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Background: Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. Methods: For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m2) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients. Findings: 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p

With the approval of a vaccine to prevent human papillomavirus (HPV) infection and the pending approval of a second vaccine, an exciting era has dawned that provides clinicians the opportunity to prevent a majority of lower genital tract cancers. Herein, we describe the quadrivalent and bivalent prophylactic HPV vaccines and examine how they can be incorporated into clinical practice. Efficacy and safety of the vaccines are discussed as are potential barriers to vaccination. Future questions and challenges are also reviewed. A quadrivalent virus-like particle vaccine has now been approved for use in girls and women ages 9-26 years. A second bivalent vaccine could be available soon. The development of these vaccines targeted against 2 oncogenic types of HPV infection (HPV 16 and 18) has made it possible to eliminate approximately 70% of all invasive cervical cancers in women worldwide and decrease the incidence of other lower genital tract cancers and precancers. Vaccine efficacy in clinical trials has been outstanding, with nearly 100% protection against high-grade lesions because of HPV vaccine types. It is extremely important that vaccinated and unvaccinated women continue with recommended cervical cancer screening because not all oncogenic HPV types are covered in currently developed vaccines. Prevention of most cervical cancer and a notable proportion of cervical precancers and other lower genital tract cancers is now possible with the clinical availability of prophylactic vaccination for girls and young women. Prevention of genital warts is also possible with the quadrivalent vaccine. However, knowledge about HPV infection and cervical cancer as well as the need to vaccinate against oncogenic HPV infection is still lacking among women and physicians; thus, continued education of patients and clinicians is necessary to optimize vaccine use and assure ongoing cytologic screening. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We analyzed the content, quality, and accuracy of information provided on hospital web sites about robotic gynecologic surgery. STUDY DESIGN: An analysis of hospitals with more than 200 beds from a selection of states was performed. Hospital web sites were analyzed for the content and quality of data regarding robotic-assisted surgery. RESULTS: Among 432 hospitals, the web sites of 192 (44.4%) contained marketing for robotic gynecologic surgery. Stock images (64.1%) and text (24.0%) derived from the robot manufacturer were frequent. Although most sites reported improved perioperative outcomes, limitations of robotics including cost, complications, and operative time were discussed only 3.7%, 1.6%, and 3.7% of the time, respectively. Only 47.9% of the web sites described a comparison group. CONCLUSION: Marketing of robotic gynecologic surgery is widespread. Much of the content is not based on high-quality data, fails to present alternative procedures, and relies on stock text and images. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We analyzed the effect of lymphadenectomy on the use of adjuvant radiation treatment for women with stage I-II endometrial cancer. STUDY DESIGN: Women with stage I-II endometrioid adenocarcinomas treated between 1988 and 2006 and recorded in the Surveillance, Epidemiology, and End Results database were identified. The influence of lymphadenectomy (LND) on receipt of external beam radiation and brachytherapy stratified was examined. RESULTS: We identified 58,776 women including 26,043 who underwent LND (44.3%). Among women younger than 60 years of age with stage IA (grades 1, 2, and 3) tumors, LND had no impact on the use of radiation. Patients with stage IB (grade 2 or 3) and stage IC (grade 1 or 2) tumors who underwent lymph node dissection were less likely to undergo external beam radiation and more likely to receive vaginal brachytherapy (P < .05 for all). Furthermore, the extent of lymphadenectomy influenced the receipt of radiation. CONCLUSION: Women who undergo lymphadenectomy are less likely to receive whole pelvic radiotherapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We