Targeting VEGF, PARP, and FRα Pathways in Ovarian Cancer: Clinical Advances with Bevacizumab, Rucaparib, and Mirvetuximab Soravtansine

Bevacizumab, commercially known as Avastin, is a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A). It was the first monoclonal antibody developed to inhibit tumor angiogenesis through direct neutralization of VEGF-A signaling and is classified as an antiangiogenic biologic agent. Structurally, bevacizumab is an IgG1 antibody engineered by grafting murine complementarity-determining regions derived from the VEGF-binding antibody A.4.6.1 onto a human IgG1 framework, thereby reducing immunogenicity while preserving binding affinity [ 39 , 40 ]. VEGF is a central proangiogenic cytokine that binds VEGF receptors (VEGFR-1 and VEGFR-2) on endothelial cells, activating downstream signaling pathways that promote endothelial cell proliferation, migration, and survival. Bevacizumab binds all biologically active isoforms of VEGF-A, preventing receptor activation and thereby suppressing angiogenesis [ 41 , 42 ]. This inhibition reduces vascular permeability, limits neovascularization, and constrains tumor growth and metastatic spread. A transient phase of “vascular normalization” may occur following treatment initiation, during which immature vessels are pruned and perfusion is temporarily improved, enhancing the delivery of cytotoxic chemotherapy [ 43 ]. However, sustained VEGF blockade may lead to excessive vessel regression, exacerbating tumor hypoxia and triggering compensatory activation of alternative proangiogenic pathways such as fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF), thereby contributing to adaptive resistance [ 44 ]. The mechanistic basis of bevacizumab’s therapeutic effects is illustrated in Figure 2 . The concept of targeting angiogenesis as a therapeutic strategy was first proposed by Judah Folkman in the 1970s [ 46 ]. Subsequent identification of VEGF as a key regulator of tumor vascularization, together with the demonstration that anti-VEGF antibodies inhibited tumor growth in preclinical models, provided the rationale for clinical development. Bevacizumab, developed by Genentech, entered first-in-human testing in 1997. Phase I studies established acceptable safety and tolerability at doses up to 10 mg/kg, with hypertension identified as the principal dose-limiting toxicity [ 47 ]. The pivotal phase III AVF2107g trial evaluated bevacizumab in combination with irinotecan, 5-fluorouracil, and leucovorin (IFL) in patients with metastatic colorectal cancer. Compared with chemotherapy alone, bevacizumab significantly improved median OS (20.3 vs. 15.6 months), PFS (10.6 vs. 6.2 months), and ORR (45% vs. 35%) [ 48 ]. These results led to U.S. Food and Drug Administration approval in 2004, making bevacizumab the first antiangiogenic agent approved for cancer treatment. Subsequent trials expanded its indications across multiple malignancies. In ovarian cancer, the GOG-0218 and ICON7 trials established the benefit of incorporating bevacizumab into carboplatin–paclitaxel regimens for advanced disease, resulting in significant prolongation of PFS [ 18 , 19 ]. In the recurrent setting, the OCEANS trial demonstrated that bevacizumab combined with carboplatin–gemcitabine significantly improved PFS in patients with platinum-sensitive recurrent ovarian cancer (12.4 vs. 8.4 months), although no overall survival (OS) benefit was observed, supporting its use at first recurrence [ 49 ]. The AURELIA trial further showed that adding bevacizumab to single-agent chemotherapy (weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan) significantly improved PFS (6.7 vs. 3.4 months) and ORRs in platinum-resistant ovarian cancer, supporting its incorporation into treatment strategies [ 50 ]. In GOG-0213, bevacizumab combined with paclitaxel–carboplatin at platinum-sensitive recurrence resulted in a significant OS benefit (42.2 vs. 37.3 months), providing the first evidence of an OS advantage for bevacizumab in ovarian cancer [ 51 ]. More recently, the MITO16B/ENGOT-ov17 (MaNGO-OV2B) trial demonstrated that continuation of bevacizumab beyond progression, in combination with platinum-based chemotherapy at platinum-sensitive relapse, significantly improved PFS compared with chemotherapy alone, supporting the strategy of bevacizumab rechallenge in appropriately selected patients [ 52 ]. Across tumor types, the clinical benefit of bevacizumab is observed more consistently in PFS than in OS, in part due to crossover and the availability of effective post-progression therapies. Meta-analyses have confirmed a statistically significant improvement in PFS across solid tumors, whereas OS benefits remain variable and context-dependent [ 53 , 54 ]. Because VEGF plays a critical role in maintaining normal vascular homeostasis, systemic inhibition is associated with a distinct toxicity profile. Hypertension is among the most common adverse effects, occurring in up to 15% of patients, and is thought to result from reduced nitric oxide production and increased vascular resistance [ 55 ]. Proteinuria and renal dysfunction arise from injury to glomerular endothelial cells. Bleeding events—ranging from mild epistaxis to severe gastrointestinal or pulmonary hemorrhage—are relatively common, and arterial thromboembolic events such as myocardial infarction and stroke, while infrequent, occur at increased rates [ 56 , 57 ]. Gastrointestinal perforation, although rare (approximately 2%), is potentially life-threatening and necessitates immediate discontinuation of therapy [ 58 ]. Impaired wound healing and wound dehiscence may also occur; consequently, bevacizumab is typically withheld for at least 28 days before and after major surgical procedures [ 59 ]. Rare but serious complications include reversible posterior leukoencephalopathy syndrome (RPLS) and thrombotic microangiopathy [ 60 ]. Resistance to VEGF-targeted therapy, such as bevacizumab, is predominantly mediated through adaptive angiogenic reprogramming. Tumors may upregulate alternative proangiogenic signaling pathways, including fibroblast growth factors (FGF), platelet-derived growth factor (PDGF), and angiopoietin-2 (ANG2), thereby bypassing VEGF blockade [ 44 , 61 ]. In addition, vascular remodeling characterized by increased pericyte coverage can stabilize tumor vasculature and reduce susceptibility to antiangiogenic therapy [ 43 ]. Hypoxia induced by VEGF inhibition may activate HIF-1α–driven transcriptional programs that promote tumor cell survival, metabolic reprogramming, and immune suppression within the tumor microenvironment [ 62 ]. These adaptive mechanisms underscore the dynamic tumor–stroma interplay under sustained antiangiogenic pressure. Resistance to bevacizumab develops through multiple mechanisms, including upregulation of alternative angiogenic signaling pathways (FGF, PDGF, ANGPT), vessel co-option, and hypoxia-driven increases in tumor invasiveness [ 63 , 64 ]. These observations have prompted the development of combination strategies incorporating bevacizumab with chemotherapy, radiotherapy, or molecularly targeted agents. In particular, combinations with ICIs have demonstrated synergistic activity [ 65 ]. Beyond immunotherapy-based combinations, accumulating mechanistic evidence supports integrating bevacizumab with PARP inhibitors and FRα-targeted therapies. VEGF inhibition–induced hypoxia may downregulate homologous recombination repair genes and increase genomic instability, thereby enhancing sensitivity to PARP inhibition, consistent with established links between hypoxia and DNA damage repair pathways [ 66 , 67 , 68 , 69 ]. This biological interaction provides a strong rationale for combining antiangiogenic therapy with DNA damage–targeting agents and may partially explain the observed clinical activity of such regimens [ 21 , 29 , 30 ]. Combination approaches may introduce additive or synergistic toxicities. When bevacizumab is combined with PARP inhibitors, overlapping adverse events include hypertension, fatigue, anemia, and gastrointestinal toxicity, reflecting the established safety profiles of both drug classes [ 55 , 56 , 57 , 58 ]. Careful blood pressure monitoring, early management of proteinuria, and proactive intervention for hematologic toxicities are therefore essential. In combinations involving mirvetuximab soravtansine, ocular toxicities—such as keratopathy and blurred vision—require prophylactic corticosteroid eye drops, dose modifications, and routine ophthalmologic monitoring, in accordance with safety data from pivotal mirvetuximab soravtansine trials [ 33 , 34 ]. When combined with immune checkpoint inhibitors (ICIs), bevacizumab may further increase the incidence of immune-related adverse events by enhancing immune cell infiltration and activation within the tumor microenvironment, as observed in antiangiogenic–ICI studies [ 65 ]. VEGF inhibition also exerts broader effects on the tumor microenvironment by normalizing tumor vasculature, improving drug delivery, and facilitating immune cell infiltration [ 63 , 64 , 65 , 70 ]. These changes may enhance the efficacy of FRα-targeted antibody–drug conjugates such as mirvetuximab soravtansine, which depend on efficient intratumoral penetration and receptor-mediated internalization. Mirvetuximab soravtansine delivers a tubulin-disrupting maytansinoid payload that induces mitotic arrest and apoptosis; combining this mechanism with angiogenesis inhibition or modulation of DNA damage response pathways may yield complementary cytotoxic effects [ 33 , 34 ]. Strong mechanistic synergy has also been demonstrated between antiangiogenic therapy and immune checkpoint (IC) inhibition. VEGF suppresses dendritic cell maturation, promotes regulatory T-cell expansion, and contributes to the development of an immunosuppressive tumor microenvironment [ 71 , 72 , 73 , 74 , 75 ]. Bevacizumab counteracts these effects by enhancing T-cell infiltration and antigen presentation, whereas ICIs amplify immune activation by blocking inhibitory signaling pathways. These complementary mechanisms have been evaluated in clinical trials across multiple solid tumors; however, definitive efficacy in ovarian cancer remains to be established [ 65 ]. Ongoing research focuses on identifying predictive biomarkers to refine patient selection for bevacizumab therapy. Candidate biomarkers—including baseline VEGF levels, circulating endothelial cells, and various genomic signatures—have been investigated; however, none has yet achieved sufficient validation for routine clinical use [ 76 , 77 , 78 , 79 , 80 ]. Therapeutic drug monitoring is not currently standard practice. Overall, bevacizumab has fundamentally reshaped cancer therapeutics by validating angiogenesis inhibition as an effective anticancer strategy. Its introduction marked a pivotal advance in oncology, catalyzing the development of subsequent VEGF-targeted therapies and establishing vascular modulation as a core principle of modern cancer treatment. Despite modest OS benefits in certain settings and a distinct toxicity profile, bevacizumab remains a cornerstone antiangiogenic agent, frequently incorporated into rational combination regimens with immunotherapy or other targeted approaches. Future directions include improved biomarker-based patient selection, strategies to overcome resistance, and optimization of combination therapies to fully realize the therapeutic potential of VEGF inhibition. Table 1 summarizes treatment-emergent adverse events (TEAEs) associated with bevacizumab and corresponding management strategies, while Table 2 highlights key pivotal trials in ovarian cancer evaluating its efficacy and safety.

Rucaparib, commercially known as Rubraca, is a small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes—primarily PARP-1, PARP-2, and PARP-3—developed for malignancies characterized by defective homologous recombination repair (HRR), including tumors harboring BRCA1 or BRCA2 mutations. It is a potent and selective PARP inhibitor with nanomolar affinity and is formulated as an oral tablet [ 86 , 87 , 88 ]. Rucaparib’s mechanism of action involves inhibition of PARP enzymatic activity, thereby preventing repair of single-strand DNA breaks (SSBs) through the base excision repair pathway. Accumulation of unrepaired SSBs leads to replication fork collapse and formation of double-strand breaks (DSBs). In tumor cells with HRR deficiencies—such as those with pathogenic BRCA1 or BRCA2 mutations—the inability to repair DSBs results in cell death via synthetic lethality [ 86 , 89 ]. In addition to catalytic inhibition, rucaparib traps PARP–DNA complexes on chromatin, generating cytotoxic lesions that impede DNA replication and transcription, thereby amplifying DNA damage and promoting apoptosis [ 31 , 90 , 91 ]. Figure 3 illustrates the therapeutic mechanism of rucaparib. The drug’s origins trace to the compound AG014699 (later CO-338 and PF-01367338), which was discovered through structure–activity optimization to achieve potent PARP1 inhibition [ 93 , 94 ]. Early medicinal chemistry studies demonstrated that enhanced PARP trapping and stabilization of DNA–PARP complexes correlated with cytotoxicity in homologous recombination–deficient (HRD) tumor models, establishing the mechanistic basis for clinical development [ 93 , 94 ]. The first-in-human study, initiated in 2003, evaluated intravenous rucaparib in advanced solid tumors and subsequently transitioned to oral dosing, including combination regimens with chemotherapy [ 95 , 96 ]. Pharmacodynamic analyses confirmed effective on-target PARP inhibition, while neutropenia and thrombocytopenia emerged as dose-limiting toxicities attributable to DNA damage accumulation in hematopoietic progenitors [ 97 , 98 , 99 ]. Subsequent phase I/II trials of oral rucaparib monotherapy in patients with germline BRCA1/2-mutated ovarian carcinoma and other solid tumors established 600 mg twice daily as the recommended phase II dose [ 86 ]. These studies defined key pharmacologic properties, including sustained PARP inhibition over the dosing interval and exposure–response relationships consistent with synthetic lethality in HRD tumors. The pivotal Study 10 reported an ORR of 59.3% (95% CI 45.0–72.4%) and a median response duration of 9.7 months in heavily pretreated ovarian cancer patients [ 100 ], underscoring the central role of BRCA-dependent