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

Introduction

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.

Characteristics of Ovarian Cancer

EOC is a leading cause of death and is a prevalent gynecological malignancy. Additionally, it has the worst prognosis and highest fatality rate [1]. Although less prevalent than breast cancer, its mortality rate is 3 times higher [1]. Globally, the age-standardized mortality rate (ASMR) increased by 84.2% from 1990 to 2017 [8]. Despite advances in treatment, the 5-year survival rate remains about 48% [9], largely due to late symptom onset, silent progression, and lack of early screening tools [1].

Histopathological, molecular, and genetic research has identified multiple subtypes of EOC, based on their molecular and histological characteristics. These subtypes include high-grade serous ovarian cancer (HGSOC), low-grade serous ovarian cancer (LGSOC), endometrioid, clear cell, and mucinous carcinomas, each associated with distinct genetic mutations and clinical behaviors. This updated classification reflects the detailed understanding of ovarian cancer subtypes and aligns with contemporary descriptors rather than the historically used Type I and Type II categories [10,11]. Characteristics of all the types are summarized in Table 1.

HGSOC is the most common and aggressive subtype, accounting for the majority of EOC cases. It is characterized by high genetic instability, with frequent TP53 mutations observed in over 95% of cases, as well as alterations in DNA repair pathways, including BRCA1/2 mutations and homologous recombination deficiency (HRD). Clinically, HGSOC is associated with rapid progression, and over 75% of cases are diagnosed at an advanced stage. Molecular profiling, as revealed by The Cancer Genome Atlas (TCGA) project, has identified 4 gene expression-based subtypes within HGSOC: immunoreactive, differentiated, proliferative, and mesenchymal. These tumors are thought to originate de novo, likely from the fallopian tube epithelium or ovarian surface epithelium, and are known for their aggressive clinical course and poor prognosis [2].

In contrast, LGSOC is a rare and indolent subtype with a more stable genomic profile. Unlike HGSOC, it exhibits rare TP53 mutations but shows frequent alterations in KRAS, BRAF, and NRAS genes. LGSOC often develops through a stepwise progression from benign serous cystadenomas to serous borderline tumors (SBTs). Clinically, LGSOC is less responsive to standard chemotherapy, and alternative treatments, such as MEK inhibitors like trametinib, have shown efficacy, leading to its inclusion as a category 2A treatment by the National Comprehensive Cancer Network (NCCN). The proposed origins of LGSOC include ovarian epithelial inclusions or tubal epithelial cells adhering to the ovarian surface epithelium, which then undergo malignant transformation [12].

Endometrioid ovarian cancer, another subtype, is closely linked to endometriosis and is often associated with mutations in the PTEN tumor-suppressor gene and alterations in the PI3K/AKT signaling pathway [13]. This subtype frequently arises from atypical endometriosis, which is a precursor lesion associated with chronic inflammation and oxidative stress. Women with severe endometriosis have an elevated risk of developing endometrioid ovarian cancer, which tends to present at an earlier stage and has a relatively favorable prognosis when diagnosed promptly.

Clear cell ovarian cancer (OCCC), in contrast, is a rare and aggressive subtype that also has a strong association with endometriosis. This subtype is characterized by mutations in the ARID1A tumor-suppressor gene, as well as alterations in the PIK3CA and MET signaling pathways. OCCC typically is associated with poor outcomes due to its resistance to conventional chemotherapy. Despite its rarity, OCCC poses unique challenges in treatment and requires careful consideration of targeted therapeutic strategies [14].

Endometriosis is associated with an elevated risk of endometrioid and clear cell ovarian carcinomas (OCCC), with OCCC exhibiting the highest relative risk among EOC subtypes. Low-grade serous ovarian carcinoma (LGSOC) has also been reported in patients with endometriosis, although less frequently. Ovarian endometriosis, defined by the ectopic presence of endometrial-like tissue within the ovaries, often gives rise to endometriomas. These cystic lesions, along with deep endometriosis, are implicated in carcinogenesis through mechanisms involving oxidative stress and consequent DNA damage, frequently presenting as “atypical endometriosis” in the context of malignant transformation [11]. Barnard et al reported a significantly elevated risk for type I EOC in this population, with OCCC showing an 18.96-fold increase. Women with severe endometriosis may benefit from targeted screening, prevention strategies, and counseling to address their elevated cancer risk [15].

Mucinous carcinomas, in contrast, are well-differentiated, heterogeneous tumors, often presenting with precursor lesions such as cystadenoma or proliferative (borderline) tumors. Over 90% of mucinous carcinoma cases have KRAS, BRA,F and ERRB2 amplification mutations, but the most prevalent genetic modification is the KRAS-activating mutation, occurring in approximately 65% of cases. RNF43 inactivation is also observed in a subset of these tumors. Similarly, TP53 mutations are prevalent in mucinous carcinomas [12].

