Platinum-resistant ovarian cancer in China: Practice and challenges

Ovarian cancer (OC) is a lethal threat to females. According to the 2022 Global Cancer Observatory (GLOBOCAN), new cases of OC were estimated to reach 324,398, with mortality figures at 324,3987. China, with one-fifth of the world population, is bearing a heavy OC health burden, accounting for 18.82% of all OC new cases and 15.8% of OC-related deaths worldwide.[1] The OC incidence and mortality in China increased by 6.3% and 20% in the time intervals from 2016 to 2022, with a significant disparity between urban and rural areas in China[2] [Supplementary Figure 1A, https://links.lww.com/CM9/C570]. The new cases and deaths will reach 70,822 and 46,845 by 2050, respectively [Supplementary Figure 1B, https://links.lww.com/CM9/C570]. Moreover, females are more susceptible to OC at ages above 50 years [Supplementary Figures 1C and D, https://links.lww.com/CM9/C570]. Notably, nearly 50–70% of OC patients suffer from disease recurrence and will ultimately develop platinum resistance, causing over 90% of deaths with a median survival of less than 12 months. Currently, early detection and screening strategies in China are insufficient. Many OC patients are diagnosed at advanced stages, leading to a poor prognosis.[3] For many years, the treatment of the newly diagnosed OC centered on cytoreductive surgery followed by platinum-based chemotherapy. However, chemoresistance is very common. Over the past six years, our research team has been extensively engaged in the mechanism underlying OC and platinum resistance. Recent investigations from our laboratory have demonstrated that certain forms of cell death, such as autophagy[4] and PANoptosis,[5] could regulate platinum resistance in OC. Besides cell death, the currently recognized consensus believes chemoresistance is a complicated network that involves various mechanisms, including alteration of drug influx and efflux pathways, deoxyribonucleic acid (DNA) repair, epigenetic alterations, tumor microenvironment, and abnormal signaling pathways, such as phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) [Figure 1]. Therefore, understanding the current platinum-resistant ovarian cancer (PROC) treatment strategies in China [Supplementary Figure 2, https://links.lww.com/CM9/C570] could help develop region-specific prevention and control measures.Figure 1: The mechanisms of drug resistance in ovarian cancer (The figure was drawn by Figdraw [www.figuredraw.com]).Chemotherapy and surgery. The mainstay of treatment for PROC has been the sequential use of cytotoxic agents (non-platinum chemotherapy), with response rates of less than 12%, progression-free survival (PFS) of less than 4 months, and overall survival (OS) of 8–14 months. Although combined therapy could improve survival outcomes, monochemotherapy is still a “popular” option for PROC patients in rural areas of China. The Chinese medical insurance system is structured based on classifying individuals into urban or rural categories. This bifurcation results in significant disparities in the types of medical insurance accessible to individuals, thereby contributing to an uneven distribution of medical resources and health inequities. High-quality medical resources are predominantly concentrated in major urban centers and hospitals, rendering them inaccessible and unaffordable for rural patients. Consequently, elevated mortality rates related to OC were observed among rural populations. Besides, secondary cytoreductive surgery (SCS) is a favorable option in selected PROC patients. R0 resection and postoperative chemotherapy were proven to significantly prolong PFS and OS. Recently, a clinical trial conducted in China was expected to include 140 samples to evaluate the value of SCS in PROC patients (No. NCT05633199). Although those results have not been unveiled, promising outcomes could be expected. Targeted therapies. Increased understanding of the biology of OC has led to the development of some targeted molecules, including antiangiogenic agents, poly (ADP-ribose) polymerase inhibitors (PARPi), antibody-drug conjugates (ADCs), immunotherapies, and signaling pathway inhibitors. Antiangiogenic therapy alone, combined with chemotherapy and PARP inhibitors, could improve the survival outcomes of PROC patients. Antiangiogenic drugs include large-molecule monoclonal antibody drugs (bevacizumab) and small-molecule inhibitors, such as cediranib, pazopanib, apatinib, and anlotinib. In 2007, bevacizumab was proven to have single-agent activity in PROC patients. A meta-analysis compared nine clinical trials and demonstrated that the amalgamation of antiangiogenic agents and chemotherapy resulted in a 45.8% reduction in the hazard of disease progression or death compared to chemotherapy alone in PROC patients. However, due to medical insurance coverage and reimbursement ratio, bevacizumab has not been widely used in China for the past two years. In the meantime, many Chinese independently developed drugs were also tested for PROC treatment. For example, the AEROC study (No. NCT02867956) explored apatinib, a TKI inhibitor, combined with oral etoposide for PROC patients with a 61% objective response rate (ORR) and PFS of 8.1 months, showing promising efficacy, manageable toxicities, and possible home administration.