DNA repair deficiency in mediating tumor sensitivity to rucaparib. The ARIEL2 trial extended these findings by stratifying patients with platinum-sensitive relapsed ovarian cancer according to BRCA mutation status and genomic loss of heterozygosity (LOH). Median PFS was 12.8 months in BRCA-mutant tumors, 5.7 months in LOH-high tumors, and 5.2 months in LOH-low tumors, validating LOH as a predictive biomarker for PARP inhibitor response [ 29 ]. This biomarker-driven strategy provided one of the earliest clinical demonstrations that HRD signatures beyond BRCA mutations could identify rucaparib-sensitive populations. Phase III ARIEL3 subsequently confirmed rucaparib’s efficacy as maintenance therapy following platinum-based chemotherapy, demonstrating significant PFS prolongation across BRCA-mutated, HRD-positive, and intent-to-treat populations [ 31 ]. The confirmatory ARIEL4 trial further demonstrated improved PFS with rucaparib compared with chemotherapy (hazard ratio 0.64) in relapsed BRCA-mutated ovarian carcinoma, completing the evidence base supporting regulatory approval [ 100 ]. Building on this foundation, the ATHENA program represents the most comprehensive evaluation of rucaparib in the frontline maintenance setting. ATHENA-MONO, a randomized phase III trial, assessed rucaparib versus placebo as maintenance therapy in patients with newly diagnosed advanced ovarian cancer who achieved a response after first-line platinum-based chemotherapy. By moving rucaparib into the first-line setting, ATHENA-MONO addressed a clinically critical question with greater potential impact than later-line single-arm studies and demonstrated a significant PFS benefit in both HRD tumors and the overall study population [ 101 ]. Within the same program, ATHENA-COMBO evaluated whether the addition of the PD-1 inhibitor nivolumab to rucaparib could further improve outcomes in the first-line maintenance setting. Despite a strong biological rationale, this large phase III study showed no PFS advantage for the combination over rucaparib monotherapy, providing important negative evidence to inform clinical practice and future trial design [ 102 ]. In parallel, the MAMOC/NOGGO Ov-42 phase III trial addressed a distinct but clinically relevant treatment sequence by enrolling patients who had already received bevacizumab maintenance following first-line carboplatin-based chemotherapy. By comparing rucaparib with placebo—particularly in BRCA-wild-type populations—this study evaluates whether PARP inhibition confers incremental benefit after antiangiogenic therapy [ 103 ]. Additionally, early-phase studies investigating rucaparib in combination with bevacizumab established the feasibility, safety profile, and recommended dosing of this doublet. Although not designed to demonstrate definitive efficacy, these trials provided critical translational and clinical support for PARP–antiangiogenic combination strategies and informed the design of subsequent randomized studies [ 104 ]. The most frequent TEAEs with rucaparib include nausea, vomiting, fatigue, anemia, and elevated transaminases. These effects reflect both on-target accumulation of unrepaired DNA lesions and off-target mitochondrial and metabolic stress. In pooled analyses of more than 500 patients, grade ≥3 adverse events included anemia (22–28%), fatigue (15–18%), and elevated AST/ALT (10–12%), resulting in dose reductions in nearly half of patients and treatment discontinuation in approximately 17% [ 31 , 86 ]. Myelosuppression—particularly neutropenia and thrombocytopenia—was dose-limiting when combined with chemotherapy, consistent with cumulative DNA damage–mediated marrow suppression [ 93 , 97 ]. Safety considerations are increasingly important as rucaparib is investigated in combination with antiangiogenic agents, ICIs, and other DNA damage response (DDR)–targeting therapies [ 31 , 93 , 97 ]. In combinations with bevacizumab, overlapping toxicities include hypertension, fatigue, anemia, and gastrointestinal adverse events due to additive VEGF- and PARP-mediated effects [ 31 , 86 ]. Clinical management requires vigilant blood pressure monitoring, early intervention for proteinuria, and proactive treatment of cytopenias [ 55 , 56 , 57 , 58 ]. Combinations with ICIs aim to enhance immunogenic cell death but may increase the risk of immune-related colitis, hepatitis, dermatitis, and endocrinopathies [ 65 , 70 ]. DDR-targeting combinations, such as rucaparib with ATR or WEE1 inhibitors, carry a heightened risk of myelosuppression and necessitate individualized dose modifications, underscoring the importance of balancing efficacy with tolerability [ 31 , 86 , 93 , 97 ]. Clinical response to rucaparib strongly correlates with HRD biomarkers. The highest response rates are observed in BRCA-mutated and HRD-positive tumors identified via LOH-based assays [ 105 , 106 , 107 ]. The U.S. Food and Drug Administration–approved companion diagnostic, FoundationFocus™ CDx_BRCA, identifies germline and somatic BRCA1/2 mutations to guide patient selection. Current combination strategies under investigation include rucaparib with bevacizumab or ICIs, aiming to exploit hypoxia-driven HRD, enhance immunogenicity, and overcome intrinsic or acquired resistance [ 108 , 109 , 110 ]. Resistance to PARP inhibitors frequently involves restoration of homologous recombination (HR) repair capacity. Secondary BRCA1/2 reversion mutations can restore protein function and reverse synthetic lethality [ 111 , 112 ]. Additional mechanisms include replication fork stabilization, loss of proteins regulating DNA repair pathway choice, and epigenetic reactivation of HR-associated genes [ 24 ]. Upregulation of drug efflux transporters, such as ABCB1, may further reduce intracellular PARP inhibitor concentrations and contribute to clinical resistance [ 113 ]. Collectively, these pathways highlight the genomic plasticity of ovarian cancer under sustained DNA damage response inhibition. Resistance mechanisms include BRCA reversion mutations restoring HRR function, upregulation of drug efflux transporters, and stabilization of stalled replication forks, which reduce PARP trapping and sensitivity to DNA damage–induced cytotoxicity. Ongoing research aims to overcome these mechanisms through rational combination strategies and more refined predictive biomarkers, including targeting ATR, CHK1, or WEE1 to destabilize fork protection or suppress HRR restoration [ 114 , 115 , 116 , 117 , 118 , 119 ]. Rucaparib is a potent oral PARP inhibitor with established efficacy in BRCA-mutated and HRD-positive ovarian and prostate cancers. Its development—from preclinical discovery to phase III validation—illustrates the successful clinical translation of synthetic lethality in targeted oncology. Current trials continue to explore its use across additional malignancies, earlier lines of therapy, and synergistic combinations, while long-term safety and mechanisms of resistance remain active areas of investigation [ 120 , 121 , 122 , 123 , 124 , 125 , 126 ]. Table 3 summarizes TEAEs and management strategies for rucaparib, and Table 4 outlines key clinical trials in ovarian cancer evaluating its efficacy and safety.

