Treatment Of Ovarian Cancer Research Articles

Development of receptor-targeted and pH-responsive zeolitic imidazole framework-90 nanoplatform for anti-ovarian cancer

The covalent functionalization of the zeolitic imidazolate framework (ZIF) is rapidly progressing and is being exploited as a nanoplatform for antitumor drug delivery to improve tumor targeting and drug release. Here, a novel nanoplatform strategy was developed by encapsulating Carboplatin (CBP) in ZIF-90 nanospheres (NPs) to obtain CBP@ZIF-90 NPs and then, modifying folate-terminated methoxypoly(ethylene glycol) (FA-PEG-NH2) on the aldehyde group of ZIF-90 to form CBP@ZIF-90-NPF NPs with acid-sensitive Schiff base bond. The research results indicate that the yield of ZIF-90 was 72.77 ± 0.27 %, and the encapsulation efficiency and the loading content of CBP@ZIF-90 were 45.22 ± 0.49 % and 24.65 ± 0.34 %, respectively. The size of CBP@ZIF-90-NPF was 107.7 ± 1.7 nm in monodispersity with a single crystalline dodecahedral structure. Furthermore, the in vitro release behavior study revealed the sustained-release and the pH-responsive dissociation properties of the NPs. Only 6.84 % of CBP was released from the nanocarrier under physiological pH conditions for 48 h, while the release from the tumor microenvironment was 92.89 %. In addition, the cellular uptake result clearly showed that most of the FA-PEG-NH2 modified NPs exhibited specific selectivity in tumor cell nuclei. Finally, the cell counting kit-8 (CCK8) assay based on human ovarian cancer cell line (OVCAR-3) and human normal ovarian epithelial (IOSE-80) cell line obviously indicated that the ZIF-90 NPs had good biocompatibility and minimal cytotoxicity, as well as the high inhibition efficiency of the CBP@ZIF-90-NPF NPs meant that a much higher amount of CBP was transferred into the folate receptor (FR)-overexpressed ovarian cancer cells via FR mediated endocytosis. These results suggest that ZIF-90-NPF NPs could be an ideal targeted drug delivery vehicle for CBP, serving as a promising strategy for ovarian cancer treatment.

Mesothelin-Mediated Paclitaxel Phase-Shifted Nanodelivery System for Molecular Ultrasound Imaging and Targeted Therapy Potential in Ovarian Cancer

Background: Ovarian cancer presents a substantial risk to women's health and lives, with early detection and treatment proving challenging. Targeted nanodelivery systems are viewed as a promising approach to enhance the effectiveness of ovarian cancer treatment and ultrasonic imaging outcomes. Objective: A phase-shifted nanodelivery system (NPs) loaded with paclitaxel (PTX) and further conjugated with avidin (Ab) was studied, with the goal of investigating the effects of targeted nanodelivery strategies on the in vitro therapeutic efficacy and ultrasonic imaging of ovarian cancer. This study provides a foundation for future in vivo treatments utilizing this approach. Methods: PTX-NPs were prepared using the single water-in-oil (O/W) emulsion solvent evaporation method, with avidin coupling achieved through biotin-avidin affinity. The encapsulation efficiency and release profile of PTX were analyzed using UV spectrophotometry. The phase-shift properties of the Ab-PTX-NPs delivery system were evaluated, and the targeting efficiency, cytotoxicity against SKOV3 cells, and in vivo biosafety of various nanodelivery systems were assessed. Results: The prepared nanodelivery system showed a stable and uniform structure with a good particle size distribution and exhibited favorable release characteristics under ultrasound exposure. In vitro experiments revealed that the nanodelivery system displayed excellent targeting and cytotoxic effects against SKOV3 cells, indicating the potential of the Ab-PTX-NPs delivery system for targeted ovarian cancer therapy. In vivo safety studies demonstrated the high biosafety of the prepared nanodelivery system. Conclusion: A novel nanodelivery system was developed, and the experimental results obtained provide a solid experimental basis for further research on in vivo ultrasound molecular imaging technology, offering new insights into targeted ultrasound molecular imaging and the treatment of ovarian cancer.

