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PURPOSE: This retrospective real-world study compared overall survival (OS) between patients with BRCA wild-type (BRCAwt) recurrent epithelial ovarian cancer (OC) who received niraparib second-line maintenance (2LM) versus active surveillance (AS) using target trial emulation, cloning, inverse probability of censoring weighting (IPCW) methodology to minimize immortal time bias. METHODS: Eligible patients from a United States-based, deidentified, electronic health record-derived database were diagnosed with epithelial OC (January 1, 2011-May 31, 2021), were BRCAwt, and completed second-line (2L) therapy (January 1, 2017-March 2, 2022). Patient data were cloned at index (2L last treatment date), assigned to niraparib 2LM and AS cohorts, and censored when treatment deviated from clone assignment. Follow-up was measured from index to earliest of study end (May 31, 2022), last activity, or death. Median OS (mOS) and hazard ratios were estimated from stabilized IPCW Kaplan-Meier curves and Cox regression models. RESULTS: Overall, 199 patients received niraparib 2LM, and 707 had their care managed with AS. Key characteristics were balanced across cohorts after cloning and stabilized IPCW. Median follow-up was 15.6- and 9.3-months pre-cloning. IPCW mOS was 24.1 months (95% CI: 20.9-29.5) and 18.4 months (95% CI: 15.1-22.8) in niraparib 2LM and AS cohorts, respectively (hazard ratio, 0.77; 95% CI: 0.66-0.89). CONCLUSIONS: This real-world study provides supportive evidence of an OS benefit for patients with BRCAwt recurrent OC who received 2LM niraparib monotherapy compared with those whose care was managed with AS. The analytic strategies implemented were useful in minimizing immortal time bias and measured confounding.
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Indazoles , Recurrencia Local de Neoplasia , Neoplasias Ováricas , Piperidinas , Humanos , Femenino , Piperidinas/uso terapéutico , Piperidinas/administración & dosificación , Indazoles/uso terapéutico , Indazoles/administración & dosificación , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/mortalidad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Adulto , Espera Vigilante , Estados Unidos/epidemiología , Quimioterapia de Mantención/métodos , Bases de Datos FactualesRESUMEN
OBJECTIVE: To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. METHODS: This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). RESULTS: 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. CONCLUSION: The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759600.
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Indazoles , Neoplasias Ováricas , Piperidinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Femenino , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Anciano , Indazoles/efectos adversos , Indazoles/administración & dosificación , Indazoles/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Piperidinas/efectos adversos , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Adulto , Japón , Ftalazinas/efectos adversos , Ftalazinas/administración & dosificación , Ftalazinas/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Recombinación Homóloga , Neoplasias Peritoneales/tratamiento farmacológico , Pueblos del Este de AsiaRESUMEN
OBJECTIVE: This study presents the development and validation of a nomogram aimed at predicting platinum-sensitivity and survival outcomes in women with advanced epithelial ovarian cancer (EOC). MATERIALS AND METHODS: Data from a retrospective cohort of women diagnosed with stage III/IV EOC between Jan 2011 and Dec 2021 treated at our institute were collected. Clinical and pathological characteristics were analyzed using logistic regression analysis to identify independent predictors of platinum-sensitivity. Impact on progression-free (PFS) and overall survival (OS) was determined by Kaplan-Meier and Cox regression analysis. A nomogram was constructed based on the significant predictors, and its performance was evaluated using calibration, discrimination, and validation analyses. RESULTS: Of the 210 patients, 139 (66.19%) had platinum-sensitive and 71 (33.81%) were platinum-resistant disease. On multivariate analysis, platinum-resistance correlated with neoadjuvant chemotherapy (OR 2.15; 95% CI 1.10-4.21), clear cell/mucinous histology (OR 5.04; 95% CI 2.20-11.54), and sub-optimal debulking status (OR 3.37; 95% CI 1.44-7.91). Median PFS and OS were also significantly shorter for patients with neoadjuvant chemotherapy (23 vs. 10 months and 69 vs. 29 months, respectively), clear cell/mucinous histology (15 vs. 3 months and 63 vs. 11 months, respectively), and suboptimal debulking (26 vs. 5 months and 78 vs. 24 months, respectively). The nomogram demonstrated good predictive accuracy for platinum-sensitivity in the cohort as indicated by high concordance index of 0.745. Calibration plots showed excellent agreement and internal validation further confirmed the reliability of the nomogram's performance. CONCLUSION: A novel predictive nomogram based on type of initial treatment, histology, and debulking status was developed, which provides a friendly and reliable tool for predicting platinum-sensitivity and survival outcomes in women with advanced EOC. Its application may assist clinicians in individualizing treatment decisions.