Mirvetuximab soravtansine (MIRV; brand name Elahere) is a first-in-class antibody–drug conjugate (ADC) targeting the FRα pathway. The ADC comprises a humanized IgG1 monoclonal antibody specific for FRα, linked via a cleavable sulfo-SPDB linker to the cytotoxic maytansinoid DM4 payload, with an average drug–antibody ratio (DAR) of approximately 3.5 [ 129 , 130 ]. Owing to its macromolecular composition and heterogeneity, a single molecular formula cannot be assigned to the entire ADC [ 131 , 132 , 133 ]. Mirvetuximab soravtansine selectively binds FRα, a glycosylphosphatidylinositol-anchored cell-surface protein involved in folate transport that is highly expressed in ovarian, endometrial, and other epithelial malignancies, with limited expression in normal tissues [ 131 , 134 , 135 ]. Upon binding FRα, the ADC–receptor complex undergoes endocytosis, followed by lysosomal cleavage of the linker and intracellular release of DM4 [ 136 , 137 , 138 ]. DM4 inhibits microtubule polymerization, induces G2/M mitotic arrest, and activates apoptotic pathways. The hydrophobic payload and its membrane-permeable metabolites are thought to contribute to a bystander effect, permitting cytotoxic activity in adjacent tumor cells with low or absent FRα expression [ 135 , 139 , 140 , 141 , 142 ]. Figure 4 illustrates the mechanism of action of mirvetuximab soravtansine. The first clinical evaluation of mirvetuximab soravtansine occurred in an open-label phase I dose-escalation trial in patients with FRα-positive, platinum-resistant epithelial ovarian cancer (EOC). This study established a recommended phase II dose of 6 mg/kg based on adjusted ideal body weight and demonstrated early clinical activity with a manageable safety profile [ 33 ]. The pivotal randomized phase III FORWARD I trial ( NCT02631876 ) compared mirvetuximab soravtansine monotherapy with investigator’s-choice chemotherapy in patients with platinum-resistant ovarian cancer and medium or high FRα expression. Although the primary endpoint of PFS was not met in the intent-to-treat population (HR 0.98; p = 0.897), a clinically meaningful improvement in median PFS was observed in the FRα-high subgroup (6.7 vs. 3.9 months), underscoring the importance of biomarker-driven patient selection [ 144 ]. Building on these findings, the single-arm phase II SORAYA trial ( NCT04296890 ) enrolled patients with FRα-high, platinum-resistant ovarian cancer who had received 1–3 prior therapies, including bevacizumab, and met its primary endpoint with an ORR of 32.4% and a median duration of response (DOR) of 6.9 months, supporting accelerated U.S. Food and Drug Administration approval in November 2022 [ 33 , 131 ]. Confirmatory evidence was subsequently provided by the phase III MIRASOL trial ( NCT04209855 ), which demonstrated significant improvements in PFS (5.62 vs. 3.98 months; p < 0.001), ORR (42.3% vs. 15.9%; p < 0.001), and OS (16.46 vs. 12.75 months; HR 0.67; p = 0.005) compared with chemotherapy, leading to full U.S. Food and Drug Administration approval in 2024 and European Commission approval in 2025 [ 34 , 131 , 145 , 146 ]. Across studies, pooled analyses have demonstrated consistent efficacy in FRα-high tumors, with an ORR of approximately 36% and a median PFS of approximately 6.7 months [ 147 ]. In parallel with the development of mirvetuximab soravtansine monotherapy, the multicenter phase Ib/II FORWARD II trial explored the safety and preliminary efficacy of mirvetuximab soravtansine in combination with bevacizumab, pembrolizumab, or carboplatin in patients with FRα-positive recurrent ovarian cancer across both platinum-resistant and platinum-sensitive settings. These combination cohorts demonstrated manageable toxicity profiles and early signals of enhanced antitumor activity compared with mirvetuximab soravtansine monotherapy, particularly for the mirvetuximab soravtansine–bevacizumab regimen, thereby providing a strong biological and clinical rationale for combining FRα-targeted antibody–drug conjugates with antiangiogenic or immunotherapeutic agents [ 148 , 149 ]. Building on these data, the ongoing phase III GLORIOSA trial is evaluating mirvetuximab soravtansine plus bevacizumab versus bevacizumab alone as maintenance therapy in patients with FRα-high ovarian cancer who have responded to second-line platinum-based chemotherapy combined with bevacizumab. By addressing a common real-world treatment sequence and moving mirvetuximab soravtansine earlier in the disease course, GLORIOSA represents a critical step in defining the long-term role of FRα-targeted therapy within ovarian cancer treatment algorithms [ 150 ]. Combination strategies—including mirvetuximab soravtansine with bevacizumab, ICIs, and platinum-based chemotherapy—are under active investigation and show early evidence of synergistic activity. Mechanistically, antiangiogenic therapy normalizes tumor vasculature, improving ADC delivery and intratumoral penetration, while ICIs may amplify the immunogenic effects of DM4-induced tumor cell death. Platinum-based chemotherapy may induce DNA damage that sensitizes tumor cells to mirvetuximab soravtansine–mediated cytotoxicity, collectively producing complementary antitumor effects. These combination regimens, however, may introduce additive or synergistic toxicities requiring careful management. For example, ocular toxicity associated with mirvetuximab soravtansine may be exacerbated in combinations with agents that induce microvascular or inflammatory stress, while overlapping hematologic or gastrointestinal adverse events may occur with chemotherapy or antiangiogenic therapy. Proactive management strategies include ophthalmologic monitoring, dose adjustments, prophylactic ocular lubrication, and close surveillance for hematologic or gastrointestinal adverse events [ 147 , 151 , 152 ]. Resistance to FRα-targeted antibody–drug conjugates (ADCs), such as mirvetuximab soravtansine, may arise through both target-dependent and payload-dependent mechanisms. Heterogeneous or reduced FRα expression can limit effective antibody binding and internalization [ 153 ]. Alterations in receptor-mediated endocytosis and intracellular trafficking may impair lysosomal processing and cytotoxic payload release [ 154 ]. Additionally, resistance to the microtubule-targeting payload may develop through tubulin alterations or increased expression of multidrug resistance transporters, resulting in efflux pump–mediated drug export [ 155 ]. Collectively, these mechanisms underscore the importance of sustained antigen expression and intact intracellular processing for optimal ADC efficacy. Common adverse events with mirvetuximab soravtansine monotherapy include blurred vision (≈41–43%), keratopathy (≈30%), nausea (≈41%), diarrhea (≈39%), and fatigue (≈35%). Grade ≥3 toxicities (48%) are primarily ocular events and fatigue, although discontinuation rates remain relatively low (approximately 12%) [ 33 , 132 ]. Ocular toxicity is attributed to DM4-mediated microtubule disruption in corneal epithelial cells and is managed with dose modifications, prophylactic ocular lubrication, and routine ophthalmologic monitoring [ 147 , 151 ]. High FRα expression—defined as ≥75% of tumor cells demonstrating ≥2+ membrane staining using the VENTANA FOLR1 RxDx assay—is essential for optimal patient selection and therapeutic efficacy [ 147 , 156 , 157 ]. Collectively, these characteristics position mirvetuximab soravtansine as a paradigm of precision ADC therapy in ovarian cancer, combining targeted receptor engagement with potent intracellular cytotoxicity. Its pharmacologic profile and emerging combination strategies provide clinically meaningful benefit in a population with limited treatment options while underscoring the importance of monitoring and managing additive toxicities [ 158 , 159 , 160 , 161 ]. Table 5 summarizes treatment-emergent adverse events and management strategies for mirvetuximab soravtansine, while Table 6 highlights major clinical trials in ovarian cancer evaluating its efficacy and safety, including completed, ongoing, and planned studies.