performed a population-based analysis to compare the clinical characteristics of women with mucinous tumors with women with other epithelial tumors. STUDY DESIGN: The Surveillance, Epidemiology, and End Results database was queried to identify all women with epithelial ovarian cancer diagnosed from 1988 to 2007. The natural history, clinical characteristics, and survival of women with serous tumors were compared with women with mucinous carcinomas. RESULTS: A total of 40,571 women including 4811 with mucinous carcinomas (11.9%) were identified. Among women with stage I neoplasms, the presence of mucinous histology had no effect on either cancer-specific survival (hazard ratio, 0.87; 95% confidence interval, 0.74-1.04). Survival was inferior in patients with advanced-stage mucinous compared with serous tumors. The hazard ratio for cancer-specific survival for women with stage III mucinous tumors was 1.55 (95% confidence interval, 1.43-1.96). CONCLUSION: Although survival for early-stage mucinous and serous tumors is similar, survival for advanced-stage mucinous neoplasms is inferior to that of serous carcinomas. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We examined the influence of physician and hospital volume on the morbidity and mortality of radical hysterectomy for cervical cancer. STUDY DESIGN: Women who underwent radical hysterectomy for cervical cancer between 2003 and 2007 were examined. The effect of surgeon and hospital volume on morbidity and mortality was examined using multivariable generalized estimating equations. RESULTS: A total of 1536 women who underwent radical hysterectomy were identified. Patients treated by high-volume surgeons had fewer medical complications (odds ratio, 0.55; 95% confidence interval, 0.34-0.88) and shorter lengths of stay (odds ratio, 0.49; 95% confidence interval, 0.25-0.98). After adjustment for case mix and surgeon volume, hospital volume had no independent effect on any of the variables of interest. CONCLUSION: High-volume surgeons have fewer postoperative medical complications, shorter lengths of stay, and lower transfusion requirements. Hospital volume appears to have only a minor influence on outcomes after radical hysterectomy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Although endometrial cancer commonly occurs in elderly women, little is known about the perioperative outcomes of the oldest women (>80 years of age) who are treated surgically. STUDY DESIGN: We performed an analysis of women >=65 years of age with endometrial cancer who underwent hysterectomy from 1998-2007 and who were registered in the Nationwide Inpatient Sample. RESULTS: A total of 25,698 women were identified. Compared with women who were 65-69 years old, women who were >=85 years old were more likely to have perioperative surgical complications (12% vs 17%), postoperative medical complications (24% vs 34%), and a longer length of stay (3 vs 5 days) and to require a transfusion (6% vs 10%; P < .05 for all). The perioperative mortality rate was 0.4% in women who were 65-69 years old compared with 1.6% in women who were >=85 years old (P < .0001). CONCLUSION: The morbidity that is associated with surgery for endometrial cancer is significantly higher in women who are >80 years old, even after medical comorbidities have been considered. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We examined the prognostic significance of uterine risk factors (RF) compared to nodal metastases in endometrial cancer. STUDY DESIGN: Women with stage I-IIIC endometrioid cancer were stratified based on the presence of positive or negative lymph nodes. Each patient was characterized by the number of RF present: myoinvasion >=50%, cervical stromal involvement, and grade 3 histology. RESULTS: A total of 26,967 women were identified. In a multivariable model, uterine RF strongly influenced survival but nodal disease was a more important negative prognostic factor. Five-year overall survival was 68% (95% confidence interval [CI], 63-72%) for group 1 (node positive/no RF) vs 69% (95% CI, 66-72%) for group 5 (node negative/multiple RF). Five-year survival was lower for node-positive patients with RF (58%; 95% CI, 54-61%) than node-positive patients without RF (68%; 95% CI, 63-72%). CONCLUSION: Uterine RF strongly influenced survival both in the presence and absence of nodal metastasis. [ABSTRACT FROM AUTHOR]

