapy, including olaparib and niraparib, significantly prolongs PFS in patients with PSR epithelial ovarian, tubal, or primary peritoneal cancer, irrespective of BRCA mutation status. PARP inhibitors can be recommended as a standard maintenance therapy for PSR epithelial ovarian cancer.

Ovarian cancer ranks as the second most prevalent cause of mortality among gynecological malignancies, resulting in over 300,000 new diagnoses and more than 200,000 fatalities annually [1]. This highly heterogeneous tumor presents a wide range of types, with epithelial ovarian cancer(EOC) comprising over 90% of malignant ovarian tumors, among which high-grade serous carcinoma (HGSC) stands out as the most prevalent and deadliest subtype [2]. HGSC is notorious for its fast-growing and aggressive nature, with approximately 70% of patients experiencing disease relapse within 2 years, significantly impacting their quality of life [3].

Patients with recurrent EOC are typically categorized into platinum-sensitive (recurrence > 6 months after treatment) and platinum-resistant (nonresponse, progression, or recurrence within 6 months after treatment) groups. For those who respond to treatment, maintenance therapy becomes a consideration to delay recurrence or reduce the risk thereof. However, the available options for maintenance treatment have been limited. While bevacizumab is one such option, its efficacy tends to be short-lived. Nevertheless, the emergence of Poly (ADP-ribose) polymerase (PARP) inhibitors in recent years has injected new hope into recurrent EOC patients, leading to a notable increase in the 5-year survival rate from 29 to 40% [4].

Tumor cells exhibiting homologous recombination deficiency (HRD) undergo a loss of double-stranded DNA repair functionality, coupled with the inhibition of single-strand repair by PARP inhibitor, resulting in “synthetic lethality” and eventual tumor cell demise [5]. A growing body of clinical evidence suggests that the benefits of PARP inhibitors extend beyond EOC patients with BRCA mutations or HRD positivity; patients with platinum-sensitive recurrent (PSR) ovarian cancer can also derive significant benefit from them. The SOLO-2 study demonstrated that olaparib prolongs progression-free survival (PFS) in PSR patients with germline BRCA (gBRCA) mutations [6], while the OPINION study confirmed its effectiveness for patients with non-gBRCA mutations [7]. Similarly, both the NOVA and NORA studies have shown that niraparib improves PFS in PSR ovarian cancer patients regardless of their genetic status [8, 9]. However, discrepancies exist in the guidelines regarding the usage of these drugs, with NCCN Clinical Practice Guidelines (Version 1.2024) limiting olaparib and niraparib to patients with BRCA-mutated PSR disease, while ESMO Clinical Practice Guidelines (Version 2023) advocated for olaparib use in BRCA1/2-mutated patients and niraparib use regardless of BRCA1/2 status [10].

Despite the advancements, the controversies persist regarding maintenance treatment for patients with PSR disease. Therefore, a comprehensive analysis of PARP inhibitors applications in PSR ovarian cancer is imperative to inform clinical decisions. Herein, we present our retrospective data on patients with recurrent epithelial ovarian cancer to elucidate the efficacy of PARP inhibitors and offer insights for future treatment strategies.

Data collection

Retrospective data were gathered from electronic medical records of patients with recurrent ovarian, tubal, and primary peritoneal cancer treated and followed up in our hospital between May 2017 and September 2023. Data included patient age, tumor characteristic (stage, location, residual tumor status), BRCA mutation status, and response to platinum therapy. Patients were excluded if they: (i) previously used PARP inhibitors in primary treatment; (ii) had progressive disease (PD) or stable disease (SD) according to WHO recommended criteria. Out of the initial pool of 82 patients, 16 had prior exposure to PARP inhibitors during primary treatment, and 11 were lost to follow-up. Subsequently, 55 eligible patients were included in the study. Those with good performance status, minimal ascites (< 500 ml), and resectable disease underwent secondary cytoreduction. Some patients received only platinum-based chemotherapy regimens. All patients underwent 4–6 cycles of chemotherapy (carboplatin + paclitaxel, cisplatin + paclitaxel, carboplatin + gemcitabine, carboplatin + liposomal doxorubicin, or carboplatin + albumin-bound paclitaxel) and were assessed for partial response (PR) or complete response (CR) post-treatment. After chemotherapy, 18 patients opted for observation (observation group), 18 received olaparib as maintenance therapy (olaparib group), and 19 received niraparib (niraparib group). The selection of the PARP inhibitor was based on the NCCN guidelines.