The therapeutic landscape of ovarian cancer has been fundamentally transformed by the advent of targeted therapies directed against the VEGF, PARP, and FRα pathways. These approaches have redefined modern treatment algorithms by enabling biomarker-driven patient selection, tailoring therapy to molecular vulnerabilities, and exploiting tumor-specific dependencies. Their integration marks a shift from traditional cytotoxic regimens toward precision oncology frameworks that account for intratumoral heterogeneity, dynamic molecular evolution, and tumor microenvironmental influences as key determinants of therapeutic efficacy. However, despite these advances, the clinical impact of targeted therapies remains constrained by several important limitations that warrant critical consideration. Key challenges include intrinsic and acquired resistance, variability in target expression both between and within patients, and unresolved questions regarding the optimal sequencing, duration, and combination of therapies. In addition, treatment-related toxicities, while often more manageable than those associated with conventional cytotoxic chemotherapy, remain clinically meaningful and may limit long-term adherence—particularly in the context of chronic maintenance strategies. Accessibility and cost represent additional barriers, as the widespread implementation of biomarker testing, antibody–drug conjugates, and prolonged targeted therapy may exacerbate disparities across health systems and geographic regions. These considerations underscore the need for treatment strategies that not only improve efficacy but also preserve tolerability, affordability, and real-world feasibility. Emerging strategies—including deubiquitinase (DUB) inhibitors, nanoparticle-based delivery systems, and bispecific antibody platforms—reflect ongoing innovation and highlight the necessity of integrated approaches that address both tumor biology and the broader clinical context [ 164 , 165 , 166 , 167 , 168 , 169 ]. Future directions are expected to emphasize refined biomarker-guided allocation, mechanistically rational combination strategies, and advanced delivery technologies designed to maximize therapeutic index while minimizing systemic toxicity and financial burden [ 170 , 171 , 172 , 173 ]. The integration of biomarker testing into routine clinical workflows is essential for optimizing therapeutic sequencing in epithelial ovarian cancer. With the expanding use of PARP inhibitors and antibody–drug conjugates, timely and appropriate assessment of BRCA mutation status, HRD, and FRα expression has become central to individualized treatment planning [ 174 , 175 ]. BRCA1/2 testing is recommended at the time of diagnosis for all patients with epithelial ovarian cancer, regardless of family history [ 174 ]. Germline testing should be performed first because of its therapeutic and hereditary implications. If germline testing is negative, somatic tumor testing is recommended to identify acquired BRCA mutations [ 175 ]. Identification of pathogenic BRCA variants directly informs eligibility for PARP inhibitor therapy in both first-line maintenance and recurrent settings, given the established benefit of PARP inhibition in BRCA-mutated disease [ 26 , 27 ]. Early testing ensures that maintenance strategies can be implemented without delay following response to platinum-based chemotherapy. HRD testing is typically performed on tumor tissue at diagnosis or during first-line treatment planning. Commercial genomic instability assays evaluate loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions as markers of genomic scarring [ 176 ]. HRD status has predictive value for PARP inhibitor benefit beyond BRCA-mutated tumors, particularly in the maintenance setting [ 27 , 28 ]. However, important limitations remain, including inter-assay variability, evolving definitions of HRD positivity, and the dynamic nature of homologous recombination restoration over time [ 32 ]. In recurrent disease, prior PARP inhibitor exposure may lead to reversion mutations that restore homologous recombination function, thereby complicating biomarker interpretation. FRα expression testing is required before treatment with FRα-targeted antibody–drug conjugates such as mirvetuximab soravtansine. Assessment is performed using immunohistochemistry, with expression thresholds defined according to criteria used in pivotal clinical trials [ 153 ]. In the platinum-resistant setting, high FRα expression has been associated with improved clinical benefit from mirvetuximab soravtansine compared with chemotherapy [ 143 , 153 , 177 ]. Practical considerations include intratumoral heterogeneity, potential discrepancies between archival and recent biopsy specimens, and modulation of antigen expression following prior systemic therapy. Within the domain of VEGF inhibition, bevacizumab remains the benchmark antiangiogenic agent for ovarian cancer, consistently improving PFS across first-line, interval debulking, and recurrent disease settings [ 18 , 178 ]. However, the magnitude and durability of benefit are variable, and OS gains have been inconsistent, raising questions regarding optimal patient selection and treatment duration. Resistance frequently emerges through upregulation of alternative proangiogenic pathways, extracellular matrix remodeling, pericyte-mediated vascular stabilization, and hypoxia-driven metabolic adaptation, collectively diminishing long-term efficacy. Moreover, bevacizumab-associated toxicities—including hypertension, proteinuria, thromboembolic events, and gastrointestinal perforation—necessitate careful patient selection and vigilant monitoring. To address these limitations, contemporary trials are evaluating combinations of bevacizumab with ICIs and PARP inhibitors, leveraging its capacity to normalize tumor vasculature, reduce hypoxia, enhance immune infiltration, and improve drug delivery. This strategy positions antiangiogenic therapy as a microenvironment-modifying backbone capable of potentiating immunotherapy and DNA damage response (DDR)–targeted approaches, although the optimal sequencing and safety of such combinations remain active areas of investigation [ 179 , 180 , 181 , 182 ]. PARP inhibitors, including rucaparib, have revolutionized the management of high-grade serous ovarian carcinoma by exploiting defects in homologous recombination DNA repair, particularly in BRCA1/2-mutated and HRD-positive tumors in which synthetic lethality yields robust clinical responses [ 183 , 184 ]. Nonetheless, their long-term utility is limited by the emergence of resistance mechanisms, including BRCA reversion mutations restoring homologous recombination proficiency, upregulation of drug efflux transporters, stabilization of stalled replication forks, and DDR pathway rewiring that circumvents PARP dependence [ 185 , 186 ]. In addition, cumulative toxicities—such as anemia, thrombocytopenia, fatigue, and rare cases of myelodysplastic syndrome—pose challenges for prolonged maintenance therapy, particularly in older or comorbid populations. Strategies to overcome resistance include combination regimens targeting complementary DDR pathways (ATR, WEE1, CHK1), integration with ICIs, and