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Carcinoma Epitelial de Ovario , Resistencia a Antineoplásicos , Nomogramas , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Anciano , Adulto , Estadificación de Neoplasias , Terapia Neoadyuvante/métodos , Procedimientos Quirúrgicos de Citorreducción , Supervivencia sin Progresión , Platino (Metal)/uso terapéutico , Antineoplásicos/uso terapéutico , Estimación de Kaplan-MeierRESUMEN
BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. METHODS: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. RESULTS: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells. CONCLUSIONS: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies.
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Adipocitos , Exosomas , MicroARNs , Invasividad Neoplásica , Neoplasias Ováricas , Paclitaxel , Femenino , Exosomas/metabolismo , Humanos , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Neoplasias Ováricas/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Adipocitos/patología , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Epiplón/patología , Epiplón/metabolismo , Proliferación Celular/efectos de los fármacos , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/metabolismo , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/efectos de los fármacosRESUMEN
Epithelial ovarian cancer (EOC) is an often-fatal malignancy marked by the development of resistance to platinum-based chemotherapy. Thus, accurate prediction of platinum drug efficacy is crucial for strategically selecting postoperative interventions to mitigate the risks associated with suboptimal therapeutic outcomes and adverse effects. Tissue-derived extracellular vesicles (tsEVs), in contrast to their plasma counterparts, have emerged as a powerful tool for examining distinctive attributes of EOC tissues. In this study, 4D data-independent acquisition (DIA) proteomic sequencing was performed on tsEVs obtained from 58 platinum-sensitive and 30 platinum-resistant patients with EOC. The analysis revealed a notable enrichment of differentially expressed proteins that were predominantly associated with immune-related pathways. Moreover, pivotal immune-related proteins (IRPs) were identified by LASSO regression. These factors, combined with clinical parameters selected through univariate logistic regression, were used for the construction of a model employing multivariate logistic regression. This model integrated three tsEV IRPs, CCR1, IGHV_35 and CD72, with one clinical parameter, the presence of postoperative residual lesions. Thus, this model could predict the efficacy of initial platinum-based chemotherapy in patients with EOC post-surgery, providing prognostic insights even before the initiation of chemotherapy.
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Carcinoma Epitelial de Ovario , Vesículas Extracelulares , Neoplasias Ováricas , Humanos , Femenino , Vesículas Extracelulares/metabolismo , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Anciano , Resistencia a Antineoplásicos , Platino (Metal)/uso terapéutico , Platino (Metal)/farmacología , Adulto , Proteómica/métodos , Pronóstico , Biomarcadores de Tumor/metabolismoRESUMEN
PURPOSE: Oral metronomic cyclophosphamide (OMC) implicates the daily administration of low doses of chemotherapy. Its antitumor activity combined with an oral administration route and a good toxicity profile makes OMC an attractive option for heavily pretreated patients. We retrospectively evaluated OMC's clinical benefit and objective response in recurrent ovarian cancer patients. METHODS: This is a retrospective observational study involving patients treated with OMC (50 mg daily) from 2017 to 2022 at the Academic Division Gynaecology, Mauriziano Hospital, Torino, Italy. Clinical benefit assessment included CA125 response, radiological response, and reported symptomatic improvement. Toxicities were reported using Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Thirty-eight patients (average age 72, range 49-88) were included. 90% had FIGO stage III/IV at diagnosis and 64% underwent ≥ 3 previous lines of chemotherapy. Before OMC, 79% had ECOG 1 or 2. 8.6% of patients had a partial response (PR), and 40% a stable disease (SD). Median duration of response was 7.4 months. After 3 months on OMC, 51% experienced symptom improvement, and 53.3% experienced Ca125 reduction or stabilization. 66.7% of patients older than 75 responded to treatment; in 40% of cases, responses lasted ≥ 6 months (p = 0.08). No G3-4 hematological toxicities occurred. Nausea and fatigue G1-G2 were reported in 5 (13%) and 13 (34%) cases, respectively. CONCLUSION: OMC is a feasible therapeutic option for recurrent ovarian cancer, providing satisfying clinical responses with a good toxicity profile, even in elderly and heavily pretreated patients with a suboptimal performance status.