The clinical management of patients – including prevention, early detection, cytoreduction, and tailored treatment with PARP inhibitors – is governed by the identification of a pathogenic BRCA1 or BRCA2 mutation [16]. The BRCA1 and BRCA2 genes have been associated with an elevated risk of EOC. Patients diagnosed with the HGSOC subtype have the highest proportion of BRCA1/2 mutations [17]. Over half of the invasive epithelial EOCs have hereditary susceptibility, with 65–85% being pathogenic or pathogenic variants in the BRCA genes. These BRCA variants occur in 4–14% of unselected EOCs, 5–18% of serous EOCs, and 22% of high-grade serous EOC cases [18]. Many attempts have been made to determine what effect BRCA status has on a patient. However, BRCA1/2 carriers with mutations at different gene sites do not exhibit substantial differences in survival outcomes like progression-free survival (PFS) and overall survival (OS) among HGSOC patients. This implies that additional genetic abnormalities and concomitant risk factors may play a role in influencing survival [19]. In contrast, another study showed that 39.8% of women with germline BRCA1/2 mutations had a more prolonged PFS compared to wild-type BRCA patients. The BRCA mutation group had a longer PFS compared to the wild-type BRCA group, but PFS did not differ between the 2 groups. Therefore, in advanced-stage HGSOC, patients with germline BRCA1/2 mutations have a more favorable prognosis with an extended PFS compared to individuals without BRCA mutations [20]. In conclusion, the presence of mutations in the BRCA1/2 genes enhances patient prognosis, mostly due to the increased effectiveness of PARP inhibitor treatment.

Homologous recombination repair (HRR) is a high-fidelity DNA damage repair system responsible for repairing double-stranded breaks (DSB) and interstrand crosslinks. Defects in HRR, referred to as homologous recombination deficiency (HRD), results in increased reliance on error-prone repair pathways such as end-joining mechanisms. Approximately 50% of HGSOC exhibit HRD, often due to loss-of-function mutations and epigenetic modifications [21]. Genetic alterations that induce HRD include germline and somatic BRCA mutations, as well as mutations in genes including ATM, CHEK2, RAD51, and MRE11A [5]. The BRCA1 protein, a critical tumor suppressor, plays a crucial role in cellular repair and cell cycle progression. It participates in DNA damage signaling and repair and may also regulate the choice of DSB repair pathways. BRCA1 facilitates the recruitment of BRCA2 protein complexes to initiate strand invasion or homologous repair when DNA is damaged, thereby compensating for deficiencies in single-strand DNA break repair mechanisms [22].

HRR status is a crucial metric for therapeutic selection and prognosis in EOC patients. Nevertheless, the current methods for assessing HRD are not fully standardized and often lead to binary classifications, limiting their clinical applicability. Optimal clinical outcomes require consistent data generation and careful consideration of each patient’s unique HRR status and underlying etiology. The prognostic and therapeutic relevance of HRR status in EOC is well-established [23]. Given that HRD is a significant predictive marker for PARPi response, its evaluation is essential before exploring other treatment options.

Recent advances include identification of the single base 3 substitution signature (Sig3) as a prognostic indicator in advanced HGSOC and a valuable tool for stratifying patients with HRD [24]. Furthermore, the development of the ovaHRDscar assay provides a precise, clinically feasible approach to outcome prediction and patient selection for HR-targeted therapies [25]. As noted, HRD-positive tumors exhibit distinct clinical profiles compared to HRD-negative cancers, demonstrating enhanced sensitivity to PARP inhibitors and platinum-based chemotherapy.

Despite these advances, challenges persist due to the lack of systematic methodologies for integrating diverse tumor types and genetic variables. These complexities hinder the accurate identification of HRD using artificial intelligence (AI) algorithms, which are designed to analyze somatic mutations and identify biomarkers such as HRD. The variability in genetic profiles across ovarian tumors subtypes further complicates accurate HRD detection by AI tools. To address these limitations and improve patient stratification and clinical outcomes, a systematic approach for diagnosing HRD, known as HRDscar, has been developed [25]. In conclusion, HRR/HRD status has emerged as a key prognostic and predictive biomarker, guiding therapeutic strategies and enabling the classification of specific cancer subtypes.

The Idea of Tailored Therapy

Despite being a primary treatment for EOC, reductive surgery in combination with chemotherapy or targeted therapy is associated with suboptimal outcomes. This therapeutic approach is commonly linked to significant risk of adverse effects and perioperative complications. Moreover, up to 40% of tumors are located in the upper part of the abdominal cavity, which makes resection difficult. The median overall survival (OS) and progression-free survival (PFS) for such patients are limited to 29 and 12 months, respectively [26].

Moreover, in the context of EOC, tailored therapy is essential. This method involves appropriate selection of the patient’s treatment method based on full information regarding the patient’s characteristics, clinical profile, genetics, comorbidities, allergic reactions, and mental condition, and as the disease profile based on molecular pathways. In addition, the inclusion of surrogate markers and detailed pharmacological characteristics of therapeutic agents is crucial for determination of the optimal therapeutic approach [27]. In the context of EOC, patients with a BRCA mutation are more likely to benefit from personalized treatment strategies. The BRCA1 and BRCA2 proteins, along with poly (ADP-ribose) polymerase (PARP), play a key role in selecting the appropriate treatment, as they are responsible for repairing DNA damage through homologous recombination (HR) and regulating transcription. As a result, patients with a BRCA mutation tend to respond well to agents inducing DNA damage, such as PARP inhibitors [28].