Follow-up

Patients were followed up every 3 months for 2 years, every 6 months for 3–5 years, and annually thereafter. Follow-up evaluation included history, physical examination, CA125 testing, and radiological imaging (abdominal CT and/or PET-CT scan). Disease progression was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) [11]. PFS was defined from the end of last chemotherapy until progression or last follow-up.

Statistical analysis

Descriptive statistics were analyzed using chi-square tests for categorical data and Student’s t-test or Mann Whitney U test for numerical data. Kaplan-Meier methods were employed to generate time-to event curves and calculate PFS. Statistical analysis was performed using SPSS 26, with p-values < 0.05 considered statistically significant.

Study population characteristics

Between May 2017 and September 2023, our study focused on 82 patients with PSR epithelial ovarian, tubal, and primary peritoneal cancer. After excluding 16 patients due to prior exposure to PARP inhibitors during primary treatment and 11 patients due to lost follow-up, we proceeded with 55 eligible participants (Fig. 1). Their ages ranged from 39 to 80 years, with a median of 59 years. Among these patients, 18 chose observation post-chemotherapy, while 37 received maintenance therapy with a PARP inhibitor. Specifically, 18 patients were treated with olaparib, and another 19 with niraparib.

Study profile. Of the 82 patients with platinum-sensitive recurrent epithelial ovarian, tubal, and primary peritoneal cancer eligible, 55 patients were enrolled, with 16 had prior exposure to PARP inhibitors during primary treatment and 11 patients lost to follow-up. 18 patients received olaparib as maintenance therapy, 19 received niraparib, and 18 opted for observation

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Baseline characteristics across the three groups were evenly distributed, as depicted in Table 1. The mean follow-up duration was 29.6 months (range 5–83). Notably, 67% of patients in observation group had a platinum-free interval of greater than 12 months, compared to 89% in the olaparib group and 74% in the niraparib group. The mean ages were 62.0(± 10.9) years in observation group, 56.4 (± 12.4) years in the olaparib group, and 58.0(± 10.9) years in the nirapalrib group. All patients had high grade (G3) serous carcinomas (55/55, 100%). In terms of staging, 56% of patients in the observation group were stage III-IV, while 78% in the olaparib and 79% in the niraparib groups fell into this category. Most primary tumors were located in the ovaries, although one patient in the observation group and two patients in the olaparib group had primary tumors in the fallopian tubes or primary peritoneal. The majority of tumors were bilateral across all three groups, with rates of 61% in the observation group, 78% in the olaparib group and 68% in the niraparib group. Secondary cytoreductive surgery rates were 55% in the observation and olaparib group, and 63% in the niraparib groups. All patients in the observation group achieved R0 + R1 status, while 94% of patients in the olaparib group and 95% in the niraparib group achieved the same. The overall response rate (CR + PR) was 100% in all three groups. BRCA1/2 mutation was present in 4 (22%) of 18 patients in the observation group, 12 (68%) of 18 patients in the olaparib group and 3(16%) of 19 patients in the niraparib group; the remaining patients had BRCA wild-type status or undetermined genetic status.

Effect of PARP inhibitors on maintenance therapy in PSR epithelial ovarian, tubal, and primary peritoneal cancer

To elucidate the role of PARP inhibitors in maintenance therapy for PSR epithelial ovarian, tubal, and primary peritoneal cancer, we conducted an analysis of PFS between the observation group and the PARP inhibitor maintenance therapy group. The results revealed that the mean PFS was 9.0 (95% CI; 6.0–14.0) months in the observation group, and 24.0 (95% CI; 18.0–25.0) months in the PARP group (p = 0.0005) (Fig. 2). These findings indicate that PARP inhibitors can prolong the platinum-free interval in PSR epithelial ovarian, tubal, and primary peritoneal cancer. Notably, in subgroup analysis, the mean PFS was 25.0 (95% CI; 11.0–37.0) months in the olaparib maintenance therapy group and 24.0 (95% CI; 14.0–25.0) months in the niraparib maintenance therapy group, with no statistically significant difference. This may be attributed to the fact that both drugs target PARP, thus sharing a similar mechanism of action (Fig. 3). The distribution of patients with 5-year OS data includes 10 patients in the observation group, 7 in the olaparib group, and 2 in the niraparib group, with one death in each group.