pairing with antiangiogenic agents to exploit immunologic and microenvironmental vulnerabilities [ 187 , 188 , 189 ]. Outstanding clinical questions include the role of PARP inhibitor rechallenge, optimal management after prior PARP exposure, and expansion of benefit to HRD-intermediate or homologous recombination–proficient tumors. Advances in circulating tumor DNA (ctDNA) profiling, methylation-based biomarkers, and liquid biopsy–based monitoring may enable real-time detection of emerging resistance and inform adaptive, personalized treatment strategies [ 190 , 191 ]. FRα-targeted therapy, exemplified by mirvetuximab soravtansine, represents a major advance in precision oncology by selectively targeting a glycoprotein highly expressed in epithelial ovarian cancers while sparing most normal tissues [ 192 , 193 , 194 ]. The pivotal SORAYA and MIRASOL trials demonstrated superior response rates, improved tolerability, and favorable patient-reported outcomes in FRα-high, platinum-resistant disease compared with standard chemotherapy, establishing mirvetuximab soravtansine as a key therapeutic option in this historically refractory population [ 34 ]. Nevertheless, clinical implementation raises unresolved questions regarding optimal FRα expression thresholds, resistance mechanisms, sequencing after prior ADC exposure, and access to standardized, reproducible testing platforms. Ongoing trials, including GLORIOSA and PICCOLO, aim to define its role earlier in the disease course and in combination or maintenance settings to improve response durability [ 153 ]. Future development efforts include next-generation FRα-targeted ADCs with optimized payloads, enhanced linker stability, improved internalization, and bispecific constructs capable of engaging immune effector cells. Rational combinations with ICIs or DNA-damaging agents may further enhance efficacy, although safety, cost, and cumulative toxicity will require careful evaluation [ 195 , 196 ]. Artificial intelligence–assisted imaging, digital pathology, and transcriptomic profiling may improve the accuracy and reproducibility of FRα assessment, thereby optimizing patient selection. Although this review summarizes pivotal clinical trial outcomes across antiangiogenic agents, PARP inhibitors, and FRα-targeted ADCs, careful methodological interpretation is warranted. Cross-trial comparisons are inherently limited because of substantial heterogeneity in study design and patient populations. Trials differ with respect to platinum sensitivity (platinum-sensitive versus platinum-resistant cohorts), number of prior treatment lines, maintenance versus active treatment settings, and biomarker enrichment strategies (e.g., BRCA-mutated, HRD-positive, or FRα-high populations) [ 197 , 198 ]. In addition, variability in HRD assays and companion diagnostics introduces further complexity when comparing outcomes across studies [ 176 ]. Importantly, evolving standards of care—including prior exposure to PARP inhibitors or bevacizumab—also influence trial results and limit historical comparability. Accordingly, indirect comparisons across antiangiogenic trials, PARP inhibitor maintenance studies, and FRα-targeted ADC trials should be interpreted with caution. Differences in eligibility criteria, stratification factors, control arms, and post-progression treatments may substantially affect reported efficacy outcomes [ 197 ]. Apparent variations in median PFS or ORRs across studies should not be construed as evidence of relative superiority in the absence of head-to-head randomized data. Interpretation of clinical endpoints also requires nuance. While PFS improvement is a commonly used primary endpoint—particularly in maintenance settings—it does not consistently translate into OS benefit [ 199 ]. In several first-line maintenance trials, OS data remain immature at the time of reporting, limiting definitive conclusions regarding long-term survival impact [ 27 , 28 ]. Furthermore, crossover designs and access to effective subsequent therapies may attenuate OS differences between treatment arms, thereby complicating survival analyses [ 199 ]. Variability in follow-up duration, adverse event reporting standards, and definitions of treatment discontinuation further challenges cross-study safety comparisons. By incorporating these considerations, this review promotes balanced interpretation of the evidence base, minimizes the risk of overgeneralization, and strengthens the academic rigor of the discussion surrounding contemporary therapeutic strategies in ovarian cancer. The convergence of VEGF inhibition, PARP inhibition, and FRα-directed cytotoxic delivery provides a compelling framework for rational triplet strategies that simultaneously disrupt angiogenesis, DNA repair, and receptor-mediated drug delivery. Preclinical studies suggest synergistic interactions: VEGF blockade enhances immune infiltration and drug access through vascular normalization; PARP inhibition promotes immunogenic cell death and interferon signaling; and FRα-targeted ADC cytotoxicity may be amplified in immune-active or vascularly normalized tumors [ 200 , 201 ]. However, translating these strategies into clinical practice will require careful attention to overlapping toxicities, optimal sequencing, patient selection, and cost-effectiveness, as well as validation in biomarker-driven trials. Innovations in ADC engineering—including site-specific conjugation, advanced linker chemistries, and next-generation payloads with improved safety profiles—are expanding the therapeutic window of FRα-targeted agents. Similarly, next-generation PARP inhibitors with enhanced catalytic and trapping activity may help overcome resistance while preserving tolerability [ 202 , 203 ]. Incorporation of real-world evidence, patient-reported outcomes, and adaptive clinical trial designs will be critical to defining long-term benefit–risk profiles and ensuring equitable access across diverse patient populations. Collectively, the integration of VEGF, PARP, and FRα inhibition exemplifies biologically rational, precision-guided therapy in gynecologic malignancies. Sustained progress will depend on multidisciplinary collaboration across molecular biology, pharmacology, immunology, data science, and clinical oncology to address unresolved clinical questions, mitigate toxicity, improve affordability, and translate mechanistic insights into durable and equitable clinical benefit [ 204 , 205 , 206 ]. As oncologic outcomes improve, increasing numbers of long-term survivors necessitate greater attention to survivorship issues, including quality of life and fertility preservation. This consideration is particularly relevant for reproductive-age women with ovarian or endometrial cancer, for whom oocyte vitrification and other fertility-preserving strategies should be discussed early in treatment planning [ 207 ]. Contemporary management increasingly incorporates neoadjuvant chemotherapy, targeted therapies, and minimally invasive surgical approaches. Bevacizumab-based regimens [ 208 ] and neoadjuvant chemotherapy [ 209 ] have demonstrated efficacy and acceptable safety, potentially allowing greater flexibility for fertility preservation; however, gonadotoxic