Abstract
Background/Aim: To assess response rates and survival in patients with recurrent platinum-sensitive epithelial ovarian cancer (EOC) who received PARP inhibitor (PARP-i) maintenance and who subsequently underwent salvage chemotherapy for disease progression after PARPi. Patients and Methods: This retrospective investigation analyzed 103 patients who were treated in five Italian Gynecologic centers. The PARPi used was olaparib in 46 patients, niraparib in 55, and rucaparib in 2. The interval time between the last cycle of pre- PARPi platinum–based chemotherapy and the diagnosis of progression during PARPi maintenance was defined as platinum–free interval (PFI). Results: Of the 28 patients with PFI <6 months, 23 received chemotherapy (non-platinum single agent, 20; trabectedin + pegylated liposomal doxorubicin (PLD), 3). Forty-two of the 43 patients with PFI 6-12 months underwent chemotherapy (platinum–based chemotherapy,11; trabectedin + PLD, 10; non platinum–single agent, 21). Thirty-one of the 32 patients with PFI >12 months received chemotherapy (platinum-based chemotherapy, 23; trabectedin + PLD, 3; non platinum – single agent, 5). An objective response was found in 13.0%, 26.2% and 41.9 % of the patients with PFI <6 months, 6-12 months, and >12 months (p= 0.03), respectively, and the corresponding median survivals after PARPi were 8.9 months, 17.5 months and 24.1 months (p= 0.002), respectively. Conclusion: Before the PARPi era, some randomized trials on platinum rechallenge in patients with recurrent EOC after more than 6 months from the last platinum cycle have shown response rates ranging from 47.2% to 66%. Response rates to chemotherapy for progression after PARPi appear to be lower than those expected according to PFI.
Poly(ADP-ribose) (PAR) polymerase (PARP) inhibitors (PARPi) are widely used as maintenance treatment after platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer (EOC) (1–6). Randomized placebo-controlled trials in this clinical setting have shown that olaparib significantly improved the progression free survival (PFS) of patients with mutated BRCA EOC with hazard ratio (HR)s ranging from 0.18 [95% confidence interval (CI)=0.10-0.31] to 0.30 (95%CI=0.22-0.41) (2, 3), whereas niraparib and rucaparib significantly improved PFS regardless of either BRCA status or homologous recombination status (4, 6). However, the HR for the risk of progression associated with niraparib ranged from 0.27 (95%CI=0.17-0.41) for BRCA-mutated patients to 0.38 (95%CI=0.24-0.59) for non-BRCA mutated patients with homologous recombination deficiency to 0.45 (95%CI=0.34-0.61) for the overall non-BRCA cohort (4), and similarly the HR for the risk of progression associated with rucaparib was 0.23 (95%CI=0.16-0.34) for BRCA-mutated patients, 0.32 (95%CI=0.24-0.42) for patients with homologous recombination deficiency, and 0.36 (95%CI=0.30-0.45) for intention to treat population (6). Approximately, 15-20% of patients with platinum-sensitive recurrent EOC experienced a long-term response to PARPi lasting at least two years (7, 8). However, the patients who recur after PARPi appear to be less sensitive to further therapy (9, 10).
This retrospective multicenter investigation assessed the response to subsequent chemotherapy and the clinical outcome of patients with EOC who progressed after PARPi given as maintenance treatment after response to platinum re-challenge for platinum-sensitive recurrent disease.
Patients and Methods
This retrospective study was conducted on 103 patients who i) underwent surgery and platinum-based chemotherapy for primary FIGO stage IIB-IV EOC; ii) received one or more lines of platinum-based chemotherapy for recurrent platinum-sensitive disease; iii) received at least 3 cycles of PARPi maintenance treatment after partial or complete response to the last platinum-based chemotherapy; and iv) subsequently underwent additional treatment for disease progression at the Departments of Gynecology and Obstetrics of the Universities of Pisa, Brescia, Milano (Monza) and Torino (Mauriziano Hospital), and the Division of Medical Oncology of Lecco Hospital between 2011 and 2019.
The hospital records, including surgical notes, pathological reports, chemotherapy and follow-up data, were collected using a common form with standardized items and a common database. The tumor stage and histological diagnosis of each case were determined according to the FIGO criteria and the histological typing system of the World Health Organization (WHO), respectively. The baseline characteristics (age, FIGO stage, histological type, tumor grade, presence or absence of ascites, germline and/or somatic BRCA1-2 status, timing of surgery (primary versus interval debulking), residual disease after surgery, and type of first-line chemotherapy were reported for each case. After completion of primary treatment, all the patients were followed-up at regular scheduled intervals with the modalities reported in a previous study (11). Only the patients with clinical and/or radiological evidence of relapse were included in the present analysis. The sites of recurrence and the chemotherapy regimens for recurrence after PARPi were reported for each patient. Median follow-up of survivors was 14,7 months (range=3.0-30.5 months).
Statistical analysis. IBM SPSS Statistics (Chicago, IL, USA) was used for computations. The interval between the last cycle of platinum–based chemotherapy before PARPi maintenance treatment for recurrent disease and the clinical and/or radiological diagnosis of progression during PARPi maintenance was defined as platinum–free interval (PFI). The interval between the diagnosis of progression during PARPi maintenance and death or last follow-up was defined as survival after PARPi. Response rate to chemotherapy after PARPi was correlated with PFI using Pearson’s Chi square test (or two-tailed Fisher’s exact test when appropriate). The cumulative probability of survival after PARPi was estimated by the product-limit method and the log-rank test was used to compare the survival by PFI.
