Efficacy of poly (ADP-ribose) polymerase inhibitors monotherapy and the impact to subsequent platinum-based chemotherapy in breast cancer susceptibility genes1/2-mutated ovarian cancer patients with secondary platinum-sensitive relapse

Ovarian cancer is a common malignant tumor of the female reproductive system and its mortality ranks first among gynecological malignant tumors [1]. Approximately 90% of ovarian cancer are of an epithelial cell type, and the remaining 10% are non-epithelial ovarian cancers, which include mainly germ cell tumours, sex cord-stromal tumours, and some extremely rare tumours such as small cell carcinomas [2]. More than 75% of patients eventually relapse within two years of initial treatment [3], and patients with platinum-sensitive relapse are recommended re-challenge with platinum-based chemotherapy until platinum resistance. However, once platinum resistance occurs, the response rate of subsequent therapies is only about 10-25%, and the prognosis is extremely poor, with median overall survival of only 12 months [3, 4].

BRCA1/2 germline mutations are the strongest known genetic risk factors for epithelial ovarian cancer and are found in 6–16% of patients [5, 6], and treatment with poly (ADP-ribose) polymerase inhibitors (PARPi) has a significant response based on “synergistic lethal effects” [7] . Several PARP inhibitors are currently available for the clinical treatment of patients with ovarian cancer [8], in addition, some studies have compared the differences between PARPi monotherapy and platinum-based chemotherapy. For example, in NGR-GY004 study, the median PFS of PARPi monotherapy for platinum-sensitive recurrent ovarian cancer patients with BRCA1/2 mutations was better than platinum-based chemotherapy, and the ongoing OPAL-C trial (NCT03574779) is exploring the superiority of PARPi monotherapy compared to Platinum-Taxane in neoadjuvant chemotherapy for patients with homologous recombination deficiency (HRD)-positive tumors, however, these studies have not yet published the results of overall survival. Recently, the FDA has withdrawn several indications for PARPi monotherapy due to an increased risk of death in patients with more than three lines of chemotherapy [9, 10], so further clarification is needed as to whether patients with prior 2 lines of chemotherapy would have a survival benefit with PARPi monotherapy

Platinum-free interval (PFI) can be used to predict subsequent chemotherapy response and prognosis [11], and prolongation of PFI (using non-platinum-based regimens) might restore platinum sensitivity and improve survival [12]. However, the PARPi regimen is continuous until disease progression or intolerable toxicity [13, 14], so the concept of PFI has become controversial. As a non-platinum-based regimen, PARPi monotherapy after relapse could prolong the PFI, but it was unknown whether platinum-based chemotherapy was still effective after PARPi resistance, and whether it could prolong the survival of patients .Therefore, we conducted this retrospective analysis to try to address these clinically urgent questions.

Student’s t-test was used to compare differences in continuous variables with normal distribution. Differences in clinical characteristics and post- recurrence survival between defined groups of patients were assessed using chi-square test and Kaplan–Meier methods, where appropriate, and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. In univariate analysis, p value 0.10 was defined as the upper limit for inclusion in multivariate analysis, in the latter, p<0.05 was considered significant. The SPSS program (version 16.0) was used for all statistical analysis. The significance levels were * p < 0.05 and ** p < 0.01, respectively.

To our knowledge, this is the first study on the therapeutic effect of PARPi monotherapy compared with platinum-based chemotherapy, and the impact to subsequent platinum-based chemotherapy and survival after the resistance of PARPi in BRCA1/2-mutated patients with secondary platinum-sensitive relapse.

In patients with recurrent BRCA1/2-mutated ovarian cancer, PARPi monotherapy has been studied in several clinical trials, even though the indications have been recently withdrawn [8], and it has also achieved successful application in BRCA-deficient patients with prostate cancer and pancreatic cancer [18, 19]. In BRCA1/2 mutant patients with platinum-sensitive relapse who received at least two lines of platinum-based chemotherapy, the ORR ranged from 56.0% with niraparib to 80.0% with rucaparib [20‐24]. Ovarian cancer patients with BRCA1/2 mutations were inherently more sensitive to platinum-based chemotherapy than patients with wild-type ovarian cancer [25], and the benefits of using PARPi inhibitors versus platinum-based chemotherapy at the same relapse stage were still uncertain. In our study, for patients with secondary platinum-sensitive relapse, the ORR was 77.5% and 80.0%, and the median PFS was 11.2 and 11.0 months, respectively. The therapeutic effect of PARPi monotherapy and platinum-based chemotherapy was similar.

