Advances in Systemic Therapy for Ovarian Cancer Over the Past Decade: A Clinical and Molecular Perspective.

Epithelial ovarian cancer (EOC) remains a significant global health challenge, characterized by high mortality rates due to its often-late diagnosis and aggressive progression. According to the GLOBOCAN 2022 data, EOC ranks as the eighth most commonly diagnosed cancer and the fifth leading cause of cancer-related death among women globally. The 5-year survival rate remains under 50%, primarily due to asymptomatic progression and diagnosis at advanced stages. It accounts for the highest mortality among gynecological malignancies, with over 300 000 new cases and approximately 200 000 deaths reported annually worldwide [ 1 ]. Despite being less common than other cancers, such as breast cancer, its mortality rate remains disproportionately high due to frequent late-stage diagnoses. This high lethality underscores the urgent need for more effective treatment strategies, especially in the context of rising global incidence and limited early detection methods. Unlike other cancers, EOC lacks effective early screening methods, meaning that many cases are diagnosed at an advanced stage, when treatment options are limited and outcomes are poor. These issues are compounded by the disease’s heterogeneous nature, with various histological subtypes that influence prognosis and response to therapy [ 2 ]. Over the past decade, advances in molecular biology and genomics have reshaped our understanding of EOC, leading to significant shifts in treatment strategies. Historically, the cornerstone of EOC treatment has been surgery followed by platinum- and taxane-based chemotherapy. However, despite initial responses, most patients experience recurrence, often with chemoresistant disease [ 3 ]. To address this challenge, research has increasingly focused on understanding the molecular underpinnings of EOC, particularly the role of BRCA1/2 mutations and homologous recombination deficiency (HRD), which are present in a substantial subset of high-grade serous ovarian cancers [ 4 ]. These genetic insights have facilitated the development of targeted therapies, most notably PARP inhibitors, which have transformed the treatment landscape for patients with BRCA-mutant and HRD-positive tumors [ 5 ]. Despite significant advances, the management of recurrent or chemoresistant EOC remains a clinical challenge. In particular, there is a lack of consensus on effective treatments for patients with non-BRCA mutations or HRD-negative tumors, where traditional chemotherapy offers limited benefit. This highlights the need to better stratify patients using molecular biomarkers and to explore novel therapeutic combinations that can overcome resistance mechanisms. Furthermore, we address the challenges and opportunities associated with personalized medicine in EOC, emphasizing the need for tailored treatment approaches based on the molecular profile of each patient. By integrating the latest research and clinical trials, we aim to provide a comprehensive overview of the current state of EOC treatment and identify future directions that hold promise for improving patient outcomes. Ultimately, it underscores the importance of continued investment in research and innovation to address the unmet needs of EOC patients, particularly those with advanced and recurrent disease [ 6 , 7 ]. This narrative review aims to critically evaluate recent systemic treatment developments in epithelial ovarian cancer, with a particular focus on the clinical utility of PARP inhibitors in genetically stratified patient subgroups (eg, BRCA-mutated and HRD-positive), and to explore emerging strategies to address chemoresistance in HRD-negative populations. It is based on a comprehensive literature search of PubMed, Scopus, and Web of Science databases from 2010 to 2024. Keywords included “epithelial ovarian cancer”, “PARP inhibitors”, “homologous recombination deficiency”, “platinum resistance”, and “targeted therapy”. Relevant clinical trials, reviews, and original research articles were included based on relevance to the topic.

