Abstract
Background: Polyadenosine 5′-diphosphoribose polymerase inhibitors (PARP-Is) are novel, effective agents for treating newly diagnosed epithelial ovarian cancer (EOC). However, the effect of PARP-I on the progression of recurrent EOC has not yet been determined. In particular, there is limited evidence regarding retreatment with PARP-I for recurrent EOC that has progressed on PARP-I in the short term. Case Report: A 69-year-old woman with a BRCA1 mutated EOC relapsed five months after starting olaparib maintenance following neoadjuvant chemotherapy and interval debulking surgery. Although the platinum-free interval was within six months, secondary cytoreductive surgery was performed because the tumor was locoregional. Following two cycles of weekly nedaplatin, niraparib induced a complete response, and the patient maintained a progression-free status for 15 months. Conclusion: Even with short-term progression on PARP-I, local control combined with different platinum agents and PARP-I can be used to achieve good responses.
Polyadenosine 5′-diphosphoribose polymerase inhibitors (PARP-Is) are novel, effective agents against epithelial ovarian cancer (EOC). Clinical trials have demonstrated the efficacy of PARP-I as a first-line therapy (1-3). In the SOLO1 trial, olaparib improved overall survival (OS) and progression-free survival (PFS) in patients with EOC with BRCA mutations (BRCAmt). However, >40% of patients with EOC with BRCAmt have disease progression within three years, even with olaparib maintenance (4). There is limited evidence for retreatment with PARP-I for recurrent EOC that has progressed after PARP-I administration. The OReO trial, the only prospective study of olaparib administration after PARP-I treatment, included patients with non-mucinous, platinum-sensitive, recurrent EOC with one prior PARP-I maintenance in response to their most recent platinum-based chemotherapy. This trial reported that olaparib significantly improved PFS; however, the median PFS prolongation effect was limited, ranging from 2.8 months on placebo to 4.3 months on olaparib in patients with BRCAmt (5). Nonetheless, there is little evidence for retreatment with PARP-I for recurrent EOC that has progressed in the short term. Herein, we present a case of BRCA1-mutated recurrent EOC that progressed with short-term olaparib maintenance therapy and was successfully treated with weekly nedaplatin and niraparib maintenance therapy after secondary cytoreductive surgery (SCS).
Case Report
A 69-year-old woman with bilateral ovarian tumors, multiple disseminations in the abdominal cavity, massive ascites, and multiple lymphadenopathy was referred to our hospital in February 2021. Her serum cancer antigen 125 (CA-125) was elevated at 4,685 U/ml. According to the 2014 criteria of the International Federation of Gynecology and Obstetrics, stage IIIC EOC was diagnosed because of peritoneal dissemination without distant metastases (Figure 1).
Computed tomography, magnetic resonance imaging, and positron emission tomography. (A, B, C) Before neoadjuvant chemotherapy. (D, E, F) After three cycles of paclitaxel and carboplatin.
She had previously undergone treatment for right breast cancer at the age of 44 years and for left breast cancer at the age of 56 years. She had a family history of breast and ovarian cancer. Therefore, a germline BRCA status test was performed using the BRACAnalysis (Myriad Genetics, Inc. Salt Lake City, UT, USA), which revealed a pathogenic BRCA1 variant, c.188T>A (p.Leu63*):NM_007294.3.
Paclitaxel (175 mg/m2) and carboplatin (area under the curve, 6), commonly refer to as TC therapy, was initiated as neoadjuvant chemotherapy. After three courses of TC therapy, computed tomography (CT) revealed that the tumor had shrunk and that the ascites had disappeared (Figure 1). Two months after four courses of TC therapy, she underwent interval cytoreductive surgery, which included abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right and left hemicolectomy, sigmoid colectomy, disseminated lesion resection, and colostomy, and complete surgery was achieved. The histopathological diagnosis was high-grade serous carcinoma. Postoperatively, the patient underwent another three courses of TC therapy, which resulted in a partial response with no gross lesions but no normalization of serum CA-125 (56 U/ml), and maintenance therapy with olaparib was initiated.
