Risk factors for the failure of first‐line PARP inhibitor maintenance therapy in patients with advanced ovarian cancer: Gynecologic Oncology Research Investigators Collaboration Study (GORILLA‐3004)

Abstract Objective To identify the risk factors for failure of first‐line poly (ADP‐ribose) polymerase inhibitor (PARPi) maintenance therapy in patients with advanced ovarian cancer. Method Patients with stage III‐IV epithelial ovarian cancer who received first‐line PARPi maintenance therapy were retrospectively reviewed. Clinicopathologic factors were compared between two groups—recur/progression of disease (PD) and non‐recur/PD. Results In total, 191 patients were included. Median follow‐up was 9.9 months, and recurrence rate was 20.9%. BRCA mutations were found in 63.4% patients. Postoperative residual tumor (60.5% vs. 37.8%), non‐high grade serous carcinoma (HGSC) (15.0% vs. 6.0%), neoadjuvant chemotherapy (NAC) (55.0% vs. 35.8%), and pre‐PARPi serum CA‐125 levels ≥23.5 U/mL (35.9% vs. 15.2%) were more frequently observed in the recur/PD group. Multivariate Cox‐regression analysis revealed pre‐PARPi serum CA‐125 levels ≥23.5 U/mL (HR, 2.17; 95%CI, 1.03–4.57; p = 0.042), non‐HGSC (3.28; 1.20–8.97; p = 0.021), NAC (2.11; 1.04–4.26; p = 0.037), and no BRCA mutation (2.23; 1.12–4.44; p = 0.023) as independent risk factors associated with poor progression‐free survival (PFS). A subgroup analysis according to BRCA mutation status showed that pre‐PARPi serum CA‐125 levels ≥26.4 U/mL were the only independent risk factor for poor PFS in women with BRCA mutations (2.75; 1.03–7.39; p = 0.044). Non‐HGSC (5.05; 1.80–14.18; p = 0.002) and NAC (3.36; 1.25–9.04; p = 0.016) were independent risk factors in women without BRCA mutations. Conclusion High pre‐PARPi serum CA‐125 levels, non‐HGSC histology, NAC, and no BRCA mutation might be risk factors for early failure of first‐line PARPi maintenance therapy. In women with BRCA mutations, high pre‐PARPi serum CA‐125 levels, which represent a large tumor burden before PARPi, were the only independent risk factor for poor PFS.


| INTRODUCTION
Ovarian cancer is known to be the most lethal gynecological cancer, with a 5-year survival rate of <50% for advanced disease. 1 Approximately 70% of ovarian cancer patients are initially diagnosed at advanced stage. 2 Despite adjuvant platinum-based chemotherapy after cytoreductive surgery being the standard treatment, 3,4 75% of stage IIB-IV ovarian cancer patients eventually experience a relapse, which results in poor survival outcomes. 5There has long been an unmet need to prevent recurrence and maximize progression-free survival (PFS) after completion of front-line treatments in advanced ovarian cancer.
As the concept of maintenance treatment for ovarian cancer has emerged to reduce the risk of recurrence, randomized controlled trials of poly (ADP-ribose) polymerase inhibitors (PARPi) as first-line maintenance treatment in advanced ovarian cancer have shown promising results.A study on olaparib as a first-line maintenance treatment after platinum-based chemotherapy (SOLO-1 trial) showed significant PFS and overall survival (OS) benefits in patients with newly diagnosed advanced ovarian cancer and BRCA mutations. 6,7A study using another PARPi, niraparib, as a first-line maintenance therapy (PRIMA trial) reported significantly increased PFS regardless of homologous recombination status. 8Based on these results, the National Comprehensive Cancer Network and the European Society for Medical Oncology recommend PARPi maintenance treatment for advanced ovarian cancer patients who have a complete or partial response to first-line platinum-based chemotherapy. 3,9lthough first-line PARPi maintenance has been used worldwide for a long time, failure after first-line PARPi maintenance treatment has been reported, and the issue of PARPi resistance has recently emerged. 10,11To further enhance treatment efficacy, recent studies have focused on resistance to PARPi, combination treatment with other targeted agents or immunotherapy to overcome PARPi resistance, and PARPi retreatment in patients with recurrence after using PARPi. 12,13However, it is important to understand the risk factors for recurrence after first-line PARPi maintenance treatment to select an appropriate patient group for PARPi use and to establish an optimal treatment plan for patients with newly diagnosed advanced ovarian cancer.As the duration of PARPi use as first-line maintenance treatment in a real-world clinical setting is relatively short, there are no studies evaluating the outcomes and risk factors for recurrence in patients using first-line PARPi maintenance treatment for advanced ovarian cancer.
This multicenter retrospective study aimed to identify the risk factors for the failure of first-line PARPi maintenance therapy in patients with advanced ovarian cancer.