Antibody-drug conjugates (ADCs) provide a significant advancement in targeted therapeutics for EOC by combining the precise targeting of monoclonal antibodies with the powerful cytotoxic effects of chemotherapeutic medicines [ 97 ]. The ADCs are created to target particular EOC cells that have an abundance of antigens, delivering potent cytotoxic agents directly to efficiently target resistant disease while reducing overall toxicity and minimizing adverse effects. Currently, the main foci in ADC development are the folate receptor α (FR-α) and sodium-dependent phosphate transport protein 2B (NaPi2b) ( Table 2 ). Mirvetuximab soravtansine (MIRV) is the primary ADC permitted by the FDA for treating EOC, offering a treatment possibility for most severe epithelial ovarian tumors that exhibit strong FR-α expression [ 98 – 102 ]. The SORAYA study on MIRV showed that woman with platinum-resistant epithelial EOC, whose tumors had high FR-α expression and who had received up to 3 prior lines of therapy, achieved an overall response rate (ORR) of 42% after MIRV treatment [ 103 ]. This rate was notably higher than the response rates seen with standard chemotherapy options. The medication was favorably received by patients, since just 7% discontinued it because of adverse effects. Common treatment-related adverse effects included impaired vision, keratopathy, and nausea [ 103 ]. Two ADCs focused on NaPi2b have been studied in a preliminary phase and demonstrate encouraging therapeutic prospective. Lifeastuzumab vedotin (LIFA) demonstrated a 36% response rate, whereas patients treated with pegylated liposomal doxorubicin had a 14% response rate [ 98 ]. Upifitamab rilsodotin targets NaPi2b and has shown significant therapeutic efficacy. It utilizes an advanced technology with a high drug-to-antibody ratio. This could address the challenges of analyzing complicated biomarkers and the inherent diversity of EOC [ 104 ]. Several trials are currently investigating the use of ADCs in EOC, particularly when the disease is susceptible to platinum-based treatments. MORAb-202 is an antibody-drug conjugate that targets FR-α and is composed of farletuzumab and eribulin linked by a cathepsin B cleavable linkage [ 105 ]. A phase 1 study in Japan showed that MORAb-202 exhibited anti-cancer effects among women with EOC [ 105 ]. Additional non-FR-α ADCs being studied for EOC treatment focus on TROP2, mesothelin [ 106 ], HER2, MUC16 [ 107 ], and others [ 108 – 110 ] ( Table 2 ). Most ADCs have a drug-to-antibody ratio that is typically restricted to a range of 3–4 [ 111 ]. Increasing the drug load is crucial for reducing the development of resistance to chemotherapy in cancer cells, as it can affect the targeting ability of antibodies in ADC design or result in quick clearing by the reticuloendothelial system [ 111 ]. XMT-1536 is an ADC that targets NaPi2b and demonstrated higher anti-cancer efficacy in EOC primary patient-derived xenograft models when compared to another NaPi2b-targeting ADC with a drug-antibody ratio of 3.5. The increased efficacy was linked to the elevated drug-antibody ratio of XMT-1536 [ 112 ]. It is now undergoing phase 3 clinical studies for platinum-resistant EOC ( NCT05329545 ). Further issues related to ADCs involve the potential for antibody-induced immunogenicity and changes in the recognition of antigens by the ADC antibody [ 113 ]. Antibody fragments that target numerous antigens at the same time are being used in the development of ADCs to solve these challenges [ 97 ]. Evaluating the immunogenicity of monoclonal antibodies and the causes of resistance to ADCs before clinical trials is crucial for enhancing ADC development and maximizing clinical outcomes [ 97 ]. Researchers have made significant progress in developing targeted drug conjugate systems. Currently, only Mirvetuximab soravtansine, an ADC containing DM4 as the cytotoxic payload, has been permitted for treating FR-α-overexpressing EOC resistant to initial chemotherapy. Alternative drug conjugation systems (polymer-, peptide-, small-molecule-, and nanoparticle-drug conjugates) have not achieved the same level of success in clinical development as ADCs [ 114 ]. Drug resistance limits the efficacy of anti-cancer treatment of EOC [ 115 ]. The effectiveness of current immunotherapy is affected by the diversity of the tumor microenvironment (TME), which can be classified as: (1) high immune score tumor (‘hot’ tumor with abundant T-cell infiltration and increased B7-H1/PD-L1 expression); (2) medium score tumor (T cells surround the tumor but not infiltrate the TME or presence of low T-cell infiltration in the tumor); or (3) low immune score tumor (‘cold’ tumor with minimal T-cell infiltration and low B7-H1/PD-L1 expression) [ 116 ]. Increased T-cell infiltration and function result in an enhanced response to therapy. EOC is classified as a ‘cold’ tumor, which limits the effectiveness of available immunotherapeutic approaches and constrains