Five months after olaparib initiation, a slight increase in serum CA-125 levels was observed, and CT revealed an enlarged tumor (Figure 2) but no other obvious lesions. Positron emission tomography revealed 18-F-fluorodeoxyglucose (FDG) accumulation in the tumor without other pathogenic accumulations of FDG, leading to the diagnosis of recurrent EOC. The platinum-free interval (PFI) was under six months, and the patient was deemed to have a platinum-resistant recurrence (PRR) based on the diagnosis in place prior to the advent of PARP-I (6). However, SCS was performed after laparoscopy to diagnose the resectability of the tumor because it was locoregional. Laparoscopy revealed no disseminated lesions in the peritoneum or mesentery, allowing for the possibility of complete tumor resection. Additionally, the results of washing cytology were negative. After conversion to laparotomy, the enlarged hepatoduodenal mesenteric lymph node was completely resected. The histopathological diagnosis was high-grade serous carcinoma with EOC metastasis. One month after SCS, weekly nedaplatin (7) was initiated, after which serum CA-125 levels normalized. One month after the completion of two courses of weekly nedaplatin, serum CA-125 was slightly elevated (28 U/ml), and CT revealed a new, nodular lesion in the pelvis (Figure 2). Although the evaluation was progressive disease based on the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), weekly nedaplatin was judged to be effective for normal serum CA-125 level maintenance, and oral niraparib (200 mg/day) was started. Two months later, CT revealed that the lesion had shrunk, serum CA-125 had normalized, and a partial response was observed. Fifteen months after initiating niraparib treatment, the patient achieved a complete response and maintained a progression-free status (Figure 3). Adverse events during niraparib treatment included grade 2 thrombocytopenia, which improved with a two-week rest from niraparib, after which it was safely continued.
Computed tomography of the tumor. (A) Five months after olaparib initiation. (arrowheads, metastatic hepatoduodenal mesentery lymph node). (B) Before niraparib initiation (arrows, pelvic lesion). (C) Six months after niraparib initiation (arrows, pelvic lesion).
Clinical flowchart of the patient. CA-125: Cancer antigen-125; ICS: interval cytoreductive surgery; PFS: progression-free survival; SCS: secondary cytoreductive surgery; TC: paclitaxel and carboplatin; wNDP: weekly nedaplatin.
Discussion
This case suggests that niraparib following weekly nedaplatin administration is effective for BRCA1-mutated recurrent EOC that has progressed on olaparib in the short term. In this case, the PFS with PARP-I retreatment was longer than that with prior PARP-I administration even if a novel lesion appeared soon after completion of the platinum regimen. Normal serum CA-125 during platinum administration suggested platinum sensitivity, which may have been the key to successful PARP-I re-treatment.
PARP-Is are widely used as maintenance therapy after cytoreductive surgery and platinum-based chemotherapy in patients with newly diagnosed EOC (1-3). In particular, the efficacy of olaparib maintenance was demonstrated in newly diagnosed patients with advanced EOC and BRCAmt in the SOLO1 trial, showing that olaparib significantly prolonged PFS [56.0 vs. 13.8 months; hazard ratio (HR)=0.33; 95% confidence interval (CI)=0.25-0.43] (1). In addition, updated data revealed OS prolongation (not reached vs. 75.2 months; HR=0.55; 95%CI=0.40-0.76; p=0.004) (4). However, approximately 10% of cases developed lesions at 12 months, 20% at 18 months, and 40% at 36 months (4). As in the present case, disease progression has been observed within a short period in some cases (4).