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Administración Metronómica , Antineoplásicos Alquilantes , Carcinoma Epitelial de Ovario , Ciclofosfamida , Recurrencia Local de Neoplasia , Neoplasias Ováricas , Humanos , Femenino , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Anciano de 80 o más Años , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Administración Oral , Recurrencia Local de Neoplasia/tratamiento farmacológico , Antígeno Ca-125/sangre , Resultado del TratamientoRESUMEN
BACKGROUND: Tinzaparin, a low-molecular weight heparin (LMWH), has shown anti-neoplastic properties in animal models and in in vitro studies of human cancer cell lines. The reduction of CA-125 levels during neoadjuvant chemotherapy (NACT) in patients with epithelial ovarian cancer (EOC) co-varies with the prognosis; the larger the decrease in CA-125, the better the prognosis. PURPOSE: This study aims to evaluate the potential anti-neoplastic effects of tinzaparin by investigating changes in serum CA-125 levels in advanced EOC patients who receive NACT. MATERIAL AND METHODS: This is an open randomized multicenter pilot trial. Forty patients with EOC selected to receive NACT will be randomized 1:1 to receive daily addition of tinzaparin or no tinzaparin. The processing and treatment of the patients will otherwise follow the recommendations in the Swedish National Guidelines for Ovarian Cancer. Before every cycle of chemotherapy, preoperatively, and 3 weeks after the last cycle of chemotherapy, a panel of biomarkers, including CA-125, will be measured. PATIENTS: Inclusion criteria are women aged 18 years or older, World Health Organization performance status 0-1, histologically confirmed high-grade serous, endometrioid or clear cell EOC, International Federation of Gynecology and Obstetrics (FIGO) stages III-IV. In addition, a CA-125 level of ≥ 250 kIE/L at diagnosis. Exclusion criteria are contraindications to LMWH, ongoing or recent treatment with unfractionated heparin, LMWH, warfarin or non-vitamin K antagonist oral anticoagulants. INTERPRETATION: This study will make an important contribution to the knowledge of the anti-neoplastic effects of tinzaparin in EOC patients and may thus guide the planning of a future study on the impact of tinzaparin on survival in EOC.
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Biomarcadores de Tumor , Antígeno Ca-125 , Carcinoma Epitelial de Ovario , Terapia Neoadyuvante , Neoplasias Ováricas , Tinzaparina , Humanos , Femenino , Tinzaparina/administración & dosificación , Terapia Neoadyuvante/métodos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/sangre , Biomarcadores de Tumor/sangre , Antígeno Ca-125/sangre , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/sangre , Adulto , Estadificación de Neoplasias , Proyectos Piloto , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante/métodos , Heparina de Bajo-Peso-Molecular/uso terapéutico , Heparina de Bajo-Peso-Molecular/administración & dosificación , Pronóstico , AncianoRESUMEN
INTRODUCTION: Epithelial ovarian cancer (EOC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical activity of datopotamab deruxtecan (Dato-Dxd), a novel TROP2 targeting antibody drug conjugate (ADC) in ovarian cancer cell lines and xenografts with variable TROP2 expression. METHODS: In vitro cell viability with Dato-DXd was assessed using flow-cytometry based assays against a panel of EOC primary cell lines with variable TROP2 expression. Fluorescent anti-phospho-histone H2A.X antibody was used to detect dsDNA breaks by flow-cytometry. The in vivo antitumor activity of Dato-DXd was tested in TROP2 overexpressing xenografts. RESULTS: TROP2 overexpressing (3+) and moderate (2+) expressing EOC cell lines demonstrated higher sensitivity to Dato-DXd when compared to TROP2 negative tumors. Dato-DXd exposed TROP2+ EOC demonstrated increased dsDNA breaks and Annexin-V positivity (a marker of apoptosis) when compared to tumor cells exposed to the non-binding conjugate (p = 0.001 and p = 0.016, respectively). Dato-DXd induced significant antibody-dependent cellular cytotoxicity (ADCC) in the presence of peripheral-blood-lymphocytes. While negligible activity was detected against EOC cell lines with low TROP2 expression, Dato-DXd demonstrated significant bystander killing against tumor cells with low/negligible TROP2 when such cells were admixed with TROP2 3+ tumor cells in vitro. Dato-DXd showed tumor growth suppression against EOC cell line derived xenograft models that overexpress TROP2 at 3+ levels, prolonging survival when compared to controls, with minimal toxicity. CONCLUSION: Dato-DXd shows promising preclinical activity against TROP2 overexpressing ovarian cancers. Future clinical trials in ovarian cancer patients are warranted.
