Prolonged Progression-Free Survival in a Patient with Highly Pretreated Recurrent Ovarian Cancer after Developing Multisystem Immune-Related Adverse Events: A Case Report and Literature Review Open Access

Ovarian cancer, one of the most common malignancies among females, has remained the leading cause of gynecological cancer-related deaths. Given that approximately half of patients are diagnosed with advanced disease, ovarian cancer has a 5-year survival rate of approximately 49%. Historically, debulking surgery and platinum-taxane-based chemotherapy have been the standard therapies for advanced or recurrent epithelial ovarian cancer. Over the last decade, however, poly (ADP-ribose) polymerase inhibitors (PARPi) and anti-angiogenic drugs have been proven effective against recurrent ovarian cancer, thereby altering the treatment landscape. Immune checkpoint inhibitors (ICIs) have shown limited efficacy for recurrent ovarian cancer and have only been approved for mismatch repair-deficient/microsatellite instability-high or high tumor mutational burden (≥10 mutations/Mb) ovarian cancer. Although current evidence fails to validate ICI-chemotherapy combinations, emerging evidence demonstrates synergistic antitumor efficacy when combining ICIs with either PARP inhibitors or antiangiogenic [1]. This therapeutic potential is supported by the Phase III DUO-O trial (NCT03737643), which demonstrated significantly improved progression-free survival (PFS) among newly diagnosed non-BRCAm advanced ovarian cancer patients receiving paclitaxel/carboplatin/bevacizumab/durvalumab induction followed by bevacizumab/durvalumab/olaparib maintenance than among those receiving paclitaxel/carboplatin/bevacizumab with bevacizumab maintenance alone [2]. Additionally, preliminary evidence indicates that combining dual immunotherapy with chemotherapy may confer survival benefits [3]. Currently, multiple phase III randomized trials are investigating various ICI-based combination regimens for ovarian cancer management, though definitive results remain pending.

Immune-related adverse events (irAEs) have been associated with longer overall survival (OS) and PFS, as well as better objective response rates across various tumor types. However, these studies have mainly focused on non-small cell lung cancers (NSCLCs), melanomas, esophageal carcinomas, and hepatocellular carcinomas (HCCs), for which ICIs are widely used. Only a few studies have explored the effects of irAEs on ovarian cancer. In this report, we present a case involving a patient with recurrent ovarian cancer who showed notably prolonged PFS after developing multisystem irAEs.

In July 2013, a 47-year-old woman presented to our institution with recurrent lower abdominal pain. She underwent exploratory laparotomy, which revealed her unsuitability for debulking surgery. The patient was then diagnosed with FIGO stage III poorly differentiated ovarian adenocarcinoma. Thereafter, palliative chemotherapy with paclitaxel liposomes, cisplatin/nedaplatin, S-1/raltitrexed, irinotecan, doxorubicin, and vinorelbine was administered successfully from 2013 to 2019 (Fig. 1). The first debulking surgery was performed in March 2015, followed by a second one in February 2019. Histopathological examination revealed high-grade serous papillary carcinoma of the ovary.

Liver metastases were first detected in May 2020. Core biopsy of the lesion confirmed the presence of high-grade serous papillary carcinoma of the ovary. Genetic testing revealed low microsatellite instability, a programmed cell death ligand 1 combined positive score of <1, a tumor mutational burden of 6.70 mutations/Mb, and no BRCA mutations. Two cycles of toripalimab (a PD-1 inhibitor) combined with apatinib, gemcitabine, and oxaliplatin were then administered, with subsequent computed tomography (CT) confirming a partial response based on the Response Evaluation Criteria in Solid Tumors (RECIST). After liver metastasis ablation, the patient received three cycles of toripalimab with apatinib and 1 year of maintenance therapy with toripalimab and capecitabine until tumor progression (enlargement of the left iliac paravascular lymph node) in November 2021. The patient developed hypothyroidism (grade 2) after 2 days of toripalimab use, for which thyroid hormone supplementation with levothyroxine was initiated.