| METHODS
This retrospective study was conducted at six university hospitals in Korea, and all institutions were approved by the Institutional Review Board.The requirement for obtaining informed consent from the patients was waived because the study was based on retrospective review of medical charts.The medical records of consecutive patients who received first-line PARPi maintenance therapy for advanced ovarian cancer from January 2018 to June 2022 were retrospectively reviewed.The inclusion criteria were as follows: (1) patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage III-IV and histologically confirmed epithelial ovarian, tubal, or primary peritoneal cancer; (2) patients who used PARPi as first-line maintenance treatment.Patients who were diagnosed and treated for cancers other than breast cancer and endometrial cancer within the last 5 years were excluded.
Information about clinical characteristics, including age at diagnosis, the body mass index, parity, initial serum CA-125 levels at diagnosis, histologic type, FIGO stage, primary treatment for ovarian cancer, residual tumor after staging surgery, neoadjuvant and adjuvant chemotherapy, and serum CA-125 levels before starting PARPi, was collected.Data on PARPi treatment, including type, duration, discontinuation, and reason for discontinuation, were also collected.Cutoff values for initial CA-125 at diagnosis and CA-125 before starting PARPi were set as the mean values for the overall study population, patients with BRCA mutations, and patients without BRCA mutations, respectively.BRCA mutations in tumor tissue or blood were retrospectively reviewed, and subgroup analyses were performed according to BRCA mutation status.PFS was defined as the time from the initial diagnosis of cancer to disease progression, based on the Response Evaluation Criteria in Solid Tumors (RECIST) for imaging evaluation, or death from any cause.
Clinicopathological factors were compared between patients who experienced recurrence or progression of disease (PD) during PARPi maintenance (recur/PD group) and those who did not (non-recur/PD group) using Student's t-test and the χ 2 test.Univariate and multivariate Cox regression analyses were conducted to identify the risk factors for short PFS after first-line PARPi maintenance therapy.Statistical analyses were performed using IBM SPSS Statistics for Windows (version 25.0;IBM Corp.).Statistical significance was set at p < 0.05.

| RESULTS
A total of 191 patients who met the inclusion criteria were enrolled in this study.Median follow-up period from the start of PARPi was 9.9 months (range, 0.9-30.9months), and the recurrence rate was 20.9% (40/191).The baseline characteristics of the study population are shown in Table 1.The frequency of CA-125 abnormalities (i.e., > 35 U/mL) before starting PARPi was 13.2% (25/190).BRCA mutations were found in 121 patients (63.4%), with 81 showing BRCA1, and 41 showing BRCA2 mutations.One patient had mutations in both BRCA1 and BRCA 2. Seventy-seven (40.3%) and 114 (59.7%) patients took olaparib and niraparib, respectively.The median duration of PARPi use was 8.5 months (range, 0.9-30.4months).Of 40 patients in the recur/PD group, only 2 (5.0%) stopped PARPi before recur/PD because of adverse events and 38 (95.0%) continued PARPi until PD.One patient in the non-recur/PD group discontinued PARPi owing to myelodysplastic syndrome.