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Antígenos de Neoplasias , Carcinoma Epitelial de Ovario , Moléculas de Adhesión Celular , Inmunoconjugados , Neoplasias Ováricas , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Humanos , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/antagonistas & inhibidores , Animales , Inmunoconjugados/farmacología , Antígenos de Neoplasias/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Línea Celular Tumoral , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/inmunología , Carcinoma Epitelial de Ovario/patología , Ratones , Ratones Desnudos , Supervivencia Celular/efectos de los fármacosRESUMEN
OBJECTIVE: Folate receptor alpha (FRα) is overexpressed on >90% of high-grade epithelial ovarian cancers (EOC). Targeting FRα with antibody-drug conjugates has proven utility in the platinum-resistant setting. It is also a potential therapeutic target for immuno-oncologic agents, such as peptide vaccines that work primarily via adaptive and humoral immunity. We tested the hypothesis that FRα peptide immunization could improve outcomes in patients with EOC following response to platinum-based therapy. METHODS: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS). RESULTS: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event. CONCLUSION: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222.
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Vacunas contra el Cáncer , Carcinoma Epitelial de Ovario , Receptor 1 de Folato , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Neoplasias Ováricas , Humanos , Femenino , Receptor 1 de Folato/inmunología , Persona de Mediana Edad , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/terapia , Anciano , Carcinoma Epitelial de Ovario/inmunología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/terapia , Método Doble Ciego , Adulto , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/efectos adversos , Supervivencia sin Progresión , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinum-resistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoid receptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol's antiapoptotic effects, enhancing chemotherapy's efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population. METHODS: ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy. The study's primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18.
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Albúminas , Protocolos de Quimioterapia Combinada Antineoplásica , Resistencia a Antineoplásicos , Neoplasias Ováricas , Paclitaxel , Femenino , Humanos , Albúminas/administración & dosificación , Albúminas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Ensayos Clínicos Fase III como Asunto , Estudios Multicéntricos como Asunto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVE: To explore the difference in chemotherapy completion and reasons for discontinuation between older (≥70 years) and younger (<70 years) patients. DESIGN: Retrospective cohort study. SETTING: Single tertiary centre in Thailand. PARTICIPANTS: The patients who received chemotherapy from 1 January 2009 to 30 June 2021 were included and followed up until 30 June 2022. Of the 757 patients with epithelial ovarian, fallopian tube and primary peritoneal cancer (EOC), 108 were in the older group and 649 were in the younger group. PRIMARY AND SECONDARY OUTCOME MEASURES: The difference in chemotherapy completion, the association between younger and older patients and early discontinuation of chemotherapy. RESULTS: The proportion of chemotherapy completion was significantly lower in older versus younger patients (84.3% versus 92.6%, p=0.007). Excluding discontinuation due to disease progression, the chemotherapy completion was comparable (93.5 versus 95.7%, p=0.456). Dose reduction and grade 3-4 hematotoxicity occurred more often in the older group. The univariable logistic regression model showed that older age (≥70 years) was significantly associated with early chemotherapy discontinuation (OR 2.39; 95% CI 1.29-4.24). However, after adjusting for potential confounders, age was not significantly associated with early discontinuation (OR 1.20; 95% CI 0.54-2.66). Multiple comorbidities and types of surgery were identified as independent risk factors for chemotherapy discontinuation. CONCLUSION: The completion of chemotherapy was observed in a majority of older adults with EOC. Age is not the only determinant of chemotherapy completion. Comorbidity and disease status are crucial for determining chemotherapy discontinuation.