From November 2021, she received six cycles of tislelizumab (a PD-1 inhibitor), paclitaxel (albumin-bound), and carboplatin, which promoted a partial response according to the RECIST. Maintenance therapy with tislelizumab combined with olaparib was initiated in May 2022, which stabilized the tumor. However, in February 2023, the patient complained of loss of appetite, general fatigue, and poor sleep and was subsequently diagnosed with adrenal insufficiency based on the examinations showing normal blood adrenocorticotropic hormone levels (2.59 pmol/L, reference range: 1.60–13.90 pmol/L), decreased blood cortisol levels (1.71 μg/dL, reference range: 3.7–19.40 μg/dL), and decreased urine cortisol (1 µg/24 h, reference range: 4.3–176 μg/24 h). Hydrocortisone administration gradually ameliorated the patient’s clinical symptoms. In April 2023, the patient presented with chest tightness, a cough, and a small amount of white phlegm, with CT revealing interstitial lung disease. She was then diagnosed with pneumonitis (grade 4), which prompted the discontinuation of all antitumor treatments. Thereafter, the patient was treated with methylprednisolone, which improved her condition. Since then, the patient had been followed-up through CA125 tests and chest, abdominal, and pelvic CT every 3–4 months. Serum CA125 levels remained low 4 months after discontinuing antitumor treatment (Fig. 2), with CT confirming that the tumor remained stable until November 2023 (Fig. 3). The patient expressed that, since the onset of her cancer, she was the happiest she had ever been over the 7-month period in which her antitumor treatment was stopped.

This report presents a case involving a patient with highly pretreated, non-gBRCAm recurrent ovarian cancer who exhibited prolonged PFS after developing three irAEs, namely, hypothyroidism, adrenal insufficiency, and pneumonitis. The patient exhibited a PFS of approximately 24 months with tislelizumab-containing therapy and 18 months with tislelizumab plus olaparib maintenance, which were notably superior outcomes than those reported in comparable studies. For context, despite employing a similar design involving six cycles of platinum-based chemotherapy plus atezolizumab followed by maintenance niraparib plus atezolizumab for recurrent ovarian cancer patients, the phase III ANITA trial (NCT03598270) reported a median PFS of 11.2 months in the intention-to-treat population and 11.1 months in the non-gBRCAm cohort, with maintenance PFS lasting only 6.7 months [4]. Similarly, the MEDIOLA phase II trial (NCT02734004), which administered olaparib plus durvalumab in two cohorts, yielded a median PFS of 15.0 months (gBRCAm cohort) and 5.5 months (non-gBRCAm cohort) [5]. Although emerging evidence suggests that irAEs may confer survival benefits across multiple cancer types, neither the ANITA nor MEDIOLA trial included preplanned irAE subgroup analyses, leaving the relationship between irAEs and clinical benefit unresolved. However, exploratory analyses in these studies indicated that cohorts with higher irAE rates had longer PFS (Table 1). To date, the relationship between irAE development and survival in ovarian cancer remains unclear. Here, we review available literature on the association between survival outcomes and irAE development, irAE types, irAE numbers, and irAE severity.

Patients with locally advanced or metastatic NSCLC with irAEs have demonstrated better treatment outcomes than those without irAEs. In fact, a retrospective observational cohort study of 803 patients suggested that irAEs were correlated with improved OS, with a median OS of 23.7 and 9.8 months in those with and without irAEs, respectively (p < 0.001) [6]. Moreover, a study on patients with urothelial cancer found that those who developed irAEs had a significantly better OS than those who did not (hazard ratio 0.53, 95% CI: 0.43–0.66) and that the use of systemic corticosteroids had no effect on this benefit [7]. Similarly, among patients with esophageal carcinoma, those with irAEs had longer OS and PFS than those without irAEs [8]. Another study showed that the development of irAEs following atezolizumab combined with bevacizumab, which has become the first-line therapy for advanced HCC, was associated with improved OS and PFS in HCC patients [9]. Likewise, melanoma patients who experienced irAEs had significantly better OS than those who did not [10]. Taken together, these findings suggest that irAEs were often associated with enhanced clinical outcomes across a range of cancers, although the underlying mechanisms have remained an area of active research.