Blocking Oncostatin M receptor abrogates STAT3 mediated integrin signaling and overcomes chemoresistance in ovarian cancer

Chemotherapy such as cisplatin is widely used to treat ovarian cancer either before or after surgical debulking. However, cancer relapse due to chemotherapy resistance is a major challenge in the treatment of ovarian cancer. The underlying mechanisms related to chemotherapy resistance remain largely unclear. Therefore, identification of effective therapeutic strategies is urgently needed to overcome therapy resistance. Transcriptome-based analysis, in vitro studies and functional assays identified that cisplatin-resistant ovarian cancer cells express high levels of OSMR compared to cisplatin sensitive cells. Furthermore, OSMR expression associated with a module of integrin family genes and predominantly linked with integrin αV (ITGAV) and integrin β3 (ITGB3) for cisplatin resistance. Using ectopic expression and knockdown approaches, we proved that OSMR directly regulates ITGAV and ITGB3 gene expression through STAT3 activation. Notably, targeting OSMR using anti-OSMR human antibody inhibited the growth and metastasis of ovarian cancer cells and sensitized cisplatin treatment. Taken together, our results underscore the pivotal role of OSMR as a requirement for cisplatin resistance in ovarian cancer. Notably, OSMR fostered the expression of a distinct set of integrin genes, which in turn resulted into a crosstalk between OSMR and integrins for signaling activation that is critical for cisplatin resistance. Therefore, targeting OSMR emerges as a promising and viable strategy to reverse cisplatin-resistance in ovarian cancer.

Evaluation of the efficacy of marine natural products against PARP-1/2 proteins in high-grade serous ovarian cancer: insights into MD and SMD simulations

High-grade serous ovarian cancer (HGSOC) is the most malignant and ubiquitous phenotype of epithelial ovarian cancer. Originating in the fallopian tubes and rapidly spreading to the ovaries, this highly heterogeneous disease is a result of serous tubal intraepithelial carcinoma. The proteins known as poly(ADP-ribose) polymerase (PARP) aid in the development of HGSOC by repairing the cancer cells that proliferate and spread metastatically. By using molecular docking to screen 1100 marine natural products (MNPs) from different marine environments against PARP-1/2 proteins, prominent PARP inhibitors (PARPi) were identified. Four compounds, alisiaquinone A, alisiaquinone C, ascomindone D and (+)-zampanolide referred to as MNP-1, MNP-2, MNP-3 and MNP-4, respectively, were chosen based on their binding affinity towards PARP-1/2 proteins, and their bioavailability and drug-like qualities were accessed using ADMET analysis. To investigate the structural stability and dynamics of these complexes, molecular dynamics simulations were performed for 200 ns. These results were compared with the complexes of olaparib (OLA), a PARPi that has been approved by the FDA for the treatment of advanced ovarian cancer. We determined that MNP-4 exhibited stronger binding energies with PARP-1/2 proteins than OLA by using MM/PBSA calculations. Hotspot residues from PARP-1 (E883, M890, Y896, D899 and Y907) and PARP-2 (Y449, F450, A451, S457 and Y460) showed strong interactions with the compounds. To comprehend the unbinding mechanism of MNP-4 complexed with PARP-1/2, steered molecular dynamics (SMD) simulations were performed. We concluded from the free energy landscape (FEL) map that PARP-1/2 are well-stabilised when the compound MNP-4 is bound rather than being pulled away from its binding pockets. This finding provides significant evidence regarding PARPi, which could potentially be employed in the therapeutic treatment of HGSOC. Communicated by Ramaswamy H. Sarma

The oncogenic roles of GPR176 in ovarian cancer: a molecular target for aggressiveness and gene therapy

Background At present, the discovery of new biomarkers is of great significance for the early diagnosis, treatment and prognosis assessment of ovarian cancer. Previous findings indicated that aberrant G-protein-coupled receptor 176 (GPR176) expression might contribute to tumorigenesis and subsequent progression. However, the expression of GPR176 and the molecular mechanisms in ovarian cancer had not been investigated. Methods GPR176 expression was compared with clinicopathological features of ovarian cancer using immunohistochemical and bioinformatics analyses. GPR176-related genes and pathways were analysed using bioinformatics analysis. Additionally, the effects of GPR176 on ovarian cancer cell phenotypes were investigated. Results GPR176 expression positively correlated with elder age, clinicopathological staging, tumour residual status, and unfavourable survival of ovarian cancer, but negatively with purity loss, infiltration of B cells, and CD8+ T cells. Gene Set Enrichment Analysis showed that differential expression of GPR176 was involved in focal adhesion, ECM-receptor interaction, cell adhesion molecules and so on. STRING and Cytoscape were used to determine the top 10 nodes. Kyoto Encyclopaedia of Genes and Genomes analysis indicated that GPR176-related genes were involved in the ECM structural constituent and organisation and so on. GPR176 overexpression promoted the proliferation, anti-apoptosis, anti-pyroptosis, migration and invasion of ovarian cancer cells with overexpression of N-cadherin, Zeb1, Snail, Twist1, and under-expression of gasdermin D, caspase 1, and E-cadherin. Conclusion GPR176 might be involved in the progression of ovarian cancer. It might be used as a biomarker to indicate the aggressive behaviour and poor prognosis of ovarian cancer and a target of genetic therapy.

Regulatory histories of recently withdrawn ovarian cancer treatment indications of 3 PARP inhibitors in the US and Europe: lessons for the accelerated approval pathway.