their utility in treatment [ 107 , 117 ]. Active immunotherapy identifies antigens on the surface of tumor cells. It triggers reactions to eliminate cancer cells (eg, cancer vaccines, CAR-T cell treatment, trastuzumab, HER-2 targeted antibody, or cetuximab, and epidermal growth factor receptor-targeted therapy) [ 118 ]. Passive immunotherapy boosts the immune system and thereby targets tumor cells. Passive immunotherapy includes immune checkpoint inhibitors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD-L1 monoclonal antibodies [ 118 ]. Preliminary experiments employing single immune checkpoint inhibitors demonstrated limited efficacy. A recent meta-analysis included 15 clinical trials to evaluate the effectiveness of anti-PD-1/PD-L1 therapy in EOC [ 119 ]. The combined data indicated that the overall response rate (ORR) was 19%. Monotherapy with PD-1/PD-L1 inhibitors had a modest efficacy, with an ORR = 9%, but combining them with chemotherapy resulted in improved efficacy (ORR = 36%). Moreover, PD-1/PD-L1 inhibitors showed a greater ORR in platinum-sensitive EOC compared to platinum-resistant OC (31% vs 19%) [ 119 ]. Recent analysis of 20 studies revealed that 16 clinical trials focused on PD-1 (nivolumab, pembrolizumab), PD-L1 (avelumab, atezolizumab, durvalumab), and CTLA-4 (ipilimumab, Tremelimumab) did not show any survival benefits for EOC patients [ 120 ]. Some trials were stopped prematurely due to either toxicity or lack of response. Combining therapy with immune check inhibitors with chemotherapy, anti-VEGF therapy, or PARP inhibitors enhanced response rates and survival in EOC patients, but it resulted in increased toxicity [ 120 ]. Although combinations of immune checkpoint inhibitors with PARP inhibitors or cytotoxic chemotherapies have shown higher response rates, there is a lack of phase III trials that document improvements in progression-free survival (PFS) and overall survival (OS). Furthermore, inhibiting the PD1 or CTLA4 checkpoints could enhance their effectiveness by combining with other immunomodulatory drugs that reduce T-reg cells or immunosuppressive macrophages [ 121 ]. Additional novel solutions for immunotherapy involve the use of tumor vaccines designed to target tumor cells by utilizing tumor-specific antigens, in conjunction with immune checkpoint inhibitors. Women with platinum-resistant EOC may benefit the most from novel combination immunotherapies ( Table 3 ). Immunotherapy, while promising in many solid tumors, has shown limited activity in epithelial ovarian cancer due to its immunologically ‘cold’ tumor microenvironment. Response rates remain low, and immune-related adverse events – although infrequent – can be severe and require immunosuppressive management. Therefore, while novel agents hold great promise, their clinical implementation must be guided by balanced, evidence-based evaluation of benefits and risks. WEE1 is the primary regulator for the G2/M and S-phase checkpoints, exerting significant influence over cell cycle control and DNA damage restoration [ 139 ]; inhibition of WEE1 could potentially enhance the efficacy of DNA-damaging therapies, like radiotherapy, by compelling both tumor cells and cancer stem cells (CSCs) to undergo mitosis, even in the presence of DNA damage. This would result in mitotic failure and, finally, cell death. WEE1 inactivates the CDC2/cyclin B complex (CDK1/cyclin B), controlling the G2 cell cycle progression into mitosis, which is especially important for p53-mutant cells. p53 wild-type cells can arrest the cell cycle at the G1 checkpoint to repair damaged DNA. Cells with a defective p53 pathway rely mainly on DNA repair at the G2 checkpoint [ 140 ]. Wee1 is overexpressed in particular cancer types, such as EOC, and its high expression is linked to a poor outcome. Adavosertib (previously known as MK-1775 and AZD1775) is a WEE1 inhibitor developed by AstraZeneca ( Table 4 ); it is an efficient small-molecule inhibitor of the WEE1 kinase; it competes with ATP and belongs to the pyrazol-pyrimidine derivative class. Debio0123, another potent WEE1 inhibitor developed by Debiopharm, is undergoing evaluation in combination with carboplatin in phase 1 clinical trial ( NCT03968653 , no results published yet). Based on the results of the above-mentioned clinical trials, further studies on AZD1775 in EOC treatment are justified, especially in patients with p53 mutation [ 145 ., 150 ]. The combination of DNA-damaging drugs and WEE1 inhibition in therapy demonstrates encouraging outcomes. Also, it is essential to determine the most convenient treatment regimen to enhance the overall efficacy of the combination treatment. However, the wide range of research and lack of sufficient data make it difficult to accurately compare the safety profiles of various treatment regimens. Particular attention is needed on monitoring adverse effects such as hematological toxicity, including anemia, thrombocytopenia, and neutropenia.