Tailored therapy in EOC highlights the importance of therapy-free interval (TFI) as an essential parameter in treatment planning. TFI refers to the duration between the last administration of platinum-based chemotherapy to the recurrence of the disease. It encompasses the various therapeutic categories of therapeutic method used, such as TFInp (non-platinum free interval) (non-PFI), TFIp (PFI-platinum free interval), TFIb (biologic agent-free interval) and histology, BRCA1/2 mutation status (BRCAm), previous therapy, surgery, and patient’s symptoms [29–31]. These parameters are essential to consider, as they significantly influence the course of the disease and therapeutic response. Moreover, the molecular and clinical heterogeneity of EOC has led to the development of alternative therapeutic strategies beyond conventional platinum- and taxane-based chemotherapy [7], as the low-grade mucinous, clear cell, and serous subtypes (LGS-OC) have less response to chemotherapy compared to HGSOC [31].

Understanding the causes of EOC heterogeneity provides essential information for further selection of the appropriate therapeutic strategy based on specific genetic biomarkers. Therefore, detailed knowledge of the BRCA1 and BRCA2 mutations was crucial for the developing new targeted therapies such as platinum chemotherapy or PARP enzyme inhibitors [32]. PARP therapy is a treatment method that is specifically indicated for carriers of BRCA mutations, either somatic or germline [33]. Nonetheless, drug resistance mechanisms, such as non-homologous end-joint (NHEJ) repair alterations and drug efflux pumps, complicate the treatment outcomes [34].

In summary, genetic testing for BRCA1/2 mutations is particularly important for patients with HGSOC, as it provides essential information to guide personalized therapy and optimize treatment strategies in EOC. However, this recommendation does not extend to all EOC subtypes, and mucinous and clear cell EOC have significantly lower rates of BRCA1/2 mutations. For these subtypes, routine genetic testing for BRCA1/2 is generally not recommended unless there is a specific clinical indication or a family history suggestive of hereditary cancer syndromes [35]. The assessment of these mutations allows not only the establishment of preventive measures or genetic counseling but also serves an important predictive factor influencing the tumor’s response to DNA-damaging factors. In addition, efforts should be made to further elucidate the mechanisms of resistance in BRCA-mutated EOC resistance, which may allow the development of new treatment methods with fewer adverse effects [36]. Considering the diverse characteristics of EOC, we have provided a comprehensive review of the treatment methods used in EOC in the following sections of our article. Furthermore, we reviewed recent research, the results of which may serve as a basis for implementing new strategies such as antibody-drug conjugates and immunotherapy.

Mechanisms of Action of Currently Used Agents

PLATINUM:

Platinum-based chemotherapeutics, particularly cisplatin and carboplatin, are among the most effective agents in oncology. Discovered serendipitously by Barnett Rosenberg in 1965, cisplatin’s antimitotic properties led to its clinical use in cancer therapy [37]. Carboplatin, developed later, retained similar efficacy while significantly reducing ototoxicity, neurotoxicity, and nephrotoxicity, and becoming the standard platinum compound used in EOC treatment [38].

By entering the cell, platinum compounds undergo a process of aquation in the low cellular concentration of chloride ions. Although the aquated form of cisplatin interacts with various components within the cell, its main biological target is DNA. The drug’s platinum atom covalently binds to the N7 positions of purine bases, predominantly creating 1,2- or 1,3-intrastrand crosslinks and fewer interstrand crosslinks. These connections form at the sites previously occupied by chloride ions or, in the case of carboplatin cyclobutane-1,1-dicarboxylate (CBDCA) ligand within the original platinum compound. Alterations caused by platinum lead to significant changes in DNA structure. Platinum-DNA complexes trigger multiple signal transduction pathways, including p38 MAPK, c6ABL, p38MAPK, ERK, JNK, and p53, as well as necrosis and apoptosis pathways leading to cell death [39].

It is generally accepted that the principal mechanism of cisplatin anti-cancer action is platinum binding to DNA by forming intra-stranded and inter-stranded crosslinks. Nonetheless, some studies suggest that only about 1–10% of cisplatin inside a cell reaches the nucleus and interacts with DNA, leading to cell cycle arrest and apoptosis in fast-growing tumor cells. Given this, additional mechanisms of action have been identified, including cytoplasmic acidification, induction of estrogen receptor (ER) stress, interference with RNA transcription, inhibition of crucial oncogenic proteins, reduction in the metabolic adaptability of cancer cells, and alterations in their mechanobiology [40].

Carboplatin ranks among the most potent chemotherapeutic agents for treating EOC, yet the development of resistance to the drug is widespread. Initially, up to 80% of patients responded to platinum-based chemotherapy, but most of those with advanced disease eventually relapse and die due to the emergence of drug resistance. The mechanisms behind platinum resistance are multifaceted, encompassing issues like multidrug resistance, DNA repair mechanisms, cellular metabolism, oxidative stress, cell cycle regulation, persistence of cancer stem cells, immune response, pathways of apoptosis, autophagy, and dysregulated signaling pathways. To improve the treatment results with platinum compounds, novel strategies aimed at platinum resistance mechanisms are currently being investigated [41].