Background/objectives: Patients with recurrent or metastatic endometrial cancer (EC) have poor prognoses with limited therapeutic options following immunotherapy or immunochemotherapy treatments. Inhibitors of KRAS mutations (KRAS-mut) have shown efficacy in early solid tumor studies, but data in EC are lacking. This study describes the frequency of KRAS-mut relative to other oncogenic alterations in EC to identify genomic characteristics of KRAS-mut tumors that could lead to novel therapeutic options., Methods: A molecular database of 7870 ECs was queried for presence of oncogenic mutations and immunotherapy biomarkers. Comparisons were performed using Fisher-Exact/ChiSquare (p-values) and adjusted for multiple tests by Benjamini-Hochberg (q) and pairwise nonparametric analysis using Wilcoxon Method., Results: KRAS-mut is a relatively frequent genotype in EC, detected in 16% of cases. Codon 12 was most frequently mutated, with G12D (31%) and G12V (27%) the most common subtypes. Biomarkers of immunotherapy response co-occur with KRAS-mut. Microsatellite instability-high and tumor mutational burden-high status were observed in 34.1% and 36.5% in KRAS-mut compared to 19.8% and 16.9% in KRAS-WT, respectively (p < 0.05). PD-L1 >1% was detected in 8.4% vs 6.4% of KRAS-mut vs KRAS-WT (p < 0.05). BRCA1/2 mutations were detected with similar low frequency (5.9% vs 4.9%) among KRAS-mut and KRAS-WT ECs (p > 0.05). KRAS-mut was inversely associated with Her-2 overexpression (1.8% KRAS-mut vs 13% KRAS-WT. (p < 0.001)., Conclusions: KRAS-mut represents a genotypically distinct group of ECs. Overlap exists with genomic predictors (TMB-high, MSI-high) of immunotherapy response, suggesting a possible biomarker-driven combination option with immunotherapy. Clinical trials to evaluate these strategies should be developed., Competing Interests: Declaration of competing interest RWH has Speaking Honoraria with AstraZeneca, Eisai, Merck, Natera, and Tesaro/GSK; and Consulting or Advisory Roles with Caris, Genelux, Natera, ImmunoGen, and GSK. PHT has done advisory boards or consulting work with Iovance, Astra Zeneca, Glaxo Smith Kline, Clovis Oncology, Zentalis, Novocure, Seagen, Abbvie, R Pharm, Aadi Pharmaceuticals, Caris, Merck, Imunon, Verastem; and has institutional grant funding from Merck and Glaxo Smith Kline. TJH has done advisory boards or consulting work with Aadi, Astra Zeneca, AbbVie (Immunogen), Caris, Clovis, Corcept, Eisai, Genmab, GSK, GOG Foundation, Merck, Pfizer (Seagen), Roche (Genentech). There are no conflicts to report for other co-authors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported., Patients and Methods: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024)., Results: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed., Conclusions: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: In the ENGOT-EN6-NSGO/GOG3031/RUBY trial, dostarlimab+carboplatin-paclitaxel demonstrated significant improvement in progression free survival and a positive trend in overall survival compared with placebo+carboplatin-paclitaxel, with manageable toxicity, in patients with primary advanced or recurrent endometrial cancer. Here we report on patient-reported outcomes in the mismatch repair-deficient/microsatellite instability-high population, a secondary endpoint in the trial., Methods: Patients were randomized 1:1 to dostarlimab+carboplatin-paclitaxel or placebo+carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo monotherapy every 6 weeks for ≤3 years or until disease progression. Patient-reported outcomes, assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Endometrial Cancer Module, were prespecified secondary endpoints. A mixed model for repeated measures analysis, a prespecified exploratory analysis, was conducted to generate least-squares means to compare between-treatment differences while adjusting for correlations across multiple time points within a patient and controlling for the baseline value. Results are provided with 2-sided, nominal p values., Results: Of 494 patients enrolled, 118 were mismatch repair-deficient/microsatellite instability-high. In this population, mean change from baseline to end of treatment showed visual improvements in global quality of life (QoL), emotional and social function, pain, and back/pelvis pain for dostarlimab+carboplatin-paclitaxel. Meaningful differences (least-squares mean [standard