Over the past decade, the systemic treatment of epithelial ovarian cancer (EOC) has undergone a significant transformation, driven by advances in molecular biology and a growing emphasis on personalized medicine. The historical reliance on platinum-based chemotherapy and cytoreductive surgery, although still foundational, has increasingly been supplemented – and in some cases challenged – by biomarker-driven approaches. A central breakthrough has been the identification of BRCA1/2 mutations and homologous recombination deficiency (HRD) as predictive biomarkers for response to PARP inhibitors (PARPi). Clinical trials such as SOLO1, PAOLA-1, and PRIMA have demonstrated the utility of PARPi in maintenance therapy, particularly among BRCA-mutant and HRD-positive patients. These findings have helped to refine patient selection criteria and extend progression-free survival (PFS), signaling a shift toward genomically-guided treatment. However, recent studies also highlight the limitations of this paradigm. The modest benefit of PARPi in HRD-negative populations raises concerns about overtreatment and the need for more precise biomarkers, such as RAD51 foci or functional assays of DNA repair capacity. This has led to a new wave of research exploring alternative mechanisms of resistance and the integration of next-generation diagnostics into treatment decision-making. Emerging therapeutic trends – including antibody-drug conjugates (ADCs), immunotherapies, and WEE1 inhibitors – reflect an ongoing shift from “one-size-fits-all” protocols toward treatment tailored to tumor biology. For example, Mirvetuximab soravtansine, which targets folate receptor-α, offers a promising approach for platinum-resistant disease, while WEE1 inhibitors may benefit patients with p53 mutations, a common aberration in high-grade serous ovarian cancer (HGSOC). The increasing complexity of molecular classifications is shaping not only drug development but also regulatory strategies and clinical trial design, favoring basket trials and molecular stratification. Despite these advances, several challenges remain. There is an urgent need for harmonized HRD testing methodologies, improved management of PARPi resistance, and long-term safety data for novel agents. Additionally, most trials have focused on select populations, often excluding older patients or those with comorbidities, thereby limiting the generalizability of findings. Real-world data and broader inclusion criteria will be essential to ensure equitable access to precision therapies. Looking ahead, future research should focus on optimizing combination regimens – such as PARPi with immunotherapies or angiogenesis inhibitors – and exploring adaptive treatment strategies guided by real-time biomarker monitoring. Furthermore, multi-omics profiling, including transcriptomic and proteomic data, may yield more robust classifiers of treatment response and resistance. In summary, the integration of molecular insights into the treatment of EOC represents a paradigm shift with profound implications for clinical practice. Continued innovation in diagnostics, trial design, and biomarker development will be critical to translating these advances into durable improvements in patient outcomes.

Advances in molecular profiling have significantly influenced the treatment landscape of EOC. Biomarkers such as BRCA1/2 mutations and HRD have enabled more personalized treatment approaches, particularly using PARP inhibitors in maintenance settings. Clinical trials – including SOLO1, PRIMA, and PAOLA-1 – have demonstrated improved progression-free survival in biomarker-positive populations, reinforcing the clinical value of genetic stratification. However, limitations remain. The benefit of PARP inhibitors in HRD-negative patients is modest, and their use in this population should be considered with caution. Additionally, issues such as drug resistance, toxicity, and access to standardized biomarker testing continue to hinder optimal treatment outcomes. Emerging therapies like immunotherapy and antibody-drug conjugates offer new directions, but their clinical effectiveness in EOC is still limited and requires further validation. Combining these agents with existing therapies may enhance efficacy, yet current evidence remains inconclusive. Future research should focus on improving biomarker accuracy, managing resistance mechanisms, and expanding access to genomic testing. A balanced, evidence-based integration of molecular diagnostics and emerging therapies will be critical for advancing EOC treatment in the coming years.