PACLITAXEL:

Paclitaxel, a plant-derived chemotherapeutic, is crucial in primary EOC treatment alongside platinum-based therapies due to its microtubule-stabilizing properties. Its anti-tumor activity is largely attributed to its oxygenated tetracyclic structure, with a bridged bicyclo[5.3.1]undecane ring [6]. The compound was discovered through collaboration between the National Cancer Institute (NCI) and the US Department of Agriculture (USDA) in a plant-screening program, which analyzed over 15 000 species. Paclitaxel was extracted from the bark of Taxus brevifolia in 1962 and later shown to stabilize microtubules in vivo. By December 1992, it was FDA-approved for EOC treatment [42,43].

The main targets of paclitaxel are cellular microtubules, which are elongated, thread-like structures made of protein polymers that are key components of the cytoskeleton in all eukaryotic cells. They play a critical role in shaping and maintaining cell structure, facilitating intracellular transport, participating in cell signaling, and orchestrating cell division and mitosis. These structures are built from α-tubulin and β-tubulin heterodimers, which assemble into narrow, tube-like filaments forming mitotic spindles during cell division [44].

In contrast to previously identified microtubule poisons, such as colchicine and vinca alkaloids, which inhibit microtubule polymerization, paclitaxel acts as a cancer-fighting drug. It selectively attaches to the β subunit of tubulin proteins, facilitating their assembly and polymerization, and thus stabilizing microtubule formation [45]. The compound activates the mitotic checkpoint (also known as the spindle assembly checkpoint), a crucial regulatory system that operates during cell division to prevent the incorrect distribution of chromosomes. This checkpoint mechanism postpones the separation of chromosomes, which enter the division phase as duplicated pairs of sister chromatids until each pair is securely connected to both ends of the spindle to ensure that each new cell will inherit 1 copy of the sister chromatid. Chromatids are linked to the spindle fibers through kinetochores, which are protein structures formed at the chromosome’s centromeric DNA. Kinetochores that have not formed stable links with the spindle fibers polarized by paclitaxel initiate a series of signaling events that hold back the progression of mitosis by blocking the activity of the anaphase-promoting complex/cyclosome. As a result, paclitaxel leads to significant arrest of the cell cycle at the G2/M phase and ultimately triggers cell death via apoptosis [42].

The cytotoxic effect of paclitaxel is significantly influenced by its concentration within the cell, as shown in laboratory studies. Giannakakou observed that administering paclitaxel at concentrations higher than 12 nM led to a decrease in the proliferation of lung cancer and breast cancer cells, causing these cells to be arrested in the G2/M phase. Notably, even lower doses of paclitaxel (3–6 nM) were found to have a comparable ability to inhibit cancer cell growth without causing mitotic arrest. At these minimal concentrations, paclitaxel triggers the activation of p53 and p21, which are proapoptotic proteins, leading to cell cycle arrest in both the G1 and G2 phases. However, this effect is not observed in cells that lack p53 expression, indicating the crucial role of p53 in this process [46].

Paclitaxel triggers additional toxic effects on cells by disruption of the pathway that phosphorylates Bcl-2, a key regulator of cell death. Additionally, paclitaxel causes a decrease in calcium levels within the mitochondria, which leads to release of a factor that initiates cell death through apoptosis. It also affects the expression of certain microRNAs (miRNAs), playing a role in hindering tumor growth. Moreover, paclitaxel can influence the immune system’s response to cancer by altering the production of chemokines and cytokines, thereby contributing to its cytotoxic effects [47]. The combination of anti-proliferative and cytotoxic properties contributes to the anti-tumor efficacy of paclitaxel.

BEVACIZUMAB:

Bevacizumab is one of the first targeted therapy medications approved for front-line, maintenance, and recurrent treatment of advanced EOC [48]. Before the advent of anti-angiogenic agents, systemic EOC therapies primarily targeted rapidly dividing cells. In 1971, Folkman proposed the role of angiogenesis in tumor growth, initiating extensive research into angiogenesis inhibition as a therapeutic strategy [49].

Angiogenesis, the formation of new blood vessels from pre-existing ones, supports tumor progression by meeting the metabolic and oxygen demands of cancer cells. Targeting this process is a novel mechanism of action, focused on the tumor microenvironment rather than direct cytotoxicity [50]. Vascular endothelial growth factor (VEGF) is the principal proangiogenic factor, upregulated under hypoxic conditions through enhanced transcription and mRNA stabilization [51].

Bevacizumab is a VEGF-A-targeting monoclonal antibody that selectively binds to VEGF and inhibits its linkage to VEGF receptor tyrosine kinases (VEGFR1–3) on the surface of endothelium cells. By these means, VEGF cannot stimulate further proliferation and survival of endothelial cells. The formation of new blood vessels stops; thus, blood supply, specifically within the tumor microenvironment, is limited. Without the presence of vascular support, the tumor cannot continue to grow, and remains in situ for several months to years, which eventually leads to apoptosis [52]. It has been used in combination with chemotherapy, based on the hypothesis that VEGF inhibition normalizes abnormal tumor vasculature, enhancing drug delivery despite reduced angiogenesis [53].