The mechanisms of PARPi and platinum-based chemotherapy are both related to DNA damage repair, which mainly resulted from a variety of lesions affecting homologous recombination (HR), nonhomologous end joining (NHEJ) for double strand breaks, and mismatch repair (MMR), etc [26] , and the drug resistance mechanisms of PARPi include alterations in DNA damage repair, reactivation of HR, and replication fork protection [27]. Theoretically, PARPi resistance may lead to subsequent platinum-based chemotherapy resistance. In Joo Ern's study [28], BRCA1/2 mutation patients who received 3-11 lines of platinum-based chemotherapy before Olaparib were included. After Olaparib resistance, the ORR of platinum-based chemotherapy was 40% (19/48), and the median PFS was 22 weeks, suggesting that there was still a partial response to platinum-based chemotherapy after PARPi resistance. Another study found that both platinum and non-platinum chemotherapy had a response rate after resistance of PARPi maintenance therapy, with median PFS of 7.0 and 8.5 months, respectively [29]. In our study, the median PFS of platinum-based chemotherapy after PARPi resistance was 7.0 months, which was similar to previous studies, and it was noteworthy that the effectiveness of platinum-based chemotherapy after PARPi resistance was positively correlated with the duration of PARPi administration. These results verified, to some extent, that although platinum-based chemotherapy had cross-resistance with PARPi, the application of PARPi would not have negative impact on the efficacy of platinum-based chemotherapy in the posterior line. Besides, it is worth noting that with the development of next-generation sequencing technologies such as genomics, metabolomics, and especially proteomics, it is hoped that accurate choices can be provided for the treatment of PARPi-resistant patients [30].

PFS is currently the most widely used primary endpoint in clinical trials of PARP inhibitors, and most clinical studies have been conducted in recent years, so data on OS are still limited. Based on the limited OS data, the FDA withdrew Niraparib, as well as Olaparib and Rucaparib for ovarian cancer patients after three lines of treatment or more, following an increased risk of death [9, 10]. In our study, survival analysis confirmed that PARPi monotherapy significantly prolonged the survival of patients with BRCA1/2 mutations with secondary platinum-sensitive relapse, and patients who received PARPi treatment in the posterior lines also had a better prognosis than those without PARPi history, which has guiding significance for clinical decisions.

Factors affecting survival of ovarian cancer patients included tumor histology, FIGO stage, BRCA mutation status, ascites, and whether no residual lesions could be achieved after primary debulking surgery [31]. In a study with up to 10 years of follow-up, the initial survival advantage in patients with BRCA1/2 mutations may reflect a higher initial sensitivity to chemotherapy, but this response does not predict long-term survival, the strongest predictor of long-term survival was no residual lesions at resection, however, widespread treatment of PARPi was not involved in this study [32]. Our study demonstrated that treatment with PARPi was the independent factor affecting the prognosis of BRCA1/2 mutant patients, which in part reflects the superior efficacy of PARP inhibitors in this population.

To a certain extent, our research has significant advantages. The most significant limitation of our retrospective study was the limited number of patients. BRCA1/2 mutations account for less than 30% of ovarian cancer patients [33], and those who did not met the criteria for secondary platinum-sensitive relapse were excluded, as were those on maintenance therapy with PARPi or bevacizumab. In addition, it was difficult to collect treatment information after the progression of PARPi. Although the results of the analysis in our study were significantly different, further studies with large samples should be necessary. The findings of this study were applied only to a specific subset of the ovarian cancer patient population, not to all patients in general.

For patients with BRCA1/2-mutated ovarian cancer with secondary platinum-sensitive recurrence, the therapeutic effect of PARPi monotherapy and platinum-based chemotherapy was similar. PARPi monotherapy does not negatively affect the efficacy of subsequent platinum-based chemotherapy after the progression of PARPi monotherapy, and could improve prognosis.