error]) favoring the dostarlimab arm were reported for change from baseline to end of treatment for QoL (14.7 [5.45]; p=0.01), role function (12.7 [5.92]); p=0.03), emotional function (14.3 [4.92]; p<0.01), social function (13.5 [5.43]; p=0.01), and fatigue (-13.3 [5.84]; p=0.03)., Conclusions: Patients with mismatch repair-deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer receiving dostarlimab+carboplatin-paclitaxel demonstrated improvements in several QoL domains over patients receiving placebo+carboplatin-paclitaxel. The observed improvements in progression free survival and overall survival while improving or maintaining QoL further supports dostarlimab+carboplatin-paclitaxel as a standard of care in this setting., Trial Registration: ClinicalTrials.gov NCT03981796., Competing Interests: Competing interests: GV reports consulting fees from GSK; honoraria from AstraZeneca, GSK, and MSD; travel support from AstraZeneca and PharmaMar; participation in advisory boards for AstraZeneca, Eisai, GSK, and MSD. MAP reports consulting fees from GSK, Tesaro, Merck, Eisai, SeaGen, Clovis Oncology, and AstraZeneca. SH reports consulting fees from AstraZeneca, Eisai, GSK, and MSD and honoraria from AstraZeneca and GSK. EMM reports advisory board meeting fees from AstraZeneca, GSK, and Tempus; honoraria from OncLive and Opinions in Gyn Malignancies; and support for attending meetings from Opinions in Gyn Malignancies and OncLive. ZN reports honoraria from Sofmedica, AstraZeneca, and MSD; support for attending meetings from Sofmedica and Preglem; participation on a data safety monitoring board or advisory board for AstraZeneca and Richter Gedeon; stock options from Richter Gedeon; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from AstraZeneca. RH reports honoraria from GSK, AstraZeneca, Clovis Oncology, Eisai, and Merck. DD reports receiving consulting fees from AstraZeneca, GSK/Tesaro, Roche, Eisai Germany, and MSD Oncology; honoraria for advisory roles from Roche, AstraZeneca, GSK/Tesaro, Intuitive Surgical, KLS Martin, MSD, PharmaMar, and Seagen; and travel support from AstraZeneca. TM reports honoraria from Immunogen. LG reports institutional grants from Alkermes, AstraZeneca, Clovis Oncology, Esperas, IMV, ImmunoGen, Karyopharm, MSD, Mersana, Novocure, OncoQuest Pharmaceuticals, Pfizer, Roche, and Tesaro; consulting fees from Merck; honoraria from Alkermes, AstraZeneca, Eisai, Eisai-Merck, and GSK. BA reports honoraria from AstraZeneca, Eisai, GSK, MSD, Norartis, and Roche; support for attending meetings from AstraZeneca, GSK, and Roche; participation on a data safety monitoring board or advisory board for Eisai, GSK, MSD, Roche, and Sanofi Aventis. RG reports participation on a data safety monitoring board or advisory board for Pionyr Pharmaceuticals and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Bausch+Lomb. NC reports advisory board fees for Aadii, GSK, Kartos, Novita Pharmaceuticals, Tarveda Therapeutics, Toray, Umoja, and Zentalis. BJM reports consulting fees from Agenus, Akeso Biopharma, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, Macrogenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL and speakers’ bureau honoraria from AstraZeneca, Clovis Oncology, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. TJH reports personal consulting fees from Aadi, AstraZeneca, Caris, Clovis Oncology, Eisai, Epsilogen, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen; participation on a data safety monitoring board or advisory board for Corcept; and leadership role on the GOG Foundation Board and President of GOG Partners. AS reports royalties as an UptoDate reviewer. BP reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Eisai, Genentech/Roche, Karyopharm, Merck, Mersana, SeaGen, Sutro Biopharma, Takeda Pharmaceuticals, Tesaro/GSK, Toray, and VBL Therapeutics; consulting fees from AstraZeneca, Atossa, Clovis Oncology, Deciphera, Elevar Therapeutics, I-Mab Biopharma, Merck, Mersana, Sutro Biopharma, Tesaro/GSK, and Toray; support for attending meetings from GOG Foundation; advisory board fees from Arquer Diagnostics, AstraZeneca, Atossa, Clovis Oncology, Deciphera, Eisai, Elevar Therapeutics, GOG Foundation, I-Mab Biopharma, Lilly, Merck, Mersana, Seagen, Sutro Biopharma, Tesaro/GSK, Toray, and VBL Therapeutics; and noncompensated leadership fees from NYOB Society Secretary, SGO Clinical Practice Committee Chair, and