Additionally, bevacizumab can modulate tumor immune responses by disrupting VEGF-mediated immunosuppression. This includes effects on hematopoiesis, dendritic and T-cell function, and expansion of immunosuppressive populations, such as regulatory T cells and myeloid-derived suppressor cells. As a result, VEGF blockade is also being explored as a strategy to enhance anti-tumor immunity, particularly in combination with immunotherapies [54].

PARP INHIBITORS:

PARP inhibitors are a form of targeted therapy based on DNA damage repair mechanisms, a central aspect of cancer pathology. Poly (ADP-ribose) polymerases (PARPs) are multifunctional enzymes that modify various proteins through a process called PARylation [55]. Among the 17 known human PARPs, PARP1, PARP2, and PARP3 are DNA-dependent and play key roles in therapies targeting DNA repair. They bind to DNA, facilitating repair and nucleosome remodeling [56].

PARP was first identified when nicotinamide mononucleotide induced polyadenylic acid synthesis in rat liver extracts. By 1980, PARP-1 was recognized for its role in single-strand break (SSB) repair via the BER pathway. Its inhibition enhanced the cytotoxicity of methylating agents in leukemic cells, supporting the use of PARP inhibitors (PARPi) as chemosensitizers. PARPi were later found to be effective as monotherapies in tumors with homologous recombination deficiencies, including BRCA1/2 mutations [57]. PARP1 is rapidly recruited to SSBs, where its catalytic domain hydrolyzes NAD+, triggering PARylation and recruitment of repair proteins. PARPi, as nicotinamide analogs, compete with NAD+ and inhibit this process. This blocks PAR chain synthesis, traps PARP1 on DNA, and prevents its release. The accumulation of unrepaired SSBs leads to replication fork stalling and DSB formation, ultimately promoting cell death [58].

In BRCA1/2-mutated or HRD-positive patients treated with PARP inhibitors we observe the synthetic lethality effect, which occurs when 2 molecular defects occur simultaneously. Blocking of SSB repair pathways leads to accumulation of damaged DNA, resulting in DSB. In non-HRD patients’ pathways, those DSBs would get repaired, as opposed to the situation in HRD-positive and BRCA-mutated patients. BRCA-mutated patients specifically have mutations in the BRCA1 or BRCA2 genes, while HRD-positive patients have a broader defect in the homologous recombination repair pathway, which can result from BRCA mutations or mutations in other genes involved in DNA repair [59].

Olaparib, Niraparib, and Rucaparib are PARP inhibitors used in clinical practice. Olaparib was the first one introduced in treatment of BRCA-associated EOC. It inhibits the PARP-mediated repair of SSB and DBs, leading to synthetic lethality. It specifically inhibits PARP-1 and PARP-2, similarly to niraparib, whereas rucaparib also inhibits PARP-3 [60]. The efficacy of PARP inhibitors has been clearly demonstrated in several key clinical trials. The SOLO-1 study included patients with advanced ovarian cancer harboring BRCA mutations and showed that Olaparib as maintenance therapy significantly improved progression-free survival (PFS) compared to placebo (PFS not reached vs 13.8 months) [61]. Similarly, the PAOLA-1/ENGOT-OV25 study assessed the combination of Olaparib with bevacizumab in patients with newly-diagnosed advanced ovarian cancer and demonstrated a significant PFS benefit, particularly in HRD-positive patients (37.2 months vs 17.7 months) [62]. The PRIMA/ENGOT-OV26 trial evaluated niraparib in patients with advanced ovarian cancer, both HRD-positive and HRD-negative, and showed improved PFS across both subgroups, with the most pronounced benefit in HRD-positive patients (21.9 months vs 10.4 months) [63]. Lastly, the VELIA/GOG-3005 trial focused on rucaparib in combination with chemotherapy followed by maintenance therapy, and reported significant PFS improvement, particularly in HRD-positive patients (19.6 months vs 14.7 months) [64]. Several pivotal trials (eg, SOLO1, PAOLA-1, and PRIMA) have consistently demonstrated that PARP inhibitors significantly prolong progression-free survival in BRCA-mutated and HRD-positive patients. However, the magnitude of this benefit varies. Whereas SOLO1 reported a median PFS not reached in the Olaparib group, PRIMA demonstrated more modest gains, especially in HRD-negative patients, underscoring that biomarker status remains a critical determinant of efficacy.

Before the advent of PARPi, 70% of patients with advanced EOC relapsed within 3 years from the initial diagnosis and the 5-year overall survival was extremely poor (5–20%), with a median time to progression of 10–20 months. Clinical trials designed to evaluate PARPi in EOC are divided into 5 main indications: (1) first-line treatment - SOLO1, PRIMA, PAOLA-1, and NEO; (2) platinum-sensitive relapse - AVANOVA2, SOLO3, and ARIEL4; (3) maintenance after chemotherapy in platinum-based disease - NOVA, SOLO2, and ARIEL3; (4) platinum-resistant disease – Study 42 and CLIO; and (5) combination with target drugs, immune checkpoint inhibitors, or other biological agents [65].