| CONCLUSIONS
The present study showed that high serum CA-125 levels before starting PARPi were the only independent risk factor for short PFS in women with BRCA mutation, whereas non-HGSC (vs.HGSC) and NAC (vs.primary debulking surgery [PDS]) were risk factors in women without BRCA mutation.Non-HGSC histology, NAC, high serum CA-125 levels before starting PARPi, and no BRCA mutation were independent risk factors for poor PFS in patients receiving first-line PARPi maintenance therapy for advanced ovarian cancer.
It is well known that BRCA mutation itself is a potent and favorable prognostic factor and is associated with high F I G U R E 1 Progression-free survival in patients with BRCA mutation according to pre-PARPi serum CA125 levels (A) and in patients without BRCA mutation according to histologic type, (B) and primary treatment, (C).PARPi, poly (ADP-ribose) polymerase inhibitor; HGSC, high-grade serous carcinoma; PDS, primary debulking surgery; NAC, neoadjuvant chemotherapy.
5][16] Consistently, our study demonstrated that the absence of a BRCA mutation was one of the significant risk factors for a poor PFS.Fu et al. reported that PDS stage 3, compared to stage 4, and no gross residual lesion after debulking surgery were associated with favorable prognosis in patients with germline BRCA mutations. 17As the above-mentioned study focused on BRCA mutation status and excluded patients who received first-line maintenance treatment, the impact of first-line maintenance PARPi was not evaluated.Our subgroup analysis of patients with BRCA mutations showed that high serum CA-125 levels before starting PARPi were the only independent risk factor for a poor PFS.This finding is consistent with that of a subgroup analysis of SOLO 1. 18 This study demonstrated that patients who underwent surgery with no gross residual tumor and had a complete response after platinum-based chemotherapy were more likely to benefit from first-line PARPi maintenance than those who had residual tumors and a partial response to adjuvant chemotherapy, respectively.These results suggest that first-line PARPi maintenance might be more effective in patients with low tumor loads than in those with high tumor loads, which is believed to be related to the synthetic lethality and antitumor mechanism of PARPi. 19Synthetic lethality is where the loss of one gene is compatible with cell viability; however, simultaneous disruption of two genes results in cell death. 20Because  of its synthetic lethality, the antitumor effect of PARPi is thought to be lower than that of conventional chemotherapeutic drugs, and PARPi is mainly recommended as maintenance therapy for ovarian cancer. 19Interestingly, tumor burden only at the time of starting PARPi was a significant risk factor in our study; however, other factors reflecting overall tumor burden, such as stage, pretreatment CA-125 levels, and postoperative gross residual tumor, were not.This finding suggests that additional cycles of platinumbased adjuvant chemotherapy causing further reduction in the pre-PARPi tumor burden could benefit ovarian cancer patients with BRCA mutations.
In contrast, our study showed that in patients without BRCA mutations, non-HGSC histology, and NAC were independent poor prognostic factors for PFS.Nonserous histological type is known to be associated with a poor prognosis in advanced ovarian cancer. 21The deleterious impact of low sensitivity to platinum-based chemotherapy and PARPi might be substantial in women without BRCA mutations, particularly in non-HGSC patients. 22n the current study, the recurrence rate was 20.9% in patients with first-line PARPi maintenance treatment during a relatively short median follow-up period from the start of PARPi of 10 months.This is consistent with the results of SOLO1 and PRIMA studies.One-year progression rates in these studies were 12% and 35%, respectively. 6,8ewer stage IV disease (15% vs. 33%) and higher rate of BRCA mutation (100% vs. 63.9%) in SOLO1 than in our study were noted. 6More patients received NAC as primary treatment in PRIMA studies than in our study (63% vs. 37%). 8These differences in the study populations may explain the differences in recurrence rates between our study and previous studies.
Of 40 patients in the recur/PD group, 38 (95.0%) stopped taking PARPi because of recurrence or PD during PARPi use.Thirty-two (84.2%) recur/PD group cases had recurrence or PD within 1 year of PARPi use.SOLO1 and PRIMA studies lacked data regarding the timing of recurrence or PD after PARPi use.Our data will help clinicians manage patients.
Tumor biology and treatment strategies for newly diagnosed and recurrent ovarian cancers are different. 23Randomized controlled trials on PARPi demonstrated greater survival benefit in first-line maintenance settings than in second-line or more maintenance settings. 6,8,24,25In line with this, the risk factors for poor PFS in the first-line maintenance of PARPi are thought to be different from those in the second-line or beyond.However, the existing studies of risk factors for poor survival during PARPi maintenance therapy focused on second-line or more settings in recurrent ovarian cancer. 26A previous metaanalysis has shown that BRCA mutation, homologous recombination deficiency (HRD)-positive status, and sensitivity to platinum-based chemotherapy are the factors indicating favorable prognosis in patients using PARPi.In contrast, the response to platinum-based chemotherapy, surgery type, residual disease after surgery, stage, and age could not predict the efficacy of PARPi use. 15This metaanalysis included prospective studies on every treatment setting for PARPi use, such as first-line, second-line, or more maintenance settings.Therefore, the risk factors for a poor PFS in the first-line PARPi maintenance setting could not be identified. 26Our study focused on first-line PARPi maintenance treatment.
The strength of this study is that it is the first to focus on risk factors for the failure of first-line PARPi maintenance therapy in real-world clinical settings and to identify whether these risk factors differ according to BRCA mutation.In addition, the information of a modest number of study participants was obtained by collecting data from six large university hospitals.However, this study had some limitations as well.First, it may have a potential bias because of its retrospective nature.Second, the analysis of various genetic mutations other than BRCA mutations could not be performed because the protocols and methods of genetic testing were different for each institution.In most patients, the HRD test could not be performed because of the high cost and the insurance system in Korea.Finally, this study had a relatively short follow-up period to analyze the OS or outcomes of subsequent treatment in patients who experienced recurrence or progression after first-line PARPi maintenance therapy.
In conclusion, non-HGSC histology, NAC, high serum CA-125 levels before starting PARPi, and no BRCA mutation might be risk factors for early failure of first-line PARPi maintenance therapy in patients with advanced ovarian cancer.However, in women with BRCA mutations, pre-PARPi high serum CA125 levels, which represent a high tumor burden before PARPi, were the only independent risk factor for a poor PFS.Non-HGSC histology and NAC as primary treatments were poor prognostic factors associated with PFS in patients without BRCA mutations.Long-term follow-up data and further studies focusing on various genetic mutations, including HRD, are required.In addition, further studies on the PARPi treatment-free interval and PARPi-sensitive or -resistant recurrence after completion of PARPi use are required.
Univariate and multivariateCox regression analyses of risk factors for progression-free survival.
a Including neoadjuvant chemotherapy and palliative chemotherapy.T A B L E 3 Univariate and multivariate Cox regression analyses of risk factors for progression-free survival in patients with BRCA mutation (N = 121).
T A B L E 4Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; HGSC, high-grade serous carcinoma; PARPi, Poly (ADP-ribose) polymerase inhibitor; PDS, primary debulking surgery.a Including neoadjuvant chemotherapy and palliative chemotherapy.
Univariate and multivariate Cox regression analyses of risk factors for progression-free survival in patients without BRCA mutation (N = 70).
T A B L E 5Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; HGSC, high-grade serous carcinoma; PARPi, Poly (ADP-ribose) polymerase inhibitor; PDS, primary debulking surgery.a Including neoadjuvant chemotherapy and palliative chemotherapy.