risks persist and mandate timely counseling [ 207 ]. Emerging insights into the epigenetic landscape of endometrial cancer—including chromatin modifications—have enhanced understanding of tumor biology and therapeutic response [ 210 ]. These advances may inform personalized treatment, reproductive counseling, and long-term surveillance strategies. Quality-of-life outcomes following extensive surgical procedures, such as pelvic exenteration, further underscore the importance of addressing the physical, psychological, and reproductive consequences of treatment [ 211 ]. Fertility preservation therefore represents a critical component of survivorship care and patient-centered oncology [ 207 ]. Minimally invasive surgical approaches, including conventional and minilaparoscopic hysterectomy, demonstrate favorable perioperative outcomes and reduced morbidity, potentially facilitating fertility-sparing options while decreasing treatment burden. These approaches also raise medico-legal considerations, reinforcing the importance of informed consent and adherence to evidence-based guidelines [ 212 ]. The growing demand for fertility preservation in oncology carries ethical and legal implications, and failure to address reproductive risks and options may adversely affect patient satisfaction and long-term psychosocial outcomes [ 207 ]. Integrating fertility preservation into standard oncologic care is thus both a clinical necessity and an ethical imperative. Table 7 presents a clinically focused overview of current treatment strategies for epithelial ovarian cancer, outlining indications, representative regimens or agents, key biomarkers and toxicity considerations, and supporting guideline and clinical trial evidence. Figure 5 illustrates the contemporary management pathway of ovarian cancer.

Ovarian cancer remains one of the most challenging malignancies in gynecologic oncology, accounting for a disproportionate burden of cancer-related mortality among women worldwide despite significant advances in surgical techniques and systemic therapies [ 1 , 2 , 3 , 4 ]. Epithelial ovarian carcinoma (EOC), which comprises approximately 90% of ovarian malignancies, carries the highest mortality rate among gynecologic cancers, largely because most patients present with advanced-stage disease. This delayed diagnosis reflects the nonspecific nature of early symptoms and the persistent lack of an effective population-based screening strategy capable of reliably detecting early-stage disease [ 5 , 6 , 7 ]. Even among patients who undergo optimal cytoreductive surgery followed by first-line platinum-based chemotherapy, recurrence is common, and many ultimately develop platinum-resistant disease—an inflection point that markedly diminishes the efficacy and durability of conventional cytotoxic treatments [ 8 , 9 , 10 ]. Ovarian cancer is a biologically heterogeneous disease encompassing multiple histologic and molecular subtypes, each characterized by distinct patterns of behavior, prognosis, and therapeutic vulnerability. High-grade serous carcinoma (HGSC), the most common and lethal subtype, is defined by near-universal TP53 mutations, frequent defects in homologous recombination DNA repair—including BRCA1/2 mutations—and extensive genomic instability. These molecular features underlie both the relative chemosensitivity of HGSC and its susceptibility to DNA repair–targeted therapies. In contrast, low-grade serous carcinoma (LGSC) follows a more indolent clinical course, is frequently driven by MAPK pathway alterations such as KRAS and BRAF mutations, and demonstrates limited responsiveness to conventional chemotherapy but potential sensitivity to hormonal and MAPK-directed therapies. Endometrioid ovarian carcinoma, often associated with endometriosis, commonly harbors alterations in PTEN, ARID1A, and mismatch repair genes and typically presents at earlier stages with more favorable outcomes. Clear cell carcinoma, also linked to endometriosis, is characterized by ARID1A loss and activation of PI3K/AKT signaling and is notable for its relative chemoresistance, whereas mucinous carcinoma is rare, molecularly resembles gastrointestinal malignancies, and similarly responds poorly to standard chemotherapy. This profound biological diversity underscores the need for precision-based therapeutic strategies tailored to tumor-specific molecular features [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. The incorporation of molecularly targeted therapies into clinical practice has significantly expanded therapeutic options and reshaped the management landscape of ovarian cancer by intervening in key biological pathways that drive tumor growth and survival, including angiogenesis, DNA damage repair, and folate receptor–mediated cellular uptake [ 11 , 12 , 13 , 14 ]. Inhibition of vascular endothelial growth factor (VEGF) disrupts tumor angiogenesis and perfusion; poly(ADP-ribose) polymerase (PARP) inhibition exploits homologous recombination deficiency (HRD) to induce synthetic lethality; and folate receptor-alpha (FRα)–targeted strategies enable selective delivery of cytotoxic agents to tumor cells that overexpress this receptor [ 15 , 16 , 17 ]. Together, these approaches represent a shift away from treatment paradigms based solely on disease stage, tumor burden, or platinum sensitivity toward more individualized, biology-driven therapeutic decision-making. Although multiple narrative reviews have independently examined antiangiogenic agents, PARP inhibitors, or antibody–drug conjugates in ovarian cancer, fewer have synthesized these modalities within a unified, biomarker-driven clinical framework. The novelty of the present review lies in its integrative analysis of three cornerstone targeted strategies—VEGF inhibition, PARP inhibition, and FRα-directed therapy—across the disease continuum, with particular emphasis on therapeutic sequencing, resistance evolution, and real-world clinical decision-making. By anchoring molecular mechanisms to pivotal trial data and emerging biomarkers, this manuscript aims to clarify how these agents can be optimally deployed, alone or sequentially, to maximize durability of response while anticipating resistance. In doing so, the review provides added value beyond descriptive summaries by offering a forward-looking perspective on treatment integration and future research priorities. Bevacizumab, a monoclonal antibody targeting VEGF-A, was the first antiangiogenic agent to be widely incorporated into standard ovarian cancer treatment. The pivotal GOG-0218 and ICON7 trials demonstrated that the addition of bevacizumab to platinum–taxane chemotherapy, followed by maintenance therapy, resulted in significant improvements in progression-free survival (PFS), with the greatest benefit observed in patients with high-risk clinical features such as suboptimal cytoreduction or stage IV disease [ 18 , 19 ]. These findings established bevacizumab as a key component of therapy across frontline, recurrent, and platinum-resistant settings. The subsequent development of PARP inhibitors—including rucaparib, olaparib, and niraparib—further transformed the therapeutic landscape, particularly for patients with BRCA-mutated