Results
Table I and Table II show patient characteristics at presentation and at disease progression after PARPi maintenance treatment, respectively. The PARPi used was olaparib in 46 patients (all with mutated-BRCA), niraparib in 55 (54 with wild-type BRCA, one with mutated-BRCA) and rucaparib in two (both with wild-type BRCA). As shown in Table III, of the 28 patients with PFI <6 months, 23 received chemotherapy, consisting of non-platinum single agent in 20 (87.0%) and trabectedin + pegylated liposomal doxorubicin (PLD) in 3 (13.0%). Forty-two of the 43 patients with PFI between 6 and 12 months underwent chemotherapy, consisting of platinum–based chemotherapy in 11 (26.2%), trabectedin + PLD in 10 (23.8%) and non-platinum single agent in 21 (50.0%). Thirty-one of the 32 patients with PFI >12 months received chemotherapy, consisting of platinum-based chemotherapy in 23 (74.2%), trabectedin + PLD in 3 (9.7%), and non-platinum single agent in 5 (16.1%).
An objective response of 13.0%, 26.2% and 41.9% of patients with PFI <6 months, between 6 and 12 months, and >12 months (p= 0.03), respectively, was found (Table IV). Survival after PARPi is reported in Table V. Median survival after PARPi was 8.9 months, 17.5 months and 24.1 months (p= 0.002), respectively, for patients with a PFI <6 months, between 6 and 12 months, and >12 months.
Discussion
Before the PARPi era, some randomized trials on platinum rechallenge in patients with recurrent EOC after more than 6 months from last platinum cycle have shown response rates ranging from 47.2% to 66% (12–16). PARPi maintenance significantly improves PFS in patients responsive to platinum re-treatment (1–6), but pharmacological mechanisms of resistance could reduce the sensitivity to further chemotherapy for tumor progression after PARPi (17–25). In particular, secondary reversion mutations of BRCA, and more rarely of RAD 51, can induce a genetic frameshift and restore the open reading frame of the genes, thus leading to expression of functional proteins, rendering tumors homologous recombination proficient and enhancing the resistance to both PARPi and platinum-based chemotherapy (23–28).
An Italian retrospective study conducted by Cecere et al. (9) analyzed the response rates to additional chemotherapy in 66 patients with BRCA-mutated EOC who relapsed following olaparib maintenance after one or more lines of platinum-based therapies Salvage treatment consisted mainly of platinum–based chemotherapy in the patients with PFI >12 months, either platinum-based chemotherapy or trabectedin ±PLD in those with PFI of 6-12 months, and non-platinum single agent in those with PFI <6 months. The response rates were 9.5%, 11.1% and 22.2% in patients with PFI <6 months, 6-12 months, and >12 months, respectively, and therefore they were lower than expected according to PFI.
The phase 3 SOLO2 trial that enrolled 295 platinum-sensitive, relapsed BRCA-mutated EOC patients in complete or partial response to their most recent platinum-based regimen, showed that olaparib maintenance provided a significant PFS improvement with no detrimental effect on quality of life (3). Recently, Frenel et al. (10) assessed women who failed after PARPi or placebo. Subsequent chemotherapy was platinum-based in 63% of the patients of the olaparib arm and in 56% of those of the placebo arm. Time to subsequent progression was longer in the placebo arm compared to olaparib arm in the whole series (HR=2.17; 95%CI=1.47-3.19) and even more in the patients who received salvage platinum-based chemotherapy (HR=2.89; 95%CI=1.73-4.82).
In the present retrospective multicenter study, that included both patients with mutant-BRCA and those with wild-type BRCA, response rates to chemotherapy for progression after PARPi were 41.9% and 26.2% in patients with PFI >12 months and between 6 and 12 months, respectively, and the corresponding 2-year PFS rates were 57.3% and 47.3%, respectively. These response rates were better than those reported by Cecere et al. (9) (11.1-22.2%), but worse than those reported with platinum re-treatment before the PARPi era (47.2%-66%) (12–16). In any case some degree of resistance to subsequent chemotherapy can occur in patients who recur after PARPi maintenance. The strengths of the study are the relatively large number of patients and the fact that patient information was collected using a common form with standardized items and a common database, whereas the weaknesses of the investigation are represented by its retrospective nature, by the different PARPi used and by the different salvage chemotherapy regimens administered after PARPi. Multicenter studies on larger series of patients, stratified for BRCA status and chemotherapy regimens used after PARPi, are strongly recommended to better define the clinical and biological behavior of recurrent EOC after PARPi.
Footnotes
Authors’ Contributions
Study concepts: AG; Study design: AG, Recruitment and quality control of data: SC, AAL, MEL, AA, AGambino. Data analysis and interpretation: AG, FL, AAL, PZ, ES; Statistical analysis: AG, SC; Article preparation: AG; Article editing: All Authors; Article review: All Authors.
Conflicts of Interest
The Authors declare no conflicts of interest regarding this study.
- Received February 7, 2022.
- Revision received February 21, 2022.
- Accepted March 2, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.