Withdrawals of drug indications may reveal potential inadequacies in the regulatory approval processes of new drugs. Understanding potential weaknesses of the regulatory approval process is paramount given the increasing use of expedited pathways. In this paper, we focus on three poly-ADP-ribose polymerase inhibitors (olaparib, rucaparib and niraparib) for the treatment of women with heavily pretreated, recurrent ovarian cancer, which were eventually withdrawn. We use a comparative case study approach to evaluate the regulatory histories of these drug indications in the US and Europe. Two drug indications benefited from the FDA's accelerated approval pathway, which explicitly lowers the bar for evidence of efficacy at the time of approval. Following accelerated approval, manufacturers are mandated to conduct post-marketing studies to confirm clinical benefit. The FDA granted accelerated approval to olaparib and rucaparib based on data on surrogate endpoints and converted the approval to regular approval after the submission of additional data on surrogate endpoints from one of two required confirmatory trials, that is, without data on clinical benefit. Niraparib directly received regular approval based only on data on a surrogate endpoint. By contrast, the EMA granted conditional marketing authorisation to rucaparib and was quicker to restrict usage than the FDA. The regulatory histories of these drug indications highlight the need to reform the accelerated approval pathway by ensuring that post-marketing requirements are followed, and that regular approval is only based on evidence of clinical benefit.

The potential value of cancer-testis antigens in ovarian cancer: Prognostic markers and targets for immunotherapy.

Tumor immunotherapy has become an important adjuvant therapy after surgery, radiotherapy, and chemotherapy. In recent years, the role of tumor-associated antigen (TAA) in tumor immunotherapy has become increasingly prominent. Cancer-testis antigen (CTA) is a kind of TAA that is highly restricted in a variety of tumors and can induce an immune response. This review article aimed to evaluate the role of CTA on the progression of ovarian cancer, its diagnostic efficacy, and the potential for immunotherapy. We analyzed publications and outlined a comprehensive of overview the regulatory mechanism, immunogenicity, clinical expression significance, tumorigenesis, and application prospects of CTA in ovarian cancer, with a particular focus on recent progress in CTA-based immunotherapy. The expression of CTA affects the occurrence, development, and prognosis of ovarian cancer and is closely related to tumor immunity. CTA can be used as a biomarker for the diagnosis and prognosis evaluation of ovarian cancer and is an ideal target for antitumor immunotherapy. These findings provide novel insights on CTA in the improvement of diagnosis and treatment for ovarian cancer. The successes, current challenges and future prospects were also discussed to portray its significant potential.

Homologous recombination deficiency score for predicting efficacy of platinum-based chemotherapy and PARPi maintenance therapy in ovarian cancer.

e17543 Background: Currently, homologous recombination deficiency (HRD) has been confirmed to be a predictive biomarker for poly-ADP-ribose-polymerase inhibitors (PARPi) in ovarian cancer, while its effects on the clinical outcomes of platinum-based chemotherapy and PARPi maintenance therapy are not assessed rigorously in ovarian cancer. We developed an HRD assay to evaluate the effect of HRD scores on the platinum-based chemotherapy and PARPi maintenance therapy in Chinese patients with ovarian cancer. Methods: HRD testing was performed on the samples obtained at primary cytoreductive surgery. The progression-free survival (PFS) was observed among the BRCA-mutated/HRD-positive and BRCA wild-type/HRD-negative patients. Univariate and multivariate COX analyses were performed to test the association of PFS with different variables, and hazards ratios (HR) and 95% confidence interval (CI) were calculated. The two-tailed p value less than 0.05 was considered statistically significant. Results: Totally 74 patients who received platinum-based chemotherapy were eligible for the study, among whom 81.1% responded to the initial platinum-based chemotherapy, 33.8% harbored BRCA1/2 mutations and 74.3% were HRD-positive. The median HRD score of platinum-sensitive patients (n=60) was 48.5, significantly higher than the 31 of platinum-resistant patients (n=14, p=0.0035). Analysis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) between platinum-sensitive and platinum-resistant patients showed significant differences in TAI ( p=0.0012) and LST ( p=0.004). Compared with HRD-negative patients, HRD-positive patients had a significantly longer median PFS (10 vs. 15 months, p=0.017), and multivariate analysis further indicated that HRD-positive status (HR, 0.423, 95%CI: 0.191-0.939, p=0.035) was a significant predictor for the improvement of PFS. Conclusions: The HRD assay developed in our study can accurately predict the response to platinum-based chemotherapy and PARPi efficacy in patients with ovarian cancer, providing powerful evidence for implementation of genetic testing and guidance of clinical treatment in ovarian cancer.