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Carcinoma Epitelial de Ovario , Neoplasias de las Trompas Uterinas , Neoplasias Ováricas , Neoplasias Peritoneales , Humanos , Femenino , Neoplasias Peritoneales/tratamiento farmacológico , Estudios Retrospectivos , Tailandia/epidemiología , Persona de Mediana Edad , Anciano , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Factores de Edad , Adulto , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversosRESUMEN
BACKGROUND: Neoadjuvant chemotherapy followed by interval debulking surgery is currently a common treatment option for advanced epithelial ovarian cancer (EOC). The Standardized CA-125 ELIMination rate constant K (Std KELIM) and the Platinum Resistant Recurrence (PtRR) Score have been proposed as markers of tumor chemosensitivity. The aim of our study was to validate these tools for predicting platinum sensitivity in a real-world population of patients with advanced EOC treated with neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: All patients with advanced EOC treated with neoadjuvant chemotherapy at the Institut Curie between 2000 and 2015 were included. The Std KELIM was calculated with the CA-125 concentrations during the first 100 days of chemotherapy. The predictive value of Std KELIM and PtRR scores for the risk of subsequent PtRR was assessed using receiver operating characteristic (ROC) curve analysis, logistic regression and calibration curve. Kaplan-Meier survival analysis was performed for the treatment-free interval from platinum (TFIp) therapy and overall survival (OS). RESULTS: Std KELIM data were available for 149 patients. The AUC was 0.67 for PtRR. A low Std KELIM was significantly associated with PtRR (OR = 0.19 (95% CI [0.06, 0.53], p = 0.002)) according to the univariate analysis. The calibration curve of the PtRR showed a slight but significant underestimation (p = 0.02) of the probability of platinum resistance. Favorable Std KELIM (≥ 1) alone and combined with the completeness of surgery were associated with significantly better survival in terms of TFIp and OS. CONCLUSIONS: Std KELIM is an early prognostic marker of chemosensitivity in a real-life setting complementary to surgical status. It could help the clinician in the early management of patients by identifying those with a worse prognosis.
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Carcinoma Epitelial de Ovario , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Persona de Mediana Edad , Anciano , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Adulto , Antígeno Ca-125/sangre , Terapia Neoadyuvante/métodos , Platino (Metal)/uso terapéutico , Curva ROC , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
There is an urgent unmet need for more targeted and effective treatments for advanced epithelial ovarian cancer (EOC). The emergence of drug resistance is a particular challenge, but small molecule covalent inhibitors have promise for difficult targets and appear less prone to resistance. Michael acceptors are covalent inhibitors that form bonds with cysteines or other nucleophilic residues in the target protein. However, many are categorized as pan-assay interference compounds (PAINS) and considered unsuitable as drugs due to their tendency to react non-specifically. Targeting RPN13/ADRM1-mediated substrate recognition and deubiquitination by the proteasome 19S Regulatory Particle (RP) is a promising treatment strategy. Early candidate RPN13 inhibitors (iRPN13) produced a toxic accumulation of very high molecular weight polyubiquitinated substrates, resulting in therapeutic activity in mice bearing liquid or solid tumor models, including ovarian cancer; however, they were not drug-like (PAINS) because of their central piperidone core. Up284 instead has a central spiro-carbon ring. We hypothesized that adding a guanidine moiety to the central ring nitrogen of Up284 would produce a compound, RA475, with improved drug-like properties and therapeutic activity in murine models of ovarian cancer. RA475 produced a rapid accumulation of high molecular polyubiquitinated proteins in cancer cell lines associated with apoptosis, similar to Up284 although it was 3-fold less cytotoxic. RA475 competed binding of biotinylated Up284 to RPN13. RA475 shows improved solubility and distinct pharmacodynamic properties compared to Up284. Specifically, tetraubiquitin firefly luciferase expressed in leg muscle was stabilized in mice more effectively upon IP treatment with RA475 than with Up284. However, pharmacologic analysis showed that RA475 was more rapidly cleared from the circulation, and less orally available than Up284. RA475 shows reduced ability to cross the blood-brain barrier and in vitro inhibition of HERG. Treatment of mice with RA475 profoundly inhibited the intraperitoneal growth of the ID8-luciferase ovarian tumor model. Likewise, RA475 treatment of immunocompetent mice inhibited the growth of spontaneous genetically-engineered peritoneal tumor, as did weekly cisplatin dosing. The combination of RA475 and cisplatin significantly extended survival compared to individual treatments, consistent with synergistic cytotoxicity in vitro. In sum, RA475 is a promising candidate covalent RPN13i with potential utility for treatment of patients with advanced EOC in combination with cisplatin.