Although most studies confirmed the benefit of PARP inhibitors in BRCA-mutated epithelial ovarian cancer, their role in HRD-negative patients remains a subject of debate. For instance, PRIMA reported a PFS benefit regardless of HRD status, whereas ARIEL3 showed only minimal improvements in the HRD-negative subgroup, highlighting the need for more precise predictive biomarkers beyond BRCA and HRD classification.

The updated long-term data from the SOLO1, PAOLA1, and PRIMA trials showed unprecedented survival rates in EOC, reinforcing the role of PARPi as a practice-changing treatment. In the updated analysis of the SOLO1 trial after 7 years of follow-up, nearly 70% of patients treated with Olaparib were alive and half of them did not receive any subsequent treatment. Notably, PAOLA1 is the first trial showing a statistically significant increase in 5-year overall survival, an extraordinary result in the history of EOC. Moreover, the updated progression-free survival data from the PRIMA trial confirmed the clinical benefit of PARPi in non-HRD patients [66].

Across these landmark trials, the incorporation of PARP inhibitors as maintenance therapy has reshaped the standard of care for advanced epithelial ovarian cancer. SOLO1 focused exclusively on BRCA-mutant patients, PAOLA-1 expanded its scope to HRD-positive disease in combination with bevacizumab, and PRIMA extended its eligibility to all patients regardless of BRCA status, illustrating the evolving strategies for patient selection and highlighting the growing clinical role of PARP inhibitor therapy.

PARPis are increasingly being approved for use in EOC patients without homologous recombination deficiency (HRD), a feature once considered essential for treatment. Initially, these inhibitors were approved for patients with BRCA mutations or HRD-positive tumors. However, recent studies and clinical trials have demonstrated that PARPis, such as niraparib and Olaparib, can also benefit patients without these genetic alterations, thereby broadening their applicability. Notably, niraparib has been approved for maintenance therapy in EOC regardless of BRCA status [63]. This includes its global approval as a first-line maintenance treatment for ovarian cancer (EOC), extending to countries such as China. Evidence supporting this broader application, such as the findings from Mirza et al (2016), demonstrates that niraparib improves progression-free survival (PFS) in recurrent EOC, even in patients who are HRD-negative. This broader approval underscores the evolving understanding of PARPis’ mechanisms of action, which can confer therapeutic benefits through alternative pathways, even in the absence of HRD. These advances are a significant step toward more personalized treatment strategies [67].

Despite the significant extension of PFS in patients receiving PARPi, the lack of biomarkers that predict sensitivity remains a challenge. Recent studies suggest that RAD51 protein may serve as a key biomarker for PARPi response. RAD51 is an ATPase that promotes homologous recombination repair through the formation of nucleoprotein filaments on single-stranded DNA and mediates strand invasion [68]. Overexpression of RAD51 can lead to genomic instability and aberrant recombination, which are typical features of cancer. RAD51 is recruited to DNA damage sites by BRCA2, and the presence of RAD51 foci serves as a functional marker of homologous recombination efficiency. The formation of RAD51 foci has been correlated with BRCA1/2 functionality and PARPi sensitivity [69]. High levels of RAD51 expression have also been linked to chemotherapy resistance [70], whereas lower expression was associated with better PFS in ovarian cancer patients receiving PARPi [71]. Further studies confirmed its predictive value: RAD51 foci were associated with platinum and PARPi response in HGSC [72], and higher expression was linked to poorer PFS and OS [73]. An inverse correlation was found between RAD51 lesions and Olaparib sensitivity [74]. These data indicate that RAD51 can identify patients likely to benefit from PARPi treatment, regardless of BRCA status, and its assessment is both feasible and cost-effective for clinical use.

Although all PARPis share a mechanism of action, their toxicity profiles differ. PARP1 is linked to circadian metabolism and PARP2 to red blood cell regulation. Their differing affinities to PARP1, PARP2, and PARP3 result in variable on-target effects. PARP3 can enhance PARP1 activity independently of DNA; therefore, its inhibition by rucaparib can enhance efficacy compared to Olaparib or niraparib [75].

PARPis show teratogenicity and embryo-fetal toxicity in animal models and are contraindicated in pregnancy. The most common toxicities are hematologic – anemia, thrombocytopenia, neutropenia – requiring monthly blood counts. Gastrointestinal symptoms, especially nausea, are frequent, with rucaparib sometimes elevating creatinine. Fatigue is a universal adverse effect. Less common toxicities can affect neurological, respiratory, musculoskeletal, cutaneous, and cardiovascular systems, but are usually mild and manageable. Persistent toxicities may require dose reduction per existing guidelines [76,77].

Severe but rare toxicities include secondary malignancies like myelodysplastic syndrome and acute myeloid leukemia, which necessitate treatment discontinuation. These events generally arise after prolonged exposure, and their rarity increases with broader clinical experience [77].

