Search Results (17)

Ovarian cancer is a major cause of gynecological cancer mortality, frequently associated with platinum-resistant recurrences. Given the limited efficacy of conventional chemotherapy in this setting, alternative targeted therapeutics are needed. Mirvetuximab soravtansine (MIRV) is an antibody–drug conjugate designed to deliver the cytotoxic maytansinoid DM4 to folate receptor alpha (FRα)-overexpressing cells. This systematic review of PubMed, ClinicalKey, and SpringerLink databases (2019–2026) evaluates five publications across three clinical trials (one phase II, two phase III) encompassing 925 patients with platinum-resistant disease. Notably, the phase III MIRASOL trial demonstrated improved survival outcomes with MIRV over standard chemotherapy, extending median overall survival (16.46 vs. 12.75 months; HR 0.67) and progression-free survival (5.62 vs. 3.98 months; HR 0.65), with an objective response rate (ORR) of 42.3% versus 15.9%. Furthermore, the single-arm phase II SORAYA trial reported an ORR of 32.4% in pretreated patients, including those with prior PARP inhibitor and bevacizumab exposure. Although the preceding FORWARD I trial missed its primary endpoint in the unselected population, its high-FRα subgroup analysis revealed a clinical benefit that influenced subsequent biomarker-driven enrollment strategies. From a safety perspective, MIRV exhibited lower rates of severe neutropenia and anemia than chemotherapy, with toxicities primarily consisting of manageable, reversible ocular events. Ultimately, MIRV serves as a therapeutic option for platinum-resistant, FRα-positive ovarian cancer, offering survival advantages; however, rigorous biomarker-based screening remains necessary to optimize therapeutic outcomes. Full article

Background: Folate receptor alpha (FRα), commonly expressed in epithelial ovarian cancers, is a clinically actionable biomarker following approval of the antibody–drug conjugate mirvetuximab soravtansine (MIRV). Pivotal trials showed that high FRα expression predicts MIRV benefit, creating the need for standardized testing to ensure timely, equitable access. Methods: To address the need for guidance on FRα testing, the Society of Gynecologic Oncology of Canada convened a multidisciplinary Expert Panel to review the evidence and integrate Canadian clinical, pathology, laboratory, and patient perspectives. Consensus recommendations were developed through structured evidence review, expert discussion, iterative revision, and patient partner input. Results: The panel issued recommendations on the clinical role and timing of FRα testing, tissue requirements, assay selection and validation, interpretation and reporting standards, laboratory quality assurance, reimbursement, and equitable access. It is recommended that FRα testing be available to all patients with epithelial ovarian cancer, with results available no later than platinum-resistant disease, using a validated assay, preferably the Ventana FOLR1 RxDx assay or an appropriately validated laboratory-developed test. Standardized synoptic reporting, participation in external quality assurance programs, and clear patient communication were deemed essential. Conclusions: These recommendations aim to promote integrated, equitable, standardized FRα testing across Canada and support timely identification of patients eligible for FRα-directed therapy, clinical trial enrollment, and future biomarker-driven treatment strategies. Full article

Background: Mirvetuximab soravtansine (MIRV) improves outcomes in FRα-positive, platinum-resistant ovarian cancer; however ocular adverse events (OAEs), particularly corneal epithelial toxicity, are frequent and warrant structured ophthalmologic monitoring. Methods: In this retrospective observational study, 31 consecutive patients receiving MIRV for FRα-positive gynecologic malignancies underwent standardized ophthalmic assessments at baseline and prior to each treatment cycle (every 21 days). The protocol included best corrected visual acuity (BCVA), slit-lamp biomicroscopy, anterior-segment optical coherence tomography (AS-OCT), corneal topography, and tear film analysis. OAEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, based on symptom severity and functional impairment. Results: OAEs occurred in all patients (31/31, 100%), predominantly grade 1–2. Corneal epithelial toxicity was documented in 28/31 patients (90.3%), while no grade ≥ 3 events were observed. Symptoms typically developed 7–14 days after the second infusion. AS-OCT and corneal topography consistently revealed epithelial microcysts and surface irregularities, which were usually detected during scheduled pre-cycle ophthalmologic evaluations. Tear-film instability (break-up time ≤ 5 s) developed in 19/31 patients (61.3%), generally within 10 days after the second infusion, and improved in all but 2 patients (6.5%) following prophylactic lubrication. Transient refractive changes occurred in 28/31 patients (90.3%) and were associated with a temporary BCVA reduction (mean nadir ~20/32 Snellen), followed by recovery during follow-up. Conclusions: MIRV-related ocular alterations are frequent but reversible and clinically manageable. Multimodal imaging combined with functional and refractive assessment provides sensitive markers of corneal epithelial toxicity and supports integrated ophthalmologic monitoring to preserve visual function and maintain oncologic treatment continuity. Full article