Asunto(s)
Neoplasias Ováricas , Femenino , Animales , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Ratones , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Compuestos de Espiro/química , Ensayos Antitumor por Modelo de Xenoinjerto , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Guanidinas/farmacología , Guanidinas/uso terapéutico , Guanidinas/química , Péptidos y Proteínas de Señalización IntracelularRESUMEN
BACKGROUND: This study aimed to determine the effect of neoadjuvant chemotherapy (NACT) on the complex surgical procedures required in addition to staging surgery for the need to achieve a residual tumor 1 cm or less in a population of stage IIIC-IV epithelial ovarian cancer patients. METHODS: Patients were referred for NACT if preoperative imaging and/or intraoperative evaluation confirmed that it was not possible to achieve a residual tumor size of 1 cm or less with cytoreductive surgery or if the patient had a poor performance status and a high American Society of Anesthesiologists (ASA) score. Surgical complexity was defined as complex or non-complex. RESULTS: One hundred and twenty-six patients with stage IIIC-IV ovarian cancer were included in the study. Primary cytoreductive surgery was performed in 67 patients, and interval cytoreductive surgery was performed in 59 patients after NACT. At least one complex surgery was performed in 74.6% of the patients in the primary cytoreductive surgery group and in 61% of the patients in the NACT group, with no statistically significant difference between the groups. However, the NACT group showed significantly decreased rates of low-rectal resection, diaphragmatic peritoneal stripping, and peritonectomy. CONCLUSIONS: The analyses showed no reduction in the requirement for at least one complex surgical procedure in the group of patients who underwent NACT. Nevertheless, this group exhibited a significant decrease in low-rectal resection, diaphragmatic peritoneal stripping, and peritonectomy due to their effectiveness in reducing peritoneal disease.
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Carcinoma Epitelial de Ovario , Procedimientos Quirúrgicos de Citorreducción , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Ováricas , Humanos , Femenino , Terapia Neoadyuvante/métodos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/cirugía , Persona de Mediana Edad , Procedimientos Quirúrgicos de Citorreducción/métodos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Neoplasias Ováricas/patología , Anciano , Quimioterapia Adyuvante/métodos , Adulto , Estudios RetrospectivosRESUMEN
Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Brain metastasis (BM) is quite an uncommon presentation. However, the likelihood of central nervous system (CNS) metastasization should be considered in the context of disseminated disease. The therapeutic management of BMs is an unmet clinical need, to date. We identified, across different cancer centers, six cases of both BRCA wild-type and BRCA-mutated EOCs spreading to the CNS. They presented either with a single brain lesion or with multiple lesions and most of them had intracranial-only disease. All cases received Poly-ADP ribose polymerase inhibitor (PARPi) maintenance, as per clinical practice, for a long time within a multimodal treatment approach. We also provide an insight into the available body of work regarding the management of this intriguing disease setting, with a glimpse of future therapeutic challenges. Despite the lack of unanimous guidelines, multimodal care pathways should be encouraged for the optimal disease control of this unfortunate patient subset. Albeit not being directly investigated in BM patients, PARPi maintenance is deemed to have a valuable role in this setting. Prospective research, aimed to implement worthwhile strategies in the multimodal patient journey of BMs from EOC, is eagerly awaited.
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Neoplasias Encefálicas , Carcinoma Epitelial de Ovario , Neoplasias Ováricas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Anciano , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/genética , Terapia Combinada , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéuticoRESUMEN
Objective: To investigate the effect of DNA methylation of laminin α3 (LAMA3) on the prognosis of platinum-resistant epithelial ovarian cancer (EOC) and its possible mechanism. Methods: (1) The relationship between DNA methylation of LAMA3 and platinum resistance in EOC was evaluated by bioinformatics. (2) A total of 67 EOC patients treated at Guangxi Medical University Cancer Hospital from January 2000 to December 2012 were selected to detect the levels of LAMA3 DNA methylation in EOC tissues using pyrophosphate sequencing technology to explore its diagnostic efficacy for platinum resistance and prognosis in EOC patients. Furthermore, its impact on chemotherapy efficacy and prognosis of platinum resistant EOC patients were also analyzed. Results: (1) Ten proteins highly interacting with LAMA3 were screened from the Gene Interaction Retrieval Platform (STRING) database, including laminin ß (LAMB) 3, laminin γ (LAMC) 3, integrin α (ITGA) 6, intestine protein ß4 (ITGB4), ITGA3, LAMC1,LAMB2, dystrophin associated glycoprotein 1 (DAG1), LAMB1 and cytochrome P450c17α (COL17A1) protein; kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that LAMA3 and its related interacting proteins participate in the regulation of malignant tumor occurrence and development through signaling pathways such as apoptosis, cell cycle, DNA damage response, epithelial mesenchymal transition (EMT), androgen receptor (AR), estrogen receptor (ER), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt), RAS/mitogen activated protein kinase (MAPK), receptor tyrosine kinase (RTK), tuberous sclerosis protein complex (TSC)/mammalian target of rapamycin (mTOR), and their expression levels were related to the sensitivity of chemotherapy drugs such as cisplatin in EOC. (2) Our clinical data analysis found that the LAMA3 DNA methylation level in EOC tissue of the platinum-sensitive group (35 cases) was 71% (25/35), which was higher than 69% (22/32) in the platinum-resistant group (32 cases), with statistically insignificant difference (χ2=0.057, P=0.811). The area under the curve (AUC) of LAMA3 DNA methylation level for assessing platinum resistance in EOC was 0.601, and the AUC for predicting EOC patient prognosis was 0.686. The chemotherapy efficacy of EOC patients with high methylation of LAMA3 DNA was worse than that of patients with low methylation, 50% (12/24) vs 15/15, with statistically significant difference (χ2=10.833, P=0.001). The level of LAMA3 DNA methylation had a significant impact on the progression free survival and overall survival of EOC patients (both P<0.05). Conclusion: The level of LAMA3 DNA methylation has certain diagnostic and predictive value for platinum resistance and prognosis in EOC patients, which may be closely related to the regulatory mechanism, platinum resistance and prognosis of EOC.