Although PARP inhibitors represent a significant advancement in the treatment of ovarian cancer, particularly in BRCA-mutated and HRD-positive populations, their broader use remains controversial. Clinical trials have demonstrated diminishing returns in HRD-negative subgroups, and real-world data suggest that not all biomarker-positive patients experience meaningful benefit. These limitations highlight the importance of careful patient selection and ongoing monitoring during therapy, especially in older patients and those with comorbidities, who are underrepresented in trials. Moreover, the inconsistent definitions of HRD across studies complicate direct comparisons and clinical decision-making.

Clinical Utilization of Targeted Treatments

FIRST-LINE TREATMENT:

Surgical removal of the tumor remains an essential method of treating EOC. It aims to reduce the tumor volume by resection. The 2017 European Society of Gynaecological Oncology (ESGO) guidelines indicate that the goal of primary surgery is complete cytoreduction. The Fagotti scale can help in performing surgery. A 2011 study on 52 patients with stage III–IV EOC showed that the Fagotti index used during laparoscopy is an essential predictor of optimal cytoreduction [78]. Unfortunately, in stages III/IV, complete reduction may not be possible due to infiltration of the mesentery of the small intestine or the liver hilum. Such women will first be treated with neoadjuvant chemotherapy in the form of 3 cycles. Then, interval debulking surgery (IDS) is possible, followed by another 3 cycles of chemotherapy [79,80]. After first-line chemotherapy, the response to treatment should be assessed. The results of imaging tests and the RECIST 1.1 criteria are used for this purpose.

After surgical cytoreduction, patients are treated with chemotherapy in the form of paclitaxel 175 mg/m2 and carboplatin area under the curve (AUC) 5 or 6, intravenously, every 3 weeks [81]. This is currently the primary and most frequently used method of treating advanced EOC. Chemotherapy may be omitted in patients with stage IA/IB EOC [80].

Currently, the study authors ask themselves which approach to first-line EOC treatment is more beneficial for the patient: neoadjuvant chemotherapy and IDS or primary cytoreduction. The first method is associated with a faster recurrence of EOC, and the second method is associated with higher mortality. The European Organization for Research and Treatment of Cancer (EORTC) 55971 trial showed longer survival in stage IIIC EOC patients after primary cytoreduction and longer survival in stage IV patients with metastases after treatment with neoadjuvant chemotherapy [82]. The SUNNY and TRUST studies are multicenter, randomized, controlled phase III studies comparing primary debulking surgery (PDS) with neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) in EOC in stages IIIC and IV, fallopian tube cancer, or primary peritoneal cancer. The study authors hypothesized that PDS would increase patient survival compared to NACT-IDS, and 456 people were included in the study. The study aims to identify and evaluate the role of NAC and IDS [83]. The TRUST study allows maintenance therapy using PARP inhibitors and bevacizumab.

Due to possible disease recurrence, it is crucial to constantly monitor patients. For example, the CA125 marker may be helpful; its increased concentration may be a predictor of disease recurrence.

Due to the constantly increasing knowledge of new molecular and histological features of OC, new approaches to the first-line treatment are being developed. Considering this, describing a drug with anti-angiogenic effects is essential. The most-described drug meeting this criterion so far is bevacizumab [84,85]. Bevacizumab was approved in 2011 by the EMA and then in June 2018 by the FDA as a first-line treatment in patients with stage III or IV EOC [3]. The GOG-218 study included 1873 patients with EOC randomly assigned to 3 groups. The first group received chemotherapy in the form of paclitaxel and carboplatin with placebo. The second group received paclitaxel and carboplatin with bevacizumab at a dose of 15 mg/kg body weight, in cycles 2 to 6 and placebo in cycles 7 to 22. The third group received paclitaxel, carboplatin, and bevacizumab in cycles 2 to 22. PFS in these groups was 10.3, 11.2, and 14.1 months [3].

MAINTENANCE THERAPY:

Maintenance therapy should be considered in patients who achieve a complete clinical response after primary treatment. Interestingly, a meta-analysis from 2013 did not show that the combination of chemotherapy regimens improved OS (HR=1.03) or PFS (HR=1.06) [86]. Moreover, the clinician must decide to prescribe supportive treatment with great caution, as it may be associated with numerous adverse effects. Toxicity and its possible impact on subsequent lines of treatment are topics of continuous research on further possible methods of supportive therapy.

Existing studies indicate the effectiveness and benefits of bevacizumab in combination with Olaparib or niraparib as an adjuvant therapy. It is important to remember the tumor’s molecular characteristics, as patients with HRD and BRCAm mutations will benefit most from this treatment method, which is why the tumor’s genetics are so important [6].

Which patients will benefit from PARP inhibitors in combination with bevacizumab? All 3 PARP inhibitors (Olaparib, niraparib, veliparib) together with bevacizumab are used in patients with stage IV disease and in patients who were previously treated with neoadjuvant chemotherapy [87]. Moreover, benefits have been demonstrated with the use of Olaparib or niraparib in patients with both somatic and germline BRCA mutations [61]. In turn, using Olaparib as monotherapy or in combination with bevacizumab or niraparib may be beneficial in patients who are bRCAwt- and HRD-positive [62]. For those patients with a negative HRD result, therapy with niraparib or bevacizumab should be considered [88].