Kaplan-Meier plot of PFS by PARP inhibitor and Observation groups. Tick mark indicates a censored observation. PFS, progression-free survival

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Kaplan-Meier estimates of PFS in the olaparib and niraparib groups

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Considering that the 2024 first version of the NCCN guidelines recommends PARP inhibitors solely for maintenance therapy in PSR ovarian cancer with BRCA mutations, we further stratified the olaparib and niraparib groups based on BRCA mutation status. The results revealed that in the olaparib group, the mean PFS for the BRCA mutation subgroup was 27.5 (95% CI; 10.0–46.0) months, and for the BRCA wild-type mutation subgroup was 20.0 (95% CI; 9.0–52.0) months, with no statistical difference observed between the two subgroups (Fig. 4A). Similarly, in the niraparib group, the mean PFS for the BRCA mutation subgroup was 16.0 (95% CI; 7.0–24.0) months, and for the BRCA wild-type subgroup was 24.0 (95% CI; 14.0–29.0) months, with no statistical difference observed (Fig. 4B). Moreover, there were no notable variances observed in PFS between subgroups receiving olaparib and niraparib, irrespective of whether they had BRCA mutations (Fig. 4C) or were BRCA wild-type (Fig. 4D). These findings indicate that the prolongation of the platinum-free interval by olaparib and niraparib in PSR epithelial ovarian, tubal, and primary peritoneal cancer is not influenced by the presence or absence of BRCA mutations.

Kaplan-Meier estimates of PFS in subgroups treated with olaparib and niraparib, categorized by the presence or absence of BRCA1/2 mutations. (A) Kaplan-Meier plot of PFS in the olaparib subgroups, distinguishing between patients with BRCA1/2 mutations and those with wild-type BRCA1/2. (B) Kaplan-Meier plot of PFS in the niraparib subgroups, stratified by patients with BRCA1/2 mutations and those with wild-type BRCA1/2. (C) Kaplan-Meier plot of PFS in the olaparib and niraparib subgroups specifically among patients with BRCA 1/2 mutations. (D) Kaplan-Meier plot of PFS in the olaparib and niraparib subgroups among patients with wild-type BRCA 1/2

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Ovarian cancer remains a formidable challenge in oncology, particularly due to its high recurrence rates and limited treatment options. PSR disease poses a specific clinical challenge, with the need for effective maintenance therapy to prolong PFS and delay recurrence. In recent years, the emergence of PARP inhibitors, such as olaparib and niraparib, has revolutionized the management of recurrent epithelial ovarian cancer, offering new hope for patients. Our retrospective study adds to the growing body of evidence supporting the efficacy of PARP inhibitors in PSR ovarian cancer. We found that maintenance therapy with PARP inhibitors significantly prolonged mean PFS compared to observation alone, regardless of BRCA mutation status. This finding aligns with previous clinical trials demonstrating the efficacy of PARP inhibitors in PSR disease, with improvements in PFS observed in both BRCA-mutated and non-BRCA-mutated patients.

Furthermore, our subgroup analysis comparing olaparib and niraparib revealed no statistically significant difference in PFS between the two drugs. This suggests that both olaparib and niraparib confer similar benefits in terms of prolonging the platinum-free interval in PSR ovarian cancer, supporting the notion that they share a common mechanism of action targeting PARP. This mechanism involves competitive inhibition at the PARP active site by nicotinamide adenine dinucleotide (NAD+), thereby inhibiting the synthesis of poly(ADP-ribose) polymers [12]. Inhibitors binding to the NAD + site on PARP1 and PARP2 induce conformational changes, stabilizing the PARP-DNA complex and thus “trapping” it to prolong its cellular presence and impede DNA repair [13, 14].