Ovarian cancer remains a leading cause of gynecologic cancer–related mortality worldwide, and long-term outcomes with conventional cytotoxic chemotherapy remain limited. The integration of targeted therapies has substantially reshaped treatment paradigms by exploiting key molecular pathways involved in angiogenesis, DNA damage repair, and folate receptor signaling. This review synthesizes evidence from pivotal phase II and III clinical trials, translational studies, and meta-analyses evaluating inhibition of the VEGF, PARP, and folate receptor-alpha (FRα) pathways, with a focus on bevacizumab, rucaparib, and mirvetuximab soravtansine. Across disease settings, these agents have demonstrated clinically meaningful improvements in progression-free survival, durability of response, and tolerability when deployed in biomarker-selected populations. Bevacizumab has shown consistent benefit when combined with platinum-based chemotherapy and as maintenance therapy in advanced disease. PARP inhibitors, including rucaparib, exploit homologous recombination deficiency (HRD) to induce synthetic lethality and are now central to frontline and recurrent treatment strategies for BRCA-mutated and HRD-positive tumors. Mirvetuximab soravtansine has emerged as an effective and well-tolerated option for patients with FRα-high, platinum-resistant ovarian cancer, addressing a longstanding unmet clinical need. Collectively, VEGF-, PARP-, and FRα-targeted therapies have enabled more rational treatment sequencing, informed combination strategies, and personalized clinical decision-making in ovarian cancer. Ongoing efforts to define optimal sequencing, overcome acquired resistance, and refine predictive biomarkers are expected to further enhance the durability and breadth of benefit from targeted therapies and advance precision oncology in gynecologic malignancies. Full article

Background: Folate receptor alpha (FRα) is a glycosylphosphatidylinositol-anchored membrane protein encoded by the FOLR1 gene. Its overexpression in various cancers, including ovarian carcinoma, makes it a promising target for antibody-drug conjugates (ADC). Mirvetuximab soravtansine-gynx, an FRα-targeting ADC, has been approved by the FDA and EMA for the treatment of FRα-positive, platinum-resistant ovarian cancer. In the United States, patient selection is tied to the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay, an immunohistochemical (IHC) test that identifies tumors with ≥75% moderate-to-strong membrane staining. However, in the European Union, no specific IHC test is mandated, and alternative antibodies are frequently used in routine pathology, necessitating validation of their diagnostic performance. Methods and Results: We report the results of the first interlaboratory proficiency trial on FRα testing conducted by the German Quality Assurance Initiative in Pathology (QuIP^®). Sixty-eight pathology institutes participated across internal and open trials using a variety of antibodies and staining platforms. The VENTANA FOLR1 RxDx Assay demonstrated the highest reliability, with 83% of participating laboratories achieving a successful result. In contrast, alternative clones such as BN3.2 (Leica/Novocastra) and EPR20277 (Abcam) showed substantially weaker staining intensity, lower concordance with reference values, and success rates of only 22–25%, while other antibodies failed entirely. Problem analysis revealed that failures with the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay were mainly due to interpretative challenges, whereas weak staining was the predominant issue with alternative clones. Participation in a preparatory online seminar improved pass rates, underscoring the importance of training. Conclusions: These findings highlight the critical importance of standardized, validated assays for FRα detection to ensure accurate patient selection for targeted therapies. The study emphasizes the need for further optimization of alternative antibodies before clinical implementation. Full article