[6] PARPi improved the prognosis of patients with platinum-sensitive OC. Until recently, olaparib and rucaparib were approved by the United States (US) in PROC patients who were not heavily pre-treated for breast cancer gene (BRCA) mutations. Fluzoparib and pamiparib are two self-independently developed PARPi in China with confirmed survival benefits in PROC patients. Moreover, improved prognosis has been exhibited with treatment combining PARP inhibitors with chemotherapy, antiangiogenic drugs, PI3K inhibitors, and immune checkpoint inhibitors in treating PROC patients. For example, the OCTOVA trial (No. ISRCTN14784018) demonstrated the activity of olaparib and cediranib in PROC patients, offering a potential non-chemotherapy option.[7] ADCs, containing an antibody, linker, and drug portion, are designed to target antigens specific to ovarian tumor cells with direct delivery of cytotoxic agents to eradicate tumors without systemic toxicity. Several ADCs are being assessed for PROC patients. Mirvetuximab soravtansine-gynx (MIRV) is the first targeted therapy approved for FRα-positive PROC. MIRASOL trial (No. NCT04209855) compared the efficacy and safety of MIRV with the investigator’s choice of chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan), exhibiting more prolonged overall survival in the MIRV group compared to that in the chemotherapy group (16.46 months vs. 12.75 months).[8] Since then, more scholars have been exploring the response rates of combination therapy of MIRV with pembrolizumab (No. NCT02606305) and chemotherapy (No. NCT02606305), as well as finding other targets, such as a human epidermal growth factor receptor 2 (HER2)-directed ADC. However, an urgent need is to stratify PROC patients with high responses to ADCs and discover effective predictive biomarkers. Currently, immunotherapy, such as pembrolizumab, nivolumab, cediranib, and ipilimumab, has not been recommended for OC treatment based on domestic and international guidelines due to less satisfactory results than expected. However, results from the JAVELIN Ovarian 200 trial[9] showed an improvement in PFS in patients with CD8+ and PD-L1+ tumors, which suggests an “inflamed” tumor phenotype. Therefore, immunotherapy in OC remains the research focus, and many clinical trials are ongoing in China [Supplementary Table 1, https://links.lww.com/CM9/C570]. In addition, alterations in specific signaling pathways, such as PI3K/AKT and MAPK pathways, play a crucial role in multiple cellular processes in OC. Preclinical and clinical studies showed the benefits of using pan-PI3K and mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitors in OC. Other therapies. Traditional Chinese medicine (TCM) has been widely used for disease treatment in China for thousands of years. TCM, such as phellopterin, echinacoside, and puerarin, are promising candidates for PROC patients. However, further clinical research is needed to support their application. Moreover, palliative care is patient-centered care that focuses on enhancing life quality by providing expert management of symptoms, psychosocial support, and assistance with complicated medical decision-making, which is crucial in OC management. However, some barriers exist in China, such as financial costs, the absence of national strategies and guidelines, and a shortage of professional palliative care staff. Clinical trials in China. According to the Chinese Clinical Trial Registry (https://www.chictr.org.cn), 8237 clinical trials have been officially registered since 2005. Despite this, data from clinical trials assessing the safety and efficacy of therapeutic agents in Chinese patient cohorts are typically published 3–5 years later than comparable data from patient cohorts in other countries. For instance, the U.S. Food and Drug Administration approved the antiangiogenesis drug bevacizumab for frontline and maintenance therapy in women with newly diagnosed OC on June 13, 2018. In contrast, the approval by the Chinese Food and Drug Administration was not granted until November 17, 2021, three years later. In response to such delays, China nowadays has implemented improvement strategies to narrow the gap, including optimizing a new clinical trial approval system and several measures to encourage greater participation of Chinese researchers and research centers. A clinical trial with an adequate size of patients, appropriate control subjects, and sufficient duration of follow-up is an ideal way to test new drugs, novel therapy combinations, and technological improvements. Moreover, cancer patients treated in clinical trials live substantially longer than those not treated in trials. Hence, clinical trials seem to be a good choice since few choices are left for PROC patients in China. We summarize the clinical trials for PROC patients at home and abroad [Supplementary Tables 1 and 2, https://links.lww.com/CM9/C570]. PROC patients in China experience high mortality and recurrence risks. Management involves chemotherapy, surgery, targeted therapy, TCM, palliative care, and their combinations, as well as clinical trials. The increasingly updated treatment techniques and standardized treatment methods will bring new hope to PROC patients. Conflicts of interest None. Funding This work was supported by grants from the National Natural Science Foundation of China (No. 82374081) and the Natural Science Foundation of Fujian Province (No. 2023J011257).