Bevacizumab combination therapy versus standard chemotherapy for ovarian cancer in shorter and longer followup duration: A systematic review and meta-analysis of randomized controlled trials.

e23296 Background: Bevacizumab is an anti-angiogenesis drug commonly added to standard chemotherapy regimens in the treatment of ovarian cancer. However, its comparative efficacy and safety in shorter and longer followup duration leaves a research gap that needs to be addressed. This systematic review and meta-analysis aims to evaluate the efficacy and safety of bevacizumab in patients with ovarian cancer in shorter and longer follow up duration. Methods: We searched Medline, Cochrane CENTRAL, Scopus, and Google Scholar for all phase 3 randomized controlled trials (RCTs) that administered bevacizumab to women with ovarian cancer. Review Manager 5.4 was used to calculate risk ratios (RR) and hazard ratios (HR) with 95% confidence intervals (95% CIs). We assessed the quality of included studies using version 2 of the Cochrane Risk of Bias tool (RoB 2). Results: After screening the titles, abstracts, and full texts, we included nine RCTs in our systematic review and meta-analysis. Four RCTs had low risk of bias while five had some concerns. Bevacizumab was associated with a progression free survival benefit for < 36 months (HR 0.59, 95% CI 0.45 to 0.76, p < 0.0001, I2= 90%) and > 36 months (HR 0.66, 95% CI 0.55 to 0.80, p < 0.0001, I2= 80%), and an overall survival benefit for < 36 months (HR 0.87, 95% CI 0.78 to 0.98, p = 0.02, I2= 0%) but not for > 36 months (HR 0.98, 95% CI 0.89 to 1.09, p = 0.77, I2= 30%). There was no difference in deaths between intervention and control groups < 36 months (RR = 0.95, 95% CI 0.86 to 1.04, p = 0.26, I2= 10%) or > 36 months (RR 1.02, 95% CI 0.97 to 1.06, p = 0.50, I2= 0%). Bevacizumab reduced disease progression < 36 months (RR 0.82, 95% CI 0.72 to 0.92, p = 0.0008, I2= 82%) but not at > 36 months (RR 0.83, 95% CI 0.58 to 1.19, p = 0.30, I2= 94%). The adverse events reported with Bevacizumab use included thrombocytopenia, neutropenia, leukocytopenia, anemia, hypertension, bleeding or hemorrhage, and gastrointestinal, cardiac, and dermatological adverse events. Conclusions: Bevacizumab may improve progression free survival within and after 36 months, overall survival within 36 months, and reduce disease progression within 36 months. Future studies should explore the long-term effectiveness of bevacizumab in diverse patient populations and focus on individual patient-tailored treatment approaches to optimize outcomes.

Utilization of PARP inhibitors in the management of ovarian cancer in Nigeria.

e13500 Background: Ovarian cancer remains a significant health concern globally, especially in countries with low Human Development Index (HDI), where there is a projected 96% increase in new cases and a 100% increase in associated deaths by 2040 compared to a 19% increase in new cases and a 28% increase in deaths in very High HDI countries. Over the years, significant strides have been made in the treatment of ovarian cancer, leading to a decrease in ovarian cancer-related mortality in High HDI countries. Poly (ADP-ribose) polymerase inhibitors (PARPi) are among the new and emerging treatment options, which have transformed the management of ovarian cancer, especially in patients with BRCA mutations. Methods: A cross-sectional survey was distributed to clinical and gynecologic oncologists practicing in Nigeria via email, text, WhatsApp, and telegram messaging. Clinical and gynecologic oncologists who are not involved in the treatment of patients with ovarian cancer and those who are not currently in practice were excluded. Results: Out of 36 respondents, 34 were analyzed. While PARP inhibitors are increasingly acknowledged (85.29% awareness), actual utilization remains modest (14.71%). The sole PARP inhibitor used is Olaparib. The majority of respondents (48.28%) who did not use PARP inhibitors cited both the lack of availability and the high cost of medications as the reasons. Key barriers to the use of PARP inhibitors include a combination of non-availability and cost (48.28%) and a combination of institutional protocols and socioeconomic status (20.59%). Conclusions: Despite increasing awareness, PARP inhibitor utilization in Nigerian ovarian cancer management is hindered by challenges, predominantly cost and availability. The study highlights a missed opportunity for optimizing advanced ovarian cancer treatment in Nigeria. [Table: see text]

Effect of circulating tumor cells (CTC) and CTC clusters with PD-L1 dynamic biomarker on cellular burden in patients with ovarian cancer.