Unfortunately, the incidence of EOC is still increasing. Therefore, one of the goals should be to optimize not only treatment but also diagnosis further. This involves conducting genetic tests on patients, which will help determine which patients will benefit most from therapy with PARP inhibitors. Moreover, it will also allow us to explore the options for maintenance treatment in women who received platinum-based compounds as first-line chemotherapy.

RECURRENT DISEASE:

Regrettably, many EOC patients will experience a relapse. This risk is as high as 70% for women with less than 1 cm of residual disease and as high as 85% for women with residual disease [89].

Chemotherapy is still the basic method for treating EOC recurrence. The tumor’s resistance to the platinum used during first-line treatment is important for selecting an appropriate second-line treatment method. Therefore, tumors can be categorized into refractory, platinum-resistant, partially sensitive, or very sensitive cancers, as shown in Figure 1.

In women with very sensitive or partially sensitive tumors, platinum treatment in combination with another drug may be appropriate, using carboplatin/cisplatin in combination with pegylated liposomal doxorubicin (PLD), gemcitabine, or paclitaxel. For patients at risk of platinum-related anaphylaxis, PLD with trabectedin is appropriate [90]. Patients who are platinum-resistant or platinum-refractory appear to not benefit from combination therapy.

However, surgical treatment may be an option in case of EOC recurrence. Surgery can be considered for patients who meet specific criteria, such as at least a 12-month disease-free period, complete remission, and a likelihood of achieving success with radical surgery. Moreover, according to the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Group, factors such as complete resection at the first surgery macroscopically, good performance status, and the absence of ascites with a volume greater than 500 ml are also important [91,92].

In 2020, the final results of a randomized, open-label, phase 3 trial were published. The study aimed to evaluate the standard treatment regimen with bevacizumab compared to treatment containing PLD in combination with bevacizumab. There were 682 patients qualified for the study, including 345 patients assigned to the group receiving carboplatin with PLD and bevacizumab and 337 patients to the group receiving carboplatin-gemcitabine-bevacizumab. The patients had confirmed epithelial EOC with disease recurrence more than 6 months after platinum chemotherapy. The median PFS was 12.4 and 13.3 months for both groups. Interestingly, this is the first phase 3 study to compare 2 treatment regimens with bevacizumab in patients with relapsed EOC. However, the limitations of this study are the lack of information on the BRCAm status of the patients and the lack of use of a PARP inhibitor [93].

The results of the ATALANTE/ENGOT-ov29 study (2023) are also interesting. The study included 614 patients with recurrent EOC who had previously been treated with 1 or 2 lines of chemotherapy. Patients were assigned in a 2: 1 ratio to receive atezolizumab 1200 mg once every 3 weeks or equivalent, or to placebo for up to 24 months plus bevacizumab and 6 cycles of doublet chemotherapy. The study results did not show that the difference in PFS between the atezolizumab and placebo groups reached statistical significance (13.5 vs 11.3 months). Although the study did not meet PFS goals, OS results are expected to appear at the end of 2024 and may be promising. The study may be limited by the heterogeneity of patients in terms of tumor histology. However, an essential feature of this study is de novo tumor sampling, which can provide a vast source of knowledge about tumor biomarkers and immunological characteristics. This approach is necessary to determine further research directions in treatment of EOC [94].

The results of the AGO-OVAR2.21 study also proved groundbreaking, thanks to which PARP inhibitors were included in the therapy of patients with EOC recurrence. They are used to maintain therapy in patients re-treated with platinum and who have a BRCA mutation [95].

Low-grade serous ovarian cancer (LGSOC) is a distinct clinical entity within epithelial ovarian cancers (EOCs), with unique molecular and histological features. A particular challenge in the treatment of relapsed LGSOC is its relatively low responsiveness to standard chemotherapy, especially compared to high-grade serous ovarian cancer (HGSOC). This has led to the exploration of alternative therapeutic approaches.

An open-label, randomized, phase II/III study assessed the effectiveness of the MEK1/2 inhibitor trametinib compared to 5 other treatment options (SoC group) – paclitaxel, PLD, topotecan, letrozole, or tamoxifen – in 260 patients with recurrent LGSOC. The median PFS was 13.0 in the trametinib group and 7.2 in the SoC group. The results of this study supported the NCCN panel’s approval of trametinib as category 2A in patients with relapsed LGSOC [96].

Although there are numerous methods of treating recurrent EOC, each patient should be individually assessed to choose the appropriate method. The lack of a standard order of drug administration in recurrent EOC requires considering features such as previous treatment, course of the disease, molecular and histological features of the tumor, and the effectiveness and toxicity of the previous treatment.

Upcoming Advances

ANTIBODY-DRUG CONJUGATES:

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].

IMMUNOTHERAPY:

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 INHIBITORS:

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.

Discussion

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.

Conclusions

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.