Endocrine and cutaneous irAEs have been widely reported to be associated with improved survival outcomes. One study found that both irAEs were associated with longer PFS and OS in patients with esophageal squamous cell carcinoma [8]. Another study found that HCC patients with hypothyroidism showed longer OS and time to progression than did those without irAEs [11]. Two retrospective studies on metastatic NSCLC demonstrated that patients who developed endocrine irAEs had significantly better OS and PFS than those who did not and that cutaneous irAEs were notably correlated with longer PFS but were not significantly associated with OS [12]. A systematic review of studies involving 3,815 patients with metastatic lung cancer or head and neck cancer who received ICIs identified a significant positive correlation between OS and endocrine irAEs [13]. Overall, these findings suggest that while endocrine and cutaneous irAEs may serve as markers for better clinical outcomes in certain types of cancers, their associations with survival can vary depending on the type of irAE and cancer.

Several studies have shown that mild irAEs can serve as predictive markers of improved immunotherapy efficacy across various tumor types. Among patients with HCC, grade 1/2 irAEs were strongly correlated with better OS than were grade 3/4 irAEs [9]. A pooled analysis of the IMpower130, IMpower132, and IMpower150 trials only patients with metastatic NSCLC who experienced low-grade irAEs demonstrated an increase in OS [14]. However, a recent retrospective study of 803 patients with metastatic NSCLC reported no significant difference in OS between outpatients and those being treated for irAEs in the hospital [6]. Another study found no significant difference in OS or PFS between patients with esophageal squamous cell carcinoma who experienced grade 1/2 and grade ≥3 irAEs [8]. Collectively, these results suggest that while low-grade irAEs may be associated with improved survival outcomes in certain types of cancers, the relationship between irAE grade and survival benefits can vary depending on cancer type and treatment context.

Two studies have consistently demonstrated that irAE number was positively correlated with increased OS and PFS in patients with advanced NSCLC [12, 15]. Similarly, 1 study reported that patients with multisystem irAEs, one irAE, and no irAEs had a median PFS of 10.9, 5.1, and 2.8 months (p < 0.001) and an OS of 21.8, 12.3, and 8.7 months, respectively [15]. Among patients with advanced melanoma, those who experienced ≥3 irAEs had longer OS than did those who experienced no or only one irAE [10]. However, 1 study on patients with esophageal cancer found no significant difference in OS or PFS between those with multisystem irAEs and those with only one irAE [8]. Altogether, these findings suggest that although a higher number of irAEs was generally linked to improved survival in certain types of cancers, the association may vary depending on cancer type.

This report presents a case involving a patient with highly pretreated non-gBRCAm recurrent ovarian cancer who demonstrated prolonged PFS after developing three irAEs. The markedly extended PFS observed in this case, along with the findings of our literature review, suggests a potential correlation between irAE occurrence and improved survival outcomes in patients with ovarian cancer. We recommend that future clinical trials incorporate irAE-based stratification to validate this relationship in larger populations. Additional mechanistic studies are warranted to elucidate the underlying biological mechanisms for this relationship.

The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546423).

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethical approval to report this case was obtained from the Ethics Committee of The Seventh Affiliated Hospital of Sun Yat-sen University (KY-2025-020-01).

The authors have no conflicts of interest to declare.

This work was supported by the National Natural Science Foundation of China (32200583) and Shenzhen Science and Technology Program (Grant No. JCYJ20230807110312026).

Writing: M.L.; review and editing: S.F. and H.D.; investigation: M.L., S.F., and H.D.; data curation: T.L. and C.G.; and supervision: B.W. All authors have read and agreed to the published version of the manuscript.

Minling Liu, Shuo Fang, and Huiru Dai contributed equally to this work and share first authorship.

All data supporting the findings in this case report are contained within the text. Additional data are available upon request from the corresponding author.