Efficacy And Safety Of Maintenance Therapy With PARP Inhibitors In Ovarian Cancer:real-world Study Data

Background and Objective:Ovarian Cancer(OC)is the most malignant gynecological tumor.Ovarian cancer has a higher mortality and recurrence rate than other gynecological tumors,requiring further maintenance treatment after a given number of chemotherapy cycles.The purpose of maintenance therapy is to delay relapse,lengthen relapse interval,and improve progression-free survival and overall survival.PARP inhibitors can inhibit the repair of DNA single strand damage and double strand break,and induce tumor cell apoptosis through synthetic lethal effect.Its emergence has revolutionized the treatment mode of ovarian cancer and popularized the concept of maintenance therapy.In the past,many large clinical trials have demonstrated the efficacy and safety of PARP inhibitors in ovarian cancer patients,but there are few research data on the treatment of PARP inhibitors in real world ovarian cancer patients.The purpose of this study was to evaluate the survival and safety of ovarian cancer patients receiving PARP inhibitor maintenance therapy in a single clinical center in the real world,and to explore the factors influencing the use of PARP inhibitor maintenance therapy in patients with ovarian cancer,so as to provide additional data support for the choice of maintenance therapy in patients with ovarian cancer.Study Methords:Newly diagnosed ovarian cancer patients and patients with platinum-sensitive recurrent ovarian cancer who had received olaparib or niraparib on maintenance therapy at Qilu Hospital of Shandong University from June 2020 to October 2022 were included.Clinicopathologic data including age,surgical pathological stage,number of previous chemotherapy lines and chemotherapy regimen,HRD and BRCA status were collected before medication.Adverse reactions during the whole medication process were followed up retrospectively and recorded,and the prognosis was statistically analyzed.The primary endpoint was progression-free survival,which was calculated using Kaplan-Meier method.log-rank test and univariate and multivariate COX regression analysis were used to determine the factors affecting progression-free survival.The General Terminology Standard for Adverse Events(CTCAE)version 5.0 was used to assess adverse events in patients with PARP inhibitors.Study Results:1.A total of 99 patients with ovarian cancer receiving PAPR inhibitor maintenance therapy were enrolled,including 76(76.6%)newly diagnosed patients and 23(23.3%)patients with platinum-sensitive recurrence.In the total population,94.9%(94/99)of the patients had serous carcinoma as pathological type,and 91.9%(91/99)of the patients had ovarian tumor as primary site.Fifty-one patients(67.1%)were treated with olaparib and 25(32.9%)were treated with niraparib in newly diagnosed patients.Of the patients with platinum-sensitive recurrence,12(52.2%)were treated with olaparib and 11(47.8%)with niraparib.In the total population,78.8%(78/99)of patients underwent BRCA gene testing.Among the newly diagnosed patients,13.7%(7/51)of olaparib patients had unknown BRCA status,86.2%(44/51)of patients had detected BRCA status,and the proportion of mutant patients was higher than that of wild type(35/44,79.5%vs.17.6%,9/51).BRCA status was detected in 84%(21/25)of patients treated with niraparib,and wild-type patients accounted for a higher proportion than mutant patients(19/25,76%vs.8%,22/25).There was a statistically significant difference in BRCA status between patients treated with olaparib and those treated with niraparib(p<0.001).Among platinum-sensitive relapsed patients,BRCA status of patients treated with olaparib was mostly mutant(5/12,41.7%vs 33.3%,4/12),while BRCA status of patients treated with niraparib was mostly wild type(5/11,45.5%vs 0%,0/11).2.In terms of survival outcome,the median follow-up time of the total population was 11 months(range:2-39 months).The median progression-free survival of newly diagnosed ovarian cancer patients was not reached,and the PFS rate at 12 months was 88.6%.The median progression-free survival of patients with platinum-sensitive recurrent ovarian cancer was 13 months and the 12-month PFS rate was 72.5%.Among newly diagnosed ovarian cancer patients,median progression-free survival was not achieved in the olaparib group,with a 12-month PFS rate of 97.2%.The median progression-free survival was 16 months and the PFS rate at 12 months was 64.5%in the niraparib-treated group.In patients with platinum-sensitive recurrent ovarian cancer,the median progression-free survival was 20 months in the olaparib group,and the PFS at 12 months was 81.8%.The median progression-free survival in the niraparib group was 9 months and the 12-month PFS rate was 31.2%.3.Uunivariate COX regression analysis showed BRCA mutations(HR=0.133,95%CI:0.043-0.410;P<0.001),HRD positive(HR=0.120,95%CI:0.038-0.379;P<0.001)was a favorable factor for prolongation of PFS in patients treated with PARP inhibitors and partial response to last chemotherapy(HR=2.732,95%CI:1.156-6.458;P=0.022)and maintenance treatment type was platinum-sensitive recurrence(HR=2.732,95%CI:1.156-6.458;P=0.001)was a negative factor affecting PFS;Multivariate COX regression showed BRCA status(HR=0.065,95%CI:0.007-0.596;P=0.016)and maintenance treatment types(HR=4.291,95%CI:0.838-21.967;P=0.008)was an independent factor affecting patients’ PFS.In subgroup analysis,univariate COX regression analysis showed that the factors affecting patients’ PFS were BRCA status(P=0.002)and HRD status(P=0.017),but in multivariate COX analysis,there was no statistical significance in their influence on PFS(P=0.051;P=1.167).In patients with platinum-sensitive recurrence,more previous chemotherapy lines were a negative factor affecting patients’ PFS(P=0.032).4.Among the 63 patients treated with olaparib,the common(>15%)hematologic adverse events were anemia(38.1%),decreased white blood cell count(17.5%),decreased platelet count(19.0%),and common(>15%)non-hematologic adverse events were nausea(23.8%)and fatigue(23.8%).The probability of grade 3 or higher adverse events was 36.9%.41.3%(26/63)of patients experienced dose reduction after treatment,and the most common causes were vomiting(5/26,17.9%)and anemia(5/26,17.9%).Dose interruption occurred in 22.2%(14/63)of patients taking olaparib,with hematologic adverse events being the most common cause(64.3%,9/14).5.Among the 36 patients treated with niraparib,the most common(>15%)hematologic adverse events were decreased platelet count(41.7%),followed by decreased white blood cell count(36.1%)and anemia(36.1%),and the most common(>15%)non-hematologic adverse events were fatigue(30.6%)and nausea(16.7%).Grade 3 or greater adverse events occurred in 30.5%of patients,of which 16.7%were reduced platelet count.The most common adverse events leading to dose reduction and treatment interruption were hematologic events(15/36,41.7%;15/36,41.7%).Conclusion:1.In the real world,ovarian cancer patients with PARP inhibitors have a good survival benefit.Ovarian cancer patients who responded to last platinum-containing chemotherapy with complete response,BRCA mutations,HRD positives,fewer previous chemotherapy lines,and initial treatment had better survival outcomes with PARP inhibitor maintenance therapy.2.When PAPR inhibitors are used,it is particularly important to identify a patient’s BRCA status,which is an independent factor affecting the prognosis of patients treated with PARP inhibitors.3.In the real world,patients with PARP inhibitors have a lower incidence of adverse reactions than in large clinical trials.4.Hematological toxic events were the most common treatment-related adverse events and the main cause of dose reduction and dose interruption after taking PARP inhibitors.Patients treated with olaparib should pay more attention to the occurrence of anemia events,while patients treated with niraparib should pay more attention to the occurrence of reduced platelet count events.