or HRD-positive tumors [ 20 , 21 , 22 ]. PARP inhibitors exert their antitumor activity through inhibition of the PARP1/2 enzymes involved in single-strand DNA break repair. In tumors with deficient homologous recombination repair—most notably those harboring BRCA1/2 mutations—PARP inhibition induces synthetic lethality by promoting the accumulation of DNA damage, replication fork collapse, and ultimately cell death [ 23 , 24 ]. In addition to catalytic inhibition, PARP trapping on DNA further enhances cytotoxicity and contributes to clinical efficacy [ 25 ]. Several PARP inhibitors have been developed and evaluated in ovarian cancer across frontline and recurrent settings. Olaparib was the first-in-class agent to demonstrate significant benefit as maintenance therapy in BRCA-mutated ovarian cancer and subsequently in broader homologous recombination–deficient populations [ 26 , 27 ]. Its clinical development has included both recurrent platinum-sensitive disease and first-line maintenance following response to platinum-based chemotherapy. Niraparib subsequently demonstrated efficacy as maintenance therapy in newly diagnosed and recurrent ovarian cancer, including in biomarker-selected (HRD-positive) as well as overall study populations [ 28 ]. Rucaparib has demonstrated durable and clinically meaningful efficacy in both treatment and maintenance settings, as evidenced by the ARIEL2 and ARIEL3 trials, while maintaining a manageable safety profile [ 29 , 30 ]. Its clinical development program has encompassed recurrent platinum-sensitive ovarian cancer and biomarker-defined subgroups, including patients with HRD, further establishing its role across distinct therapeutic contexts [ 31 ]. PARP inhibitors are now foundational therapies in both newly diagnosed and recurrent ovarian cancer, and ongoing clinical investigations are evaluating combination strategies with antiangiogenic agents and immune checkpoint inhibitors (ICIs) to enhance and extend therapeutic benefit. Although this manuscript discusses rucaparib in greater detail as a representative example in selected sections, the underlying therapeutic principles—including synthetic lethality, HRD as a predictive biomarker, and mechanisms of acquired resistance—are broadly applicable across the PARP inhibitor class [ 24 , 32 ]. More recently, mirvetuximab soravtansine, an FRα-targeted antibody–drug conjugate (ADC), has emerged as a significant therapeutic advance for patients with platinum-resistant ovarian cancer. The SORAYA and MIRASOL trials reported substantial improvements in objective response rates (ORRs), disease control, and tolerability among patients with high FRα expression, representing the first meaningful therapeutic progress for this population in several years [ 33 , 34 ]. By selectively delivering a potent maytansinoid payload to FRα-overexpressing tumor cells, mirvetuximab soravtansine achieves targeted cytotoxicity while minimizing off-target toxicity to normal tissues. Collectively, VEGF inhibitors, PARP inhibitors, and FRα-targeted ADCs exemplify the ongoing transition toward biomarker-driven, pathway-specific therapy in ovarian cancer [ 35 , 36 ]. Beyond summarizing efficacy data, this review emphasizes how these agents can be strategically positioned across lines of therapy, informed by tumor biology, prior treatment exposure, and evolving resistance mechanisms. Current and future research efforts focus on elucidating mechanisms of acquired resistance, refining predictive biomarkers, and optimizing rational combination regimens, with the overarching goal of extending therapeutic benefit to a broader and more diverse population of patients affected by this disease [ 37 , 38 ]. For this synthesis, a narrative literature review was conducted using the PubMed and Scopus databases. Search terms included “bevacizumab,” “rucaparib,” and “mirvetuximab soravtansine,” in combination with “targeted therapy” and “ovarian cancer.” Peer-reviewed publications published between 2005 and 2025 were selected based on relevance, methodological rigor, and contribution to understanding therapeutic efficacy, mechanisms of action, and resistance. Both preclinical and clinical studies were included when they provided meaningful mechanistic insight or informed clinical decision-making. This approach yielded a comprehensive synthesis of current evidence highlighting the evolving roles, benefits, and limitations of bevacizumab, rucaparib, and mirvetuximab soravtansine in contemporary ovarian cancer management. Figure 1 illustrates a clinical decision algorithm for ovarian cancer incorporating key trial anchors to guide biomarker-driven therapy.

The advent of targeted therapies against the VEGF, PARP, and FRα pathways has fundamentally transformed the therapeutic landscape of epithelial ovarian cancer. Bevacizumab, rucaparib, and mirvetuximab soravtansine exemplify three complementary strategies that address tumor angiogenesis, genomic instability, and receptor-mediated cytotoxicity. Their integration into clinical practice has improved outcomes in selected patient populations and underscores the central role of precision medicine in gynecologic oncology. VEGF inhibition with bevacizumab provided early proof that modulation of the tumor microenvironment can confer meaningful clinical benefit. PARP inhibitors subsequently revolutionized care by exploiting synthetic lethality in BRCA-mutated and homologous recombination–deficient tumors, establishing durable maintenance strategies in both frontline and recurrent settings. FRα-targeted antibody–drug conjugates, such as mirvetuximab soravtansine, have extended precision therapy into the platinum-resistant setting, offering a critical therapeutic advance for patients previously limited to palliative chemotherapy. Collectively, these developments reflect the evolution of ovarian cancer treatment into a biologically informed discipline in which tumor-specific molecular characteristics increasingly guide therapeutic selection. Despite these advances, substantial challenges remain. Therapeutic resistance, optimal sequencing, cumulative toxicity, and economic considerations continue to limit long-term benefit. The development of robust, clinically actionable biomarkers—such as dynamic measures of FRα expression, refined assessments of homologous recombination repair competency, and angiogenic signatures—will be essential to optimize patient selection and guide rational combination strategies. Future progress will likely depend on synergistic approaches incorporating ICIs and next-generation DNA damage response modulators to enhance antitumor immunity and circumvent mechanisms of resistance. Targeting VEGF, PARP, and FRα represents a decisive shift from empiric cytotoxic therapy toward mechanism-based, individualized management of ovarian cancer. Continued translational research, innovative clinical trial design, and multidisciplinary collaboration will be critical to defining the optimal integration of these agents within multimodal treatment paradigms. Ultimately, the goal remains to transform ovarian cancer into a chronic, manageable disease through earlier, more strategic intervention and precise molecular targeting.