Background: Antibody-drug conjugates (ADCs) have ushered in a new era of precision oncology by combining the targeting specificity of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic drugs. However, the cellular and molecular mechanisms underlying their dose-limiting ocular toxicity remain unclear. Elahere™, the first FDA-approved ADC targeting folate receptor α (FRα), demonstrates remarkable efficacy in platinum-resistant ovarian cancer but causes keratitis and other ocular toxicities in some patients. Notably, FRα is not expressed in the corneal epithelium—the primary site of damage—highlighting the urgent need to elucidate its underlying mechanisms. The aim of this study was to identify the cell-type-specific molecular mechanisms underlying Elahere-induced ocular toxicity. Methods: Sprague-Dawley rats were treated with intravenous Elahere (20 mg/kg) or vehicle weekly for five weeks. Ocular toxicity was determined by clinical examination and histopathology. Corneal single-cell suspensions were analyzed using the BD Rhapsody single-cell RNA sequencing (scRNA-seq) platform. Bioinformatic analyses to characterize changes in corneal cell populations, gene expression, and signaling pathways included cell clustering, differential gene expression, pseudotime trajectory inference, and cell-cell interaction modeling. Results: scRNA-seq profiling of 47,606 corneal cells revealed significant damage to the ocular surface and corneal epithelia in the Elahere group. Twenty distinct cell types were identified. Elahere depleted myeloid immune cells; in particular, homeostatic gene expression was suppressed in phagocytic macrophages. Progenitor populations (limbal stem cells and basal cells) accumulated (e.g., a ~2.6-fold expansion of limbal stem cells), while terminally differentiated cells decreased in corneal epithelium, indicating differentiation blockade. Endothelial cells exhibited signs of injury and inflammation, including reduced angiogenic subtypes and heightened stress responses. Folate receptor alpha, the target of Elahere, was expressed in endothelial and stromal cells, potentially driving stromal cells toward a pro-fibrotic phenotype. Fc receptor genes were predominantly expressed in myeloid cells, suggesting a potential mechanism underlying their depletion. Conclusions: Elahere induces complex, multi-compartmental ocular toxicity characterized by initial perturbations in vascular endothelial and immune cell populations followed by the arrest of epithelial differentiation and stromal remodeling. These findings reveal a cascade of cellular disruptions and provide mechanistic insights into mitigating Elahere-associated ocular side effects. Full article

Ovarian cancer is the most lethal gynecologic malignancy, which causes 313,959 new cases and 207,252 deaths worldwide annually. The lack of specific symptoms, together with no effective screening tools, results in 75% of patients receiving their diagnosis at an advanced stage. The combination of cytoreductive surgery with platinum-based chemotherapy plays a pivotal role in the treatment of advanced epithelial ovarian cancer, but patients still experience poor long-term survival because of frequent relapses and chemotherapy resistance. The treatment landscape has evolved because bevacizumab and Poly-ADP Ribose Polymerase inhibitors now serve as frontline and maintenance therapies for homologous recombination-deficient tumors. Treatment decisions for recurrent disease depend on platinum sensitivity assessment, which determines the appropriate therapeutic approach, while targeted agents deliver significant benefits to specific patient groups. The development of antibody-drug conjugates such as mirvetuximab soravtansine and immunotherapy, including checkpoint inhibitors and cancer vaccines, demonstrates promising investigative potential. The precision of therapy improves through the use of emerging biomarkers and molecular profiling techniques. The future management of this disease may change because of innovative approaches that include adoptive cell therapy, cytokine therapy, and oncolytic viruses. The progress made in ovarian cancer treatment still faces challenges when it comes to drug resistance, survival improvement, and life quality preservation. The development of translational research alongside clinical trials remains essential to bridge treatment gaps while creating personalized therapies based on molecular and clinical tumor characteristics. Full article

Folate receptor alpha (FRα), a glycosylphosphatidylinositol-anchored glycoprotein encoded by the FOLR1 gene, plays a crucial role in folate transport during cell growth and development. While minimally expressed in most normal adult tissues, FRα is frequently overexpressed in several epithelial malignancies, particularly in high-grade serous ovarian carcinoma. An immunohistochemical (IHC) evaluation of FRα expression using the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay is now approved as a companion diagnostic for selecting patients eligible for mirvetuximab soravtansine, an FRα-targeted antibody–drug conjugate. Clinical trials such as SORAYA and MIRASOL have demonstrated significant clinical benefit in platinum-resistant epithelial ovarian cancer patients with high FRα expression (≥75% of tumor cells with moderate to strong membrane staining). This review summarizes the biological significance of FRα in ovarian cancer progression, its predictive value for targeted therapy, and the technical aspects of IHC assessment, including scoring interpretation and pre-analytical variables. We also discuss heterogeneity in FRα expression across histological subtypes and tumor sites, as well as the impact of archival versus fresh tissue. Understanding FRα expression patterns across histologic subtypes and tissue samples is critical for optimizing clinical decision-making and expanding the role of FRα-targeted therapies in gynecologic oncology. Full article