SGO COVID-19 Taskforce Co-Chair. AAS reports support paid to her institution from GSK for the present IGCS abstract; institutional grant support from AbbVie, Aravive, AstraZeneca, Clovis Oncology, Eisai, Ellipses, I-Mab Biopharma, Immunogen, Merck, Oncoquest/Canaria Bio, Roche/Genentech, Seagen, TapImmune, Tesaro/GSK, and VBL Therapeutics; honoraria from @Point of Care Clinical Care Options Curio Science, Peerview, Bio ASCEND, RTP, GOG Foundation (Highlight reel), and GOG Foundation Symposium; patent issued for 'blood based biomarkers in ovarian cancer'; noncompensated participation on a data safety monitoring board/advisory board from AstraZeneca, Clovis Oncology, Gilead, Immunogen, Imvax, Merck, Mersana, Natera, Onconova, and OncoQuest; uncompensated leadership roles with SGO, AAOGF, and NRG and compensated role from GOG; receipt of medical writing support from AstraZeneca; and uncompensated Clinical Trial Steering Committees for the AXLerate trial (Aravive), AtTEnd trial (Hoffman-LaRoche), Oval Trial (VBL Therapeutics), FLORA-5 trial (CanariaBio), and QPT-ORE-004 (CanariaBio). DC reports consultant fees from AstraZeneca and GSK and honoraria from AstraZeneca, GSK, Seagen/Genmab, and Immunogen. MRM reports consulting fees from AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, and Zai Lab; speakers’ bureau fees from AstraZeneca and GSK; research funding (to institution) from Apexigen, AstraZeneca, Deciphera (trial chair), GSK, and Ultimovacs; and personal financial interest in Karyopharm (stocks/shares, member of board of directors). DB reports institutional grant fees from GSK; fees for being a member of GOG Partners Investigational Council; and medical director/owner of Trials365. AMT, KPP, EF, OZ, LML, IP, and SS have nothing to disclose. OM, VV, and JG are employees of GSK., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Objective: Our goal was to compare molecular and immune profiles of vulvovaginal melanoma (VVM) with cutaneous melanoma (CM) and explore the significance of immune checkpoint inhibitor (ICI) agents on survival., Methods: Samples from VVM and CM tumors underwent comprehensive molecular and immune profiling. Treatment and survival data were extracted from insurance claims data and OS was calculated from time of ICI treatment to last contact. Statistical significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons., Results: Molecular analysis was performed on 142 VVM and 3823 CM tumors. VVM demonstrated significantly (q < 0·01) less frequent BRAF and more frequent KIT, ATRX, and SF3B1 mutations. Alterations in pathways involving DNA damage and mRNA splicing were more common in VVM, while alterations in cell cycle and chromatin remodeling were less common. Immunogenicity of VVM was lower than CM, with an absence of high TMB (0% vs 46.9%) and lower PD-L1 positivity (18·0% vs 29·5%). Median immune checkpoint gene expression was lower in VVM, as were cell fractions for type I macrophages and CD8+ T-cells(q < 0·01). Myeloid dendritic cells were increased in VVM(q < 0·01). Median OS was shorter for VVM than for CM patients treated with ICIs (17·6 versus 37·9 months, HR:1·65 (95% CI 1·02-2·67) p = 0·04)., Conclusions: VVM has a distinct molecular and immune profile compared to CM, which may contribute to the worse survival in VVM compared to CM patients treated with ICI therapy. Though ICIs have been a mainstay of treatment in recent years, our findings suggest that new therapeutic strategies are needed., Competing Interests: Declaration of competing interest SW and JX are employees of Caris Life Sciences. GTG reports grants from Exelixis and Luceno Dynamics; fees for consulting for Bristol Myers Squibb, Merck, Novartis, Regeneron, Immunocore, Iovance, Lyell Immunopharma, Eisai, Incyte, Pfizer, Sapience Therapeutics, Exicure, and Genentech; fees for payment/honoraria from Immunocore; fees for participation on a Data Safety Monitoring Board/Advisory Board for Huyabio. GKI reports fees for consulting for Sanofi and Pfizer; fees for payment/honoraria from Merck, Sanofi, and Regeneron; fees for support for attending meetings from BMS and Sanofi; fees for participation on a Data Safety Monitoring Board/Advisory Board from Replimune, Castle, and Regeneron; institutional research support from BMS, Regeneron, Replimune, Pfizer, InstilBio, Checkmate Pharmaceuticals, and Xencor. TJH reports consulting fees from J & J, Clovis, AstraZeneca, GSK, Roche Genentech, Caris, Genelux, Aravive, Merck, Eisai, and Seagen. BKE reports fees for participation on a Data Safety Monitoring Board/Advisory Board for Merck and GSK. JB reports fees for consulting for Caris, AstraZeneca, Genentech, GSK Tesaro, and Verastem; fees for participation on a Data Safety Monitoring Board/Advisory Board from Caris, AstraZeneca, GSK Tesaro, and Verastem; fees for a leadership/fiduciary role from American Association of Gynecologic Laparoscopy, and Society of Gynecologic Oncology. The remaining authors have nothing to disclose. All of these disclosures mentioned above are unrelated to this study. No author declares a conflict of interest related to the study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016)., Methods: The PRIMA protocol was amended so newly enrolled patients received an ISD based on baseline body weight/platelet count. In this ad hoc analysis, the timing, duration, and resolution of the first occurrence of common any-grade hematologic (thrombocytopenia, anemia, neutropenia) and nonhematologic (nausea, asthenia/fatigue, constipation, insomnia, hypertension) treatment-emergent adverse events (TEAEs) were evaluated by treatment arm in the ISD safety population (data cutoff, November 17, 2021; median follow-up, 3.5 years)., Results: Of 733 randomized patients, 255 were enrolled after the ISD protocol amendment and received ≥ 1 dose of study treatment (niraparib, 169; placebo, 86). In the niraparib arm, median times to first events were 22.0-35.0 days for hematologic TEAEs and 7.0-56.0 days for nonhematologic TEAEs. First events resolved in ≥ 89.8% of patients for hematologic TEAEs; for nonhematologic TEAEs, resolution rates ranged from 55.3% (insomnia) to 86.0% (nausea). Median durations of first hematologic TEAEs were ≤ 16.0 days, but for first nonhematologic TEAEs ranged from 18.0 days (nausea) to 134.0 days (insomnia)., Conclusion: The niraparib ISD was generally well tolerated and TEAEs were manageable. Common hematologic and nonhematologic TEAEs occurred early and first events of hematologic TEAEs had a short duration (≈ 2 weeks) and a high resolution rate. These findings support close monitoring immediately following niraparib initiation and may help inform patient expectations for niraparib safety., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Vulsteke reports medical writing support from GSK; consulting fees from Astellas, Atheneum Partners, Bristol Myers Squibb, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme, and Roche; advisory board fees from AstraZeneca, Bayer, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme; and travel support from Pfizer and Roche. Dr Chambers has nothing to disclose. Dr Rubio Pérez has nothing to disclose. Dr Chan reports research, consulting, and speakers' bureau fees from AbbVie, Acerta, Aravive, AstraZeneca, Clovis, Eisai, GSK, Merck, and Roche. Dr Raaschou-Jensen reports advisory board fees from Eisai. Dr Zhuo has nothing to disclose. Dr Lorusso reports consulting fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, PharmaMar, and Seagen; honoraria from AstraZeneca, Clovis Oncology, GSK, MSD, and PharmaMar; payment for expert testimony from Clovis Oncology; support for attending meetings and/or travel from AstraZeneca, Clovis Oncology, GSK, PharmaMar, and Roche; personal advisory board fees from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, Merck Serono, MSD, Oncoinvent, PharmaMar, Seagen, and Sutro; member of board of directors at GCIG (no compensation); medical writing support from Clovis Oncology, GSK, MSD, and PharmaMar; and institutional funding for work in clinical trials from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, PharmaMar, Roche, and Seagen. Dr Herzog reports personal consulting fees from Aadi, AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen; participation on a data safety monitoring board or advisory board from Corcept; and leadership role on the GOG Foundation Board and president of GOG Partners. Dr de la Motte Rouge reports consulting fees from AstraZeneca, Clovis Oncology, Eisai, Gilead, GSK, MSD, Novartis, Pfizer, and Sanofi; honoraria from AstraZeneca, GSK, MSD, NetCancer, and Pfizer; and travel support from Gilead, MSD, and Pfizer. Dr Thomes Pepin has nothing to disclose. Dr Braicu reports honoraria from AstraZeneca, GSK, and Merck; consulting or advisory roles at AstraZeneca