PFI is the only factor that determines eligibility for platinum readministration. Because PRR is defined as disease recurrence or progression within six months of the end of previous platinum-based chemotherapy (6), treatment choices are generally based on the PRR for disease progression within six months of PARP-I administration. Treatment strategies are limited for patients with PRR. Although non-platinum single-agent chemotherapies, including pegylated liposomal doxorubicin, gemcitabine, paclitaxel, and topotecan, can be used, their efficacy is limited; the PFS is only approximately four months (8). In the AURELLIA study, the efficacy of a non-platinum agent combined with bevacizumab was demonstrated; however, its efficacy was limited to a PFS prolongation of approximately three months (9). Nonetheless, caution is required because these findings are based on reports before the advent of PARP-I. The decision to readminister platinum should be based on various factors besides PFI, such as histology, BRCA status, prior response, and symptoms (6). Goto et al. showed that nedaplatin treatment for platinum/taxane-resistant/refractory epithelial ovarian, tubal, and peritoneal cancers achieved 24% of the overall response rate, 59% of the disease control rate and 8 months of PFS (10). They concluded that nedaplatin can be a salvage chemotherapy agent. Additionally, Soeda et al. reported the efficacy of weekly nedaplatin followed by olaparib in the treatment of platinum-resistant, recurrent EOC (7). Their patients had no evidence of disease for >6 months after starting olaparib, despite their platinum-resistant status. It should be noted that the present case was a platinum-resistant case that progressed rapidly, even during the transition period from chemotherapy to maintenance therapy. However, the fact that serum CA-125 levels remained normal during the recent platinum regimen suggests that the patient was platinum-sensitive and may be an important predictor of the efficacy of PARP-I retreatment.
Recently, it has been reported that in recurrent settings, the response to chemotherapy for progression after PARP-I was lower than that for progression without PARP-I (11, 12). In particular, patients with BRCAmt have a lower response rate to subsequent platinum-based agents and worse survival outcomes than patients without BRCAmt (13). However, in the same report, 14.3% of patients with BRCAmt who received subsequent platinum therapy achieved a complete response, compared to 2.6% of patients with wild-type BRCA. This suggests that some patients with BRCAmt respond well to the readministration of platinum-based agents, even if they progress during PARP-I maintenance. This indicates that platinum sensitivity may be maintained in patients with BRCAmt. Additionally, the OReO study demonstrated that olaparib administration after PARP-I treatment following platinum-based chemotherapy prolonged the PFS in patients with recurrent ovarian cancer, regardless of their BRCA status. However, the trial only extended PFS from 2.8 to 4.3 months in patients with BRCAmt and did not include relapsed cases after <6 months of olaparib treatment (5). A retrospective study demonstrated the efficacy of retreatment with PARP-I in patients with recurrent EOC by reporting that five of 26 patients (17.2%) achieved longer PFS after PARP-I retreatment initiation than PFS of the first PARP-I. However, these patients did not meet the inclusion criteria of the OReO study. Furthermore, in three of these five patients, PARP-I was reinduced following local therapy for recurrence (14). Recently, the efficacy of local therapy for oligometastatic disease progression during PARP-I maintenance was reported (15); local therapies, such as surgery and radiation therapy, prolonged the median PFS by nine months. In the present case, niraparib was administered after nedaplatin treatment following SCS. The combination of local control and readministration of PARP-I may be effective for the local recurrence and progression of PARP-I.
Conclusion
Some patients may benefit from niraparib for BRCA1-mutated EOC progressing on olaparib. In cases of progression within a short period of PARP-I administration, switching to another platinum agent and PARP-I following SCS would be a novel therapeutic strategy for patients with BRCAmt. Further studies are required to identify the treatment options for recurrent EOC progression during PARP-I administration.
Acknowledgements
The Authors would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
Yuta Endo: Investigation, Data Curation, Writing – original draft, Writing – review and editing, Visualization. Norihito Kamo: Investigation, Visualization. Asami Kato,Tetsu Sato, Chikako Okabe, Shigenori Furukawa, Takafumi Watanabe: Investigation. Shu Soeda: Conceptualization, Investigation, Supervision, Writing – review and editing.
Conflicts of Interest
The Authors declare no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Received November 21, 2023.
- Revision received December 21, 2023.
- Accepted December 22, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