Patients with treatment-refractory/relapsing germ cell tumors (GCTs) have a dismal prognosis due to a lack of any effective therapy. Moreover, the efficacy of newly approved targeted therapies remains unexplored for cisplatin-resistant GCTs. Previously, it was demonstrated that folate receptor α (FRα) is overexpressed in many tumor types and efficiently targeted by the antibody–drug conjugate (ADC) mirvetuximab soravtansine (MIRV) in cisplatin-resistant cancers. We hypothesized that FRα represents an attractive target for treating treatment-refractory GCTs. We determined the expression of the FOLR1 gene in a broad range of GCT cell lines and tumor xenografts. We tested the antitumor efficacy of MIRV on cisplatin-resistant GCT cells in vitro and explored the ability of MIRV treatment to induce a bystander effect in the direct coculture of FRα-high and FRα-low cells. We found that the FOLR1 gene has significantly higher expression in testicular GCTs (TGCTs) than in normal testicular tissue. FOLR1 is highly expressed in the TCam2, JEG3, JAR, and NOY1 cell lines and their respective cisplatin-resistant variants. MIRV treatment induced apoptosis and a potent antiproliferative effect in cisplatin-resistant GCT cells in adherent and 3D spheroid cultures in vitro. A significant decrease in FRα-low 2102EP_R_NL cells was observed in the presence of FRα-high NOY1_R_SK in the presence of 12.5 nM MIRV, showing a potent bystander effect in the direct coculture. Immunohistochemical analysis confirmed significantly higher Folr1 protein expression in patients with TGCTs postchemotherapy than in chemo-naïve patients, as well as in patients with an unfavorable prognosis. In this study, we present data suggesting that the FOLR1 gene is highly expressed in (T)GCT cells in vitro and in vivo, and anti-FRα-targeting therapies should be investigated as a treatment modality in a subset of patients with TGCTs. Moreover, MIRV induced significant antitumor and bystander effects, thus showing its potential in further preclinical exploration and drug repurposing for a salvage treatment regime in refractory (T)GCT disease. Full article

Antibody–drug conjugates (ADCs) are a new class of therapeutic agents designed to target specific antigens on tumor cells, combining the specificity of monoclonal antibodies with the cytotoxicity of chemotherapy agents. ADCs have been available for over a decade, but in gynecological cancers, these agents are relatively new with great promise ahead. More than 80% of ongoing trials in gynecological cancers are evaluating ADCs’ safety and efficacy, of which 40% are early-phase trials. Around twenty ADCs are currently under investigation, either alone or in combination with chemotherapies or immune checkpoint inhibitors. Among them, mirvetuximab soravtansine has been recently approved by the Food and Drug Administration (FDA) in platinum-resistant ovarian cancer with high folate-α receptor expression, as a single agent or in combination. Tisotumab vedotin and trastuzumab deruxtecan are also now approved by the FDA in patients with pre-treated cervical and uterine cancers and further investigation is ongoing. Overall, the toxicity profiles of ADCs are acceptable. Ocular toxicity is one of the specific side effects of some ADCs, but most of the cases are manageable with the use of prophylactic steroids and dose adjustments. This review aims to provide an overview of the fundamental and operational features of ADCs and examine the latest and most promising data, with a particular focus on the Canadian viewpoint. Full article

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy worldwide. Due to its nonspecific symptoms and unreliable screening tools, EOC is not diagnosed at an early stage in most cases. Unfortunately, despite achieving initial remission after debulking surgery and platinum-based chemotherapy, most patients experience the recurrence of the disease. The limited therapy approaches have encouraged scientists to search for new detection and therapeutic strategies. In this review, we discuss the role of folate receptor alpha (FRα) in EOC development and its potential application as a biomarker and molecular target in designing new EOC screening and treatment methods. We summarize the mechanisms of the action of various therapeutic strategies based on FRα, including MABs (monoclonal antibodies), ADCs (antibody–drug conjugates), FDCs (folate–drug conjugates), SMDCs (small molecule–drug conjugates), vaccines, and CAR-T (chimeric antigen receptor T) cells, and present the most significant clinical trials of some FRα-based drugs. Furthermore, we discuss the pros and cons of different FR-based therapies, highlighting mirvetuximab soravtansine (MIRV) as the currently most promising EOC-targeting drug. Full article