and GSK; institutional research funding from AstraZeneca, Bayer, Clovis, Eisai, GSK, Merck, and Resolve; travel support from AstraZeneca; and relationship with medical director of the North Eastern German Society of Gynecological Oncology (NOGGO). Dr Chen reports author royalties from UpToDate and serves on the board of directors of the American College of Obstetricians and Gynecologists, on the board of governors of the American College of Surgeons, and as a board member for the NCI PDQ Cancer Genetics Board. Dr Levy has nothing to disclose. Dr Barter has nothing to disclose. Dr Barretina-Ginesta reports consulting or advisory role fees from AstraZeneca, Clovis Oncology, GSK, MSD, PharmaMar, and Roche; and travel support from AstraZeneca, GSK, MSD, PharmaMar, and Roche. Dr Joosens reports travel fees from MSD. Ms York and Dr Malinowska are current employees of GSK. Dr González-Martín reports fees for different educational or advisory-related activities from Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GSK, Hedera Dx, Immunogen, Illumina, Karyopharm, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Regeneron, Roche, Seagen, Sotio, Sutro, Takeda, and Tubulis. Dr Monk reports consulting fees from Agenus, Akeso Biopharma, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Declaration of competing interest JKC: AstraZeneca, Glaxosmithkline, Genmab/Seagen, Immunogen, Karyopharm, Merck, Mersana, Myriad, Roche; KT: AbbVie, AstraZeneca, Eisai, Genentech, GSK, Iovance, Merck, Morphotek, Seagen;BM: Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG foundation, Gardalis, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron Roche/Genentech, Sorrento, TESARO/GSK, US Oncology Research, VBL, Verastem, Zentalis; TJH: COI's Aadi Bioscience, Astra Zeneca, Caris, Clovis, Corcept, Eisai, Epsilogen, Genentech, GSK, J&J, Merck, Mersana, Novocure, Seattle Genetics; RLC: Genentech/Roche, AstraZeneca, Genmab, Agenus, GSK, Karyopharm, SutroBio, Laekna, Toray, Merck, Novocure, AbbVie, AstraZeneca, Aadi Bioscience, Clovis; MTR: none; DSK: none; AAF: none.

Background: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis., Patients and Methods: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint., Results: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis., Conclusions: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study., Methods: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA /homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021)., Results: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1 - and BRCA2 -mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions)., Conclusions: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy., Trial Registration Number: NCT02655016., Competing Interests: Competing interests: WSG reports consulting and speaker fees from GSK. BPB reports honoraria, support for attending meetings and/or travel from AstraZeneca, Clovis, GSK, MSD, and PharmaMar and advisory board fees from AstraZeneca, Clovis, GSK, and MSD. DMO reports personal fees (consulting and/or advisory boards) and funding for clinical research from AbbVie, Amgen, AstraZeneca, Clovis, Eisai, Genentech/Roche, GOG Foundation, Immunogen, Iovance, Janssen/J&J, Merck, Mersana, Novocure, Regeneron, SDP Oncology (BBI), Seagen, and Tesaro/GSK; funding for clinical research from Ajinomoto, Array Biopharma, Bristol-Myers Squibb, Cerulean Pharma, EMD Serono, Ergomed, Genmab, INC Research, inVentiv Health Clinical, Ludwig Cancer Research, New Mexico Cancer Care Alliance, PRA Intl, Serono, Stemcentrx, TRACON Pharmaceuticals, VentiRx, and Yale University; personal fees from Myriad Genetics, Rubis, and Tarveda; personal fees and funding for clinical research from Agenus; and personal fees (consulting and/or advisory boards) from Ambry, Arquer Diagnostics, Celsion, Corcept Therapeutics, Elevar, InxMed, Novartis, Roche Diagnostics MSA, Sorrento, Takeda, and Toray. IV reports institutional payments for corporate-sponsored research from Amgen and Roche and contracted research from Genmab and Oncoinvent AS; institutional consulting fee payments from Amgen (Europe) GmbH, AstraZeneca, Carrick Therapeutics, Clovis Oncology, Deciphera Pharmaceuticals, Elevar Therapeutics, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Octimet Oncology, Oncoinvent AS, Sotio AS, Verastem Oncology, and Zentalis; consulting fees from Deciphera Pharmaceuticals, Jazz