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Carcinoma Epitelial de Ovario , Biología Computacional , Metilación de ADN , Resistencia a Antineoplásicos , Laminina , Neoplasias Ováricas , Humanos , Femenino , Laminina/metabolismo , Laminina/genética , Biología Computacional/métodos , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/metabolismo , Pronóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Platino (Metal)/uso terapéutico , Transducción de SeñalRESUMEN
BACKGROUND: We aimed to investigate the distinct immunological characteristics of the tumor immune microenvironment in epithelial ovarian cancer (EOC) according to BRCA1/2 mutations status and differential PD-1 expression levels. METHODS: Tumor-infiltrating lymphocytes (TILs) were collected from patients with newly diagnosed advanced-stage EOC (YUHS cohort, n=117). This YUHS cohort was compared with The Cancer Genome Atlas (TCGA) data for ovarian serous cystadenocarcinoma (n=482), in terms of survival outcomes and immune-related gene profiles according to BRCA1/2 status. We used multicolor flow cytometry to characterize the immune phenotypes and heterogeneity of TILs with or without BRCA1/2 mutations. In vitro functional assays were conducted to evaluate the reinvigorating ability of CD8+ TILs on anti-PD-1 treatment. RESULTS: We found that EOC patients with BRCA1/2 mutations (BRCA1/2mt) exhibited better survival outcomes and significantly higher tumor mutation burden (TMB), compared with BRCA1/2 non-mutated (BRCA1/2wt) patients. Furthermore, CD8+ TILs within BRCA1/2mt tumors displayed characteristics indicating more severe T-cell exhaustion than their BRCA1/2wt counterparts. Notably, the capacity for anti-PD-1-mediated reinvigoration of CD8+ TILs was significantly greater in BRCA1/2wt tumors compared with BRCA1/2mt tumors. Additionally, within the BRCA1/2wt group, the frequency of PD-1highCD8+ TILs was positively correlated with the reinvigoration capacity of CD8+ TILs after anti-PD-1 treatment. CONCLUSION: Our results highlight unique immune features of CD8+ TILs in EOC and a differential response to anti-PD-1 treatment, contingent on BRCA1/2 mutation status. These findings suggest that immune checkpoint blockade may be a promising frontline therapeutic option for selected BRCA1/2wt EOC patients.
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Proteína BRCA1 , Linfocitos T CD8-positivos , Carcinoma Epitelial de Ovario , Linfocitos Infiltrantes de Tumor , Mutación , Humanos , Femenino , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/inmunología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Proteína BRCA1/genética , Persona de Mediana Edad , Proteína BRCA2/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Ováricas/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Adulto , Microambiente Tumoral/inmunología , AncianoRESUMEN
Epithelial ovarian cancer is one of the most lethal gynecologic malignancies and poses a considerable threat to women's health. Although the progression-free survival of patients has been prolonged with the application of anti-angiogenesis drugs and Poly (ADP-ribose) polymerases (PARP) inhibitors, overall survival has not substantially improved. Thus, new therapeutic strategies are essential for the treatment of ovarian cancer. Nitazoxanide (NTZ), an FDA-approved anti-parasitic drug, has garnered attention for its potential anti-cancer activity. However, the anti-tumor effects and possible underlying mechanisms of NTZ on ovarian cancer remain unclear. In this study, we investigated the anti-tumor effects and the mechanism of NTZ on ovarian cancer in vitro and in vivo. We found that NTZ inhibited the proliferation of A2780 and SKOV3 epithelial ovarian cancer cells in a time- and concentration-dependent manner; Furthermore, NTZ suppressed the metastasis and invasion of A2780 and SKOV3 cells in vitro, correlating with the inhibition of epithelial-mesenchymal transition; Additionally, NTZ suppressed the Hippo/YAP/TAZ signaling pathway both in vitro and in vivo and demonstrated a good binding activity with core genes of Hippo pathway, including Hippo, YAP, TAZ, LATS1, and LATS2. Oral administration of NTZ inhibited tumor growth in xenograft ovarian cancer mice models without causing considerable damage to major organs. Overall, these data suggest that NTZ has therapeutic potential for treating epithelial ovarian cancer.
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Antineoplásicos , Carcinoma Epitelial de Ovario , Proliferación Celular , Transición Epitelial-Mesenquimal , Ratones Desnudos , Nitrocompuestos , Neoplasias Ováricas , Tiazoles , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Nitrocompuestos/farmacología , Animales , Humanos , Tiazoles/farmacología , Tiazoles/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ratones , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos BALB C , Movimiento Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Evidence regarding chemosensitivity to different therapeutic regimens in epithelial ovarian cancer (EOC) remains limited. This study aimed to investigate EOC implementation in daily clinical practice and reveal favorable regimens for EOC among Japanese patients. METHODS: We retrospectively collected clinical data of patients newly diagnosed with EOC from 2012 to 2021 at our affiliated institutions. We evaluated overall survival (OS) and progression-free survival (PFS) of conventional paclitaxel plus carboplatin (TC) vs. dose-dense TC (ddTC) according to the eligibility of GOG262 and JGOG3016 and those with bevacizumab (BEV) vs. without BEV based on GOG218. Further, we evaluated OS and PFS of ddTC and ddTC + BEV to TC + BEV among patients with stage III/IV. RESULTS: The ddTC group (n = 402) demonstrated longer PFS and OS than the TC group (n = 165) (adjusted hazard ratios [aHRs] [95% confidential intervals (CIs)]: 0.69 [0.55-0.88] and 0.67 [0.50-0.90], respectively). The group with BEV (n = 158) demonstrated a longer PFS than those without BEV (n = 296) (0.74 [0.57-0.95]), but not for OS (0.84 [0.60-1.17]). The ddTC and ddTC + BEV groups (n = 259 and 117) demonstrated no statistically significant differences in PFS and OS than the TC + BEV group (n = 75) (1.09 [0.79-1.50] and 0.74 [0.52-1.08] for PFS and 0.89 [0.59-1.34] and 0.73 [0.50-1.05] for OS, respectively). CONCLUSION: Our study may indicate ddTC, BEV, and their combination regimen as the promising first-line chemotherapy option among Japanese patients with advanced EOC.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Carboplatino , Carcinoma Epitelial de Ovario , Neoplasias Ováricas , Paclitaxel , Humanos , Femenino , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Bevacizumab/administración & dosificación , Bevacizumab/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Japón , Adulto , Supervivencia sin Progresión , Anciano de 80 o más Años , Pueblos del Este de AsiaRESUMEN
OBJECTIVE: First-line bevacizumab plus carboplatin and paclitaxel (CP) is approved for stage III/IV ovarian cancer treatment following initial surgical resection, based on global phase III GOG-0218 and ICON7 trials. This study evaluated the efficacy and safety of bevacizumab + CP as first-line ovarian cancer therapy in Chinese patients. METHODS: Patients with newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian, fallopian tube, or primary peritoneal cancer post-primary surgery were randomized 1:1 to receive 6 cycles of CP with bevacizumab/placebo, followed by bevacizumab/placebo maintenance until unacceptable toxicity or disease progression. Primary endpoint was investigator-assessed progression-free survival (PFS). Stratification factors were FIGO stage and debulking status (stage III optimally debulked vs stage III suboptimally debulked vs stage IV) and Eastern Cooperative Oncology Group performance status (0 vs 1 or 2). RESULTS: Of randomized patients, 51 received bevacizumab + CP and 49 received placebo + CP. Median PFS was 22.6 months with bevacizumab + CP (95% confidence interval [CI]=18.6, not estimable) and 12.3 months (95% CI=9.5, 15.0) with placebo + CP (stratified hazard ratio=0.30; 95% CI=0.17, 0.53). Treatment-related grade 3/4 adverse events occurred in 46 of 49 (94%) patients receiving bevacizumab + CP, and 34 of 50 (68%) receiving placebo + CP. CONCLUSION: Bevacizumab + CP showed clinically meaningful improvement in PFS vs placebo + CP, consistent with GOG-0218 results. Safety data were aligned with the known bevacizumab safety profile. These results support first-line bevacizumab + CP therapy in Chinese patients with ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03635489.