Ovarian cancer (OC), accounting for approximately 200,000 deaths worldwide annually, is a heterogeneous disease showing major differences in terms of its incidence, tumor behavior, and outcomes across histological subtypes. In OC, primary chemotherapy, paclitaxel carboplatin, bevacizumab, and PARP inhibitors have shown prolonged progression-free survival and a favorable overall response rate compared to conventional treatments. However, treatment options for platinum-resistant recurrence cases are limited, with no effective therapies that significantly prolong the prognosis. Recently, mirvetuximab soravtansine, an alpha-folate receptor (FRα)-targeted antibody-drug conjugate (ADC), was approved by the US Food and Drug Administration for patients with FRα-positive recurrent epithelial OC (EOC). This approval was based on a Phase II study, which demonstrated its efficacy in such patients. ADCs comprise an antibody, a linker, and a payload, representing new concept agents without precedence. Advanced clinical studies are developing ADCs for patients with OC, targeting solid tumors such as gynecologic cancer. Ongoing clinical trials are evaluating ADCs targeting FRα and human epidermal growth factor receptor 2, trophoblast cell surface antigen-2, sodium-dependent phosphate transport protein 2B, and cadherin-6 in Phase II/III studies. In this review, we summarize the existing evidence supporting the use of ADCs in OC, discuss ongoing clinical trials and preclinical studies, and explore the potential of these innovative agents to address the challenges in OC treatment. Full article

Gynecologic malignancies have high incidence rates both nationally and internationally, and cervical, endometrial, and ovarian cancers account for high mortality rates worldwide. Significant research is ongoing to develop targeted therapies to address unmet needs in the field and improve patient outcomes. As tumors mutate and progress through traditional lines of treatment, new therapies must be developed to overcome resistance and target cancer-specific receptors and mutations. Recent advances in the development of immunotherapy and antibody–drug conjugates have resulted in compelling and clinically meaningful results in cervical, endometrial, and ovarian cancers. In the last decade, several immunotherapy agents have received FDA approval or NCCN guideline recommendation for the treatment of gynecologic malignancies, including dostarlimab for advanced or recurrent endometrial cancer and pembrolizumab for advanced or recurrent cervical and endometrial cancers. Several other immunotherapeutic agents are under active investigation. Development of antibody–drug conjugates including tisotumab vedotin in cervical cancer, mirvetuximab soravtansine in ovarian cancer, and trastuzumab deruxtecan in multiple gynecologic cancers has translated into exciting efficacy signals, prompting full drug approvals and additional investigation. This article aims to review recent novel advances in targeted treatments for gynecologic malignancies, highlighting the trials and data underlying these novel interventions. Full article

Folate receptor α (FR) was discovered many decades ago, along with drugs that target intracellular folate metabolism, such as pemetrexed and methotrexate. Folate is taken up by the cell via this receptor, which also targeted by many cancer agents due to the over-expression of the receptor by cancer cells. FR is a membrane-bound glycosyl-phosphatidylinositol (GPI) anchor glycoprotein encoded by the folate receptor 1 (FOLR1) gene. FR plays a significant role in DNA synthesis, cell proliferation, DNA repair, and intracellular signaling, all of which are essential for tumorigenesis. FR is more prevalent in cancer cells compared to normal tissues, which makes it an excellent target for oncologic therapeutics. FRα is found in many cancer types, including ovarian cancer, non-small-cell lung cancer (NSCLC), and colon cancer. FR is widely used in antibody drug conjugates, small-molecule-drug conjugates, and chimeric antigen-receptor T cells. Current oncolytic therapeutics include mirvetuximab soravtansine, and ongoing clinical trials are underway to investigate chimeric antigen receptor T cells (CAR-T cells) and vaccines. Additionally, FRα has been used in a myriad of other applications, including as a tool in the identification of tumor types, and as a prognostic marker, as a surrogate of chemotherapy resistance. As such, FRα identification has become an essential part of precision medicine. Full article

Antibody–drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components—an antibody, a linker molecule, and a cytotoxic agent (“payload”), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific antigen, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. A variety of payloads can be used, including most frequently microtubular inhibitors (auristatins and maytansinoids), as well as topoisomerase inhibitors and alkylating agents. Finally, linkers play a critical role in the ADCs’ effect, as cleavable moieties that serve as linkers impact site-specific activation as well as bystander killing effects, an upshot that is especially important in solid tumors that often express a variety of antigens. While ADCs were initially used in hematologic malignancies, their utility has been demonstrated in multiple solid tumor malignancies, including breast, gastrointestinal, lung, cervical, ovarian, and urothelial cancers. Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Although they demonstrate utility and tolerable safety profiles, ADCs may become ineffective as tumor cells undergo evolution to avoid expressing the specific antigen being targeted. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies. Full article