Interestingly, our study has unveiled a notable finding that challenges the current paradigm regarding the use of PARP inhibitors in PSR ovarian cancer. Contrary to the 2024 NCCN guidelines, which recommend PARP inhibitors solely for patients with BRCA-mutated PSR disease, our data suggest a broader efficacy profile for these agents. Specifically, we observed that BRCA mutation status did not significantly influence the efficacy of PARP inhibitors in terms of PFS. Our findings resonate with previous studies demonstrating the efficacy of PARP inhibitors beyond BRCA-mutated cohorts. For instance, the SOLO-2 study demonstrated that olaparib significantly extended median PFS over placebo (19.1 vs. 5.5 months; HR 0.30; P < 0.0001) and provided a substantial overall survival (OS) advantage of 12.9 months, confirming its sustained efficacy in PSR epithelial ovarian cancer patients with germline BRCA mutations [15]. Subsequent OPINION study confirmed olaparib’s effectiveness in extending median PFS (9.2 months, 95% CI 7.6–10.9) and OS (32.7 months, 95% CI 29.5–35.3) in a broader cohort, regardless of BRCA mutation status [16]. Similarly, the NOVA study revealed niraparib’s ability to significantly extend median PFS in comparison to placebo, both in PSR epithelial ovarian cancer patients with a gBRCA mutation (21.0 vs. 5.5 months; HR 0.27; P < 0.001) and those without (9.3 vs. 3.9 months; HR 0.45; P < 0.001) [17, 18]. Although the NOVA study did not demonstrate an extension in OS for patients without gBRCA mutations, recent findings from the NORA study in the Chinese population demonstrated a decreased mortality risk with niraparib, irrespective of BRCA mutation status [19]. The discrepancy between guideline recommendations and real-world evidence emphasizes the necessity for further research to determine the optimal use of PARP inhibitors in PSR ovarian cancer. In addition to BRCA mutation status, which has been a significant focus in understanding patient outcomes, future research should explore a broader range of predictive biomarkers to enhance personalized treatment strategies. For instance, multi-omics analyses, such as whole-genome sequencing and targeted gene panels [20], could reveal novel genetic alteration. Additionally, assessing HRD status through genomic instability scoring could provide further predictive value [21].

In the niraparib arm, it is noteworthy that although not reaching statistical significance, there was a trend towards longer mean PFS in the BRCA wild-type subgroup compared to the BRCA mutation subgroup, which contrasts with findings from the NOVA study [8]. This observation becomes particularly striking when comparing subgroups receiving olaparib and niraparib. In the niraparib group, the mean PFS for patients with BRCA mutations was 16.0 months, whereas in the olaparib group, the mean PFS for the same subgroup was substantially longer at 27.5 months. Despite a statistically significant difference, the olaparib group exhibited a notably longer average PFS in the presence of BRCA mutations. The discrepancies between our study findings and the guidelines may be attributed to the several reasons. Firstly, our study population may differ from those included in the guideline studies in terms of patient characteristics, disease stage, or treatment history. Differences in study design, including variations in data collection methods, endpoints, and statistical analyses could also contribute to the observed discrepancies. While our findings, grounded in real-world data, provide valuable insights. It’s important to acknowledge that our patient cohort may be relatively small as it was derived from a single center, a large-scale research is imperative to validate and elucidate the significance of such observations which might inform future revisions or adaptations of clinical practices. Moreover, due to variability in patient enrollment times, comprehensive OS data for all participants are currently unavailable. All patients are still being monitored, and further OS data will be included in future studies.

In conclusion, our study reinforces the importance of PARP inhibitors as standard maintenance therapy for PSR ovarian cancer, irrespective of BRCA mutation status. Both olaparib and niraparib demonstrate efficacy in prolonging PFS, underscoring their role as valuable treatment options in the management of recurrent epithelial ovarian cancer. Further research is warranted to refine patient selection criteria and optimize the use of PARP inhibitors in clinical practice.

No datasets were generated or analysed during the current study.

The authors would like to acknowledge the support received for this work from the Fundamental Research Funds for the Central Universities (grant number 2023QZJH54, awarded to J. Xu), the National Natural Science Foundation of China (grant number 82472891, awarded to J. Xu), the Key Program of Zhejiang Province Natural Science Foundation of China (grant number LZ24H160001, awarded to J. Xu), and 4 + X Clinical Research Project of Women’s Hospital, School of Medicine, Zhejiang University (grant number ZDFY2022-4X202, awarded to J. Xu).

Authors and Affiliations

1. Department of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China

   Yumei Zhou & Junfen Xu

Contributions

J.X. conceived the project. Y.Z. collected all clinical data . Y.Z. performed statistical analyses. Y.Z. and J.X. wrote the original draft. J.X. revised the paper. J.X. supervised the project.

Corresponding author

Correspondence to Junfen Xu.

Ethics approval and consent to participate

This study was reviewed and approved (PRO2022-2574) by the Human Research Ethics Committee of the Women’s Hospital, Zhejiang University School of Medicine, which waived the informed consent requirement due to the retrospective design of the study.

Consent for publication

We confirm that the manuscript has been read and approved by all named authors, and that there are no other persons who satisfied the criteria for authorship but are not listed. We also confirm that the order of the authors listed in the manuscript has been approved by all of us.

Competing interests

The authors declare no competing interests.

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