e17566 Background: In the precision oncology era, monitoring response to the treatments using circulating blood-based biomarkers e.g. circulating tumor DNA (ctDNA) and Circulating Tumor Cells (CTCs) are being rapidly evaluated and established. The leading cause of ovarian cancer patient mortality is owing to the delayed diagnosis, inability of patient selection for targeted therapies, including the use of immune checkpoint blockade (ICB) agents. The treatment of ovarian cancer usually involves a combination of surgery and chemotherapy. However, post operative resection and therapy with curative intent often fails in accounting the Minimal Cellular Disease (MCD). The dissemination of Circulating Tumor Cells (CTC) remains a dogma of Minimal Residual Disease (MRD) that diffuse and cause micro-metastasis through their epithelial to mesenchymal transitions (EMT) and ‘bio-mechanistic activation’ in blood circulation. Simultaneous detection of over-expression of Programmed Cell Death-Ligand 1 (PD-L1) on CTCs as a dynamic biomarker may be expedient for assessing patients for immune checkpoint inhibitor (ICT) therapy. Methods: In retrospective analysis of real-world data, 75 ovarian cancer patient’s peripheral blood was analyzed for the presence of CTCs with and without the expression of PD-L1 and CTC clusters. CTC were positively detected using OncoDiscover platform approved by CDSCO in 1.5 ml peripheral blood. The platform is multifunctional magneto nanosystem mediated by anti-epithelial cellular adhesion molecule (EpCAM) antibody. CTCs were identified as positive if they were EpCAM +ve, CK+ve, PD-L1 +ve, DAPI +ve and CD45-ve. PD-L1 expression on the CTCs was analyzed based on the linear intensity gradients of the fluorescence signals using image acquisition on an automated Zeiss Microscope. Results: At baseline sample analysis, 86 % (n=65) of the patients showed ≥ 1CTCs per 1.5 ml of blood. The CTC distribution in this study ranged from 1-9 CTCs. Whereas, 46.15 % (n=30) patients with CTCs showed the expression of PD-L1. Noteworthy, the highest number of CTCs were observed ~ 26.7 % (n=23) in age group 41-50. Interestingly, 8 % (n=6) of total patients showed the presence of CTC clusters. The presence of CTCs with expression of PD-L1 and CTC clusters did not correlate with factors like staging, follow ups, metastasis, and DFS status. Conclusions: We observed presence of MCD and MRD in CRC patients, in spite of curative intent in ovarian cancers. Detection of CTCs, CTC clusters with over-expression of PD-L1- as a real time dynamic biomarker may be useful for assessing the patients for early metastasis, regression, and selecting patient suitable for immune checkpoint inhibitor (ICT) therapy when the tissue is inadequate or unavailable for better outcome.

Safety assessments and clinical features of PARP inhibitors from real-world data of Japanese patients with ovarian cancer

Poly (ADP-ribose) polymerase inhibitors have been increasingly used in ovarian cancer treatment. However, the real-world safety data of these drugs in Japanese patients are limited. This retrospective study included 181 patients with ovarian cancer who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Regarding patient backgrounds, the olaparib group had higher proportions of patients with serous carcinoma, BRCA positivity, homologous recombination deficiency, and those receiving maintenance therapy after recurrence treatment than the niraparib group. Regarding toxicity properties, the most common reasons for discontinuation in the olaparib group were anemia, fatigue, and nausea, while the reason in the niraparib was thrombocytopenia. Thrombocytopenia caused by niraparib treatment occurred earlier than anemia caused by olaparib treatment. Patients with a low body mass index or who had undergone several previous treatment regimens were more likely to discontinue treatment within the first 3 months. Although we analyzed blood collection data, predicting treatment interruptions due to blood toxicity was challenging. In this study, we revealed the characteristics of patients and the timing of interruptions for each drug, highlighting the importance of carefully managing adverse effects.

Dual drug-loaded polymeric mixed micelles for ovarian cancer: Approach to enhanced therapeutic efficacy of albendazole and paclitaxel.

Chemotherapy resistance remains a significant challenge in treating ovarian cancer effectively. This study addresses this issue by utilizing a dual drug-loaded nanomicelle system comprising albendazole (ABZ) and paclitaxel (PTX), encapsulated in a novel carrier matrix of D-tocopheryl polyethylene glycol 1000 succinate vitamin E (TPGS), soluplus and folic acid. Our objective was to develop and optimize this nanoparticulate delivery system using solvent evaporation techniques to enhance the therapeutic efficacy against ovarian cancer. The formulation process involved pre-formulation, formulation, optimization, and comprehensive characterization of the micelles. Optimization was conducted through a 32 factorial design, focusing on the effects of polymer ratios on particle size, zeta potential, polydispersity index (PDI) and entrapment efficiency (%EE). The optimal formulation demonstrated improved dilution stability, as indicated by a critical micelle concentration (CMC) of 0.0015 mg/mL for the TPGS-folic acid conjugate (TPGS-FOL). Extensive characterization included differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), and Fourier-transform infrared spectroscopy (FTIR). The release profile exhibited an initial burst followed by sustained release over 90 h. The cytotoxic potential of the formulated micelles was superior to that of the drugs alone, as assessed by MTT assays on SKOV3 ovarian cell lines. Additionally, invivo studies confirmed the presence of both drugs in plasma and tumour tissues, suggesting effective targeting and penetration. In conclusion, the developed TPGS-Fol-based nanomicelles for co-delivering ABZ and PTX show promising results in overcoming drug resistance, enhancing solubility, sustaining drug release, and improving therapeutic outcomes in ovarian cancer treatment.

An open, prospective, single arm, phase II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) with neoadjuvant chemotherapy in patients with advanced ovarian cancer: Interim analysis from the AK104-IIT-003 study.

e17552 Background: There is an unmet need to improve neoadjuvant chemotherapy (NAC) to decrease postoperative residual disease (R0 rate: 50%) and improve prognosis in ovarian cancer (OC). R0 rate and histopathological response of interval cytoreductive surgery (IDS) after NAC combined with immune checkpoint blockades were reported to be encouraging. Cadonilimab (AK104) is a tetravalent bispecific antibody targeting PD-1 and CTLA-4. In this study, we report the efficacy and safety of AK104 with NAC in patients with advanced-stage ovarian cancer (NCT05430906). Methods: This study is an open-label, prospective, single arm, phase II study of evaluating the efficacy and safety of cadonilimab combined with chemotherapy as neoadjuvant treatment for advanced ovarian cancer. Patients received neoadjuvant therapy of cadonilimab plus platinum-taxane chemotherapy (3 to 4 cycles) followed by surgery. Surgery would be performed within 30 days of completion of neoadjuvant therapy. The primary endpoint was the R0 rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), chemotherapy response score (CRS), pathologic complete response(pCR), progression-free survival (PFS), and safety. A sample size of 35 achieves 80% power to detect a difference of 0.2 using a two-sided Z-test to estimate the standard deviation with a significance level (alpha) of 0.1. And the sample size was expected to be 40 cases to ensure that the FAS set contains 35 cases for analysis. Results: 17 patients were enrolled from Dec 12, 2022, to Dec 6, 2023. The median patient age was 57 years (range 45–70 years), and most patients presented with high-grade serous carcinoma (94.1%) and stage IVa (5.9%), IVb disease (76.5%). 15 (88.2%) patients had undergone IDS, with an R0 resection rate of 66.7%. ORR was 94.1%, with 1patient achieved CR and 15 patients achieved PR. 11.8% achieved pathological complete response, and 17.6% had a chemotherapy response score (CRS) of 3. PFS or OS data are not mature by cut-off date. Safety and adverse event (AE) were analyzed after completion of neoadjuvant therapy. Treatment-related AEs (TRAEs) of any grade were evaluated for all study populations. TRAEs of any grade occurred in 13 (76.5%) patients. Grade ≥3 TRAEs occurred in 3 (17.6%) patients. The most common TRAEs were thyroid dysfunction (23.5%) and bone marrow suppression (17.6%). Grade ≥ 3 irAE (immune⁃mediated colitis) occurred in 1 (5.9%) patient. All of the TRAEs, including severe AEs, were manageable, with no new safety concerns in this study. Conclusions: This study showed promising activity with a durable clinical response, supporting the potential of NAC with bispecific antibody AK104 in advanced-stage ovarian cancer. Meanwhile, long-term efficacy evaluation still needs following up. Clinical trial information: NCT05430906 .

Repurposing atovaquone as a STAT3 inhibitor for the treatment of platinum resistant ovarian cancer.

TPS5631 Background: Despite advances, ovarian cancer (OC) is the most lethal gynecologic cancer with 5-year survival rates for stage III and IV disease 41% and 21%, respectively. After initial treatment with cytoreductive surgery and chemotherapy, 70% of patients (pts) will relapse. Treatment of relapsed OC is dependent on the amount of time between completion of platinum-based therapy and relapse, known as the platinum-free interval (PFI). Pts with PFI of less than six months are deemed platinum-resistant with low response to further chemotherapy and median progression-free survival (PFS) of 3.6 months. Additional treatment options are needed. Oncogenic signal transduction pathways are a critical component of cancer pathogenesis. In a variety of cancer types, including OC, the transcription factor STAT3 (Signal Transducer and Activator of Transcription 3) has emerged as a key promoter of cellular proliferation and resistance to therapeutic drugs. In OC cells, STAT3 is constitutively activated in over 70% of cells, resulting in enhanced cell survival, angiogenesis, and metastasis. STAT3 also controls innate and adaptive immune response by driving myeloid-derived suppressor cells and regulatory T cells, while hampering CD8+ T cell cytotoxicity. Using the Connectivity Map database to identify drugs that induce gene expression changes contrary to the STAT3 signature, the FDA-approved antimicrobial atovaquone (ATO) was identified as the most active. ATO, a well-tolerated, readily available drug inhibits STAT3 tyrosine phosphorylation by downregulating the cell surface expression of glycoprotein 130, which is necessary for signaling of IL-6 and Janus Kinase, and subsequent phosphorylation of STAT3. Given that the STAT3 pathway is constitutively activated in OC, we hypothesize that ATO, a potent inhibitor of STAT3, could be a repurposed therapeutic agent in OC. Methods: A Phase II, single-arm, investigator-initiated clinical trial is in process at our institution where we are evaluating ATO as targeted therapy in pts with platinum resistant OC whose tumors have progressed despite standard therapies. To date, we have currently enrolled 2 of an anticipated 28 pts. The primary endpoint is PFS, with clinical secondary endpoints to include clinical benefit rate and overall survival. In addition, to confirm the STAT inhibitory effect on OC cells, pre and on-treatment tissue sampling is being obtained to assess changes in STAT3 dependent gene expression via RT-PCR and quantitate changes to the immune profile via flow cytometry. We hypothesize targeting inappropriate activation of STAT3 could be a novel and promising treatment approach in OC. This is the first clinical trial evaluating the clinical efficacy of ATO in OC and could have wide implications on treatment options in the future. Clinical trial information: NCT05998135 .

65P Chemotherapy response score (CRS) and efficacy of PARP inhibitor (PARPi) treatment in advanced epithelial ovarian cancer (AEOC)

65P Chemotherapy response score (CRS) and efficacy of PARP inhibitor (PARPi) treatment in advanced epithelial ovarian cancer (AEOC)

Efficacy and safety of luveltamab tazevibulin vs investigator’s choice of chemotherapy in patients with recurrent platinum-resistant ovarian cancer (PROC) expressing folate receptor alpha (FRα): The REFRaME-01 (GOG-3086, ENGOT-79ov, and APGOT-OV9) phase 2/3 study.

TPS5637 Background: The treatment of recurrent epithelial ovarian cancer remains a challenge, particularly for tumors with low to moderate expression levels of FRα. Luveltamab tazevibulin (luvelta) is an anti–FRα-targeting antibody-drug conjugate with a stable cleavable linker and a 3-aminophenyl hemiasterlin warhead (DAR=4), which induces cytotoxic and immunologic cell death. Luvelta was designed to treat multiple cancers with a broad range of FRα expression. Luvelta demonstrated preliminary antitumor activity in women with recurrent ovarian cancer, selected for FRα expression level of ≥25% at any intensity (tumor proportion score [TPS]). In PROC, this cutoff represents an estimated 80% of patients (pts). In a phase 1 study of luvelta in relapsed ovarian cancer, the overall response rate (ORR) was 37.5% with a median duration of response (DOR) of 5.5 months and a median progression-free survival (PFS) of 6.1 months. ORR was higher at 5.2 mg/kg compared with 4.3 mg/kg (43.8% vs 31.3%). The safety profile was manageable, with the most common grade ≥3 adverse events consisting of neutropenia, arthralgia, and anemia (Oaknin et al. J Clin Oncol 2023;41[16 suppl]:5508). These results support further investigation in pts with PROC whose tumors have a broad range of FRα expression. Herein, we describe a phase 2/3 pivotal study (REFRaME-01)of luvelta in this pt population. Methods: This randomized, global, open-label, 2-part phase 2/3 pivotal study has been designed to assess the efficacy and safety of luvelta vs investigator’s choice (IC) chemotherapy in pts with recurrent PROC expressing FRα (NCT05870748). Eligible pts are adults (≥18 years) with relapsed PROC, 1–3 prior lines of therapy (which must include bevacizumab), measurable disease, Eastern Cooperative Oncology Group performance status ≤1, and TPS for FRα expression ≥25% using Ventana validated IHC assay. Part 1 (phase 2) consists of a luvelta dose-optimization stage in which pts are randomized 1:1 to receive intravenous (IV) luvelta every 3 weeks (Q3W) at 4.3 mg/kg or IV luvelta Q3W at 5.2 mg/kg with prophylactic G-CSF for 2 cycles followed by 4.3 mg/kg luvelta from cycle 3 onward. Part 1 data will be used to select the optimal dosing regimen. In part 2 (phase 3) ~550 pts will be enrolled and randomized 1:1 to the optimal luvelta dosing regimen or IC chemotherapy (gemcitabine, paclitaxel, pegylated liposomal doxorubicin, or topotecan). Primary endpoints are PFS and ORR, with response evaluated per RECIST v1.1. Secondary endpoints include overall survival, DOR, safety, and quality of life. Clinical trial information: NCT05870748 .

A phase I/II study of maplirpacept in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (OC): Phase 1 results.

e17546 Background: CD47, an overexpressed factor correlated with poor clinical characteristics and prognosis in OC, is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a signal to suppress macrophage phagocytosis. Maplirpacept (PF-07901801) is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4, enhancing phagocytosis by blocking CD47. Blockade of CD47, both alone and combined with doxorubicin, has shown anti-tumor activity in vitro and in vivo in xenograft animal models. PLD 40mg/m2 conveyed poor efficacy (PFS 4 months; ORR 8%), as did bevacizumab + PLD (PFS 5 months; ORR 14%) (AURELIA), highlighting the need for new treatments for platinum-resistant OC. C4971002 [NCT05261490] is an open label, multicenter dose-escalation and expansion study evaluating the safety, preliminary anti-tumor activity, pharmacokinetics and -dynamics of maplirpacept in combination with PLD in patients with platinum-resistant recurrent OC. Methods: The study included adults with platinum-resistant recurrent epithelial OC (PD ≤6 months after platinum-based therapy or unable/unwilling to receive platinum-based therapy). PLD while platinum-resistant or directly prior to study was not permitted. Patients received maplirpacept (12mg/kg Dose Level [DL] 1; 24mg/kg DL2; 48mg/kg DL3) weekly in Cycle 1 and every 2 weeks in Cycle 2+, and PLD (40mg/m2) on Day 1 of each 4-week cycle. Assessments of adverse events (AEs) were based on CTCAE v5.0. Response assessments (RECIST v1.1) were performed every 8 weeks. Results of the Phase I portion, aiming to evaluate the DLTs, the MTD and the RP2D, are presented as of 18 December 2023, after all patients completed the 28-day DLT assessment period. Results: 10 patients were treated (DL1 n=3; DL2 n=3; DL3 n=4) with a median (min, max) age of 69 (53, 77) years, 80% ECOG 1, 60% serous adenocarcinoma. Median (min, max) treatment duration was 14 (8, 32) weeks. Most common adverse events are shown in the table. No DLTs occurred in the assessment period. 1 serious AE (gait disturbance & muscle weakness) related to maplirpacept was reported (DL3). 2 deaths occurred >120 days after 1st dose, both due to disease. 5 (50%) patients had a best response of stable disease, 2 of which were treated into at least Cycle 6. Conclusions: Despite immature anti-tumor activity, maplirpacept + PLD was tolerable at all dose levels, not reaching the MTD. The encouragingly tolerable dose of 48mg/kg thus represents the RP2D which could support further development for this population. Clinical trial information: NCT05261490 . [Table: see text]

The Gut Microbiome in Aging and Ovarian Cancer.

The gut microbiome changes with age and affects regions beyond the gut, including the ovarian cancer tumor microenvironment. In this review summarizing the literature on the gut microbiome in ovarian cancer and in aging, we note trends in the microbiota composition common to both phenomena and trends that are distinctly opposite. Both ovarian cancer and aging are characterized by an increase in proinflammatory bacterial species, particularly those belonging to phylum Proteobacteria and genus Escherichia, and a decrease in short chain fatty acid producers, particularly those in Clostridium cluster XIVa (family Lachnospiraceae) and the Actinobacteria genus Bifidobacterium. However, while beneficial bacteria from family Porphyromonadaceae and genus Akkermansia tend to increase with normal, healthy aging, these bacteria tend to decrease in ovarian cancer, similar to what is observed in obesity or unhealthy aging. We also note a lack in the current literature of research demonstrating causal relationships between the gut microbiome and ovarian cancer outcomes and research on the gut microbiome in ovarian cancer in the context of aging, both of which could lead to improvements to ovarian cancer diagnosis and treatment.

Controversies in the Surgical Management of Gynecologic Cancer: Balancing the Decision to Operate or Hesitate.

Cancer outcomes are largely measured in terms of disease-free survival or overall survival, which is highly dependent on timely diagnosis and access to treatment methods available within the country's existing health care system. Although cancer survival rates have markedly led in the past few decades, any improvement in the 5-year survival of gynecologic cancers has been modest, as in the case of ovarian and cervical cancers, or has declined, as in the case of endometrial cancer. The lack of effective screening options contributes to many women presenting with advanced-stage disease and the need for radical approaches to treatment. Although treatment for early-stage disease can lead to a cure, advanced-stage disease is fraught with a high potential for morbidity and mortality, and recent clinical trials have aimed to assess the noninferiority of minimally invasive options versus aggressive surgical approaches. Of particular interest is fertility-sparing treatments for endometrial and cervical cancers, which have recently been on the rise among younger women. Balancing morbidity with the risk of mortality, and loss of fertility and quality of life requires a targeted patient-centered approach to treatment. This is an ongoing area of intense research and sometimes may challenge current treatment paradigms. In this two-part review, we present an overview of current approaches to gynecologic cancer treatment and the need to de-escalate radical surgical approaches and preserve fertility. We also review the intricacies of ovarian and advanced endometrial cancer treatment, exploring the nuances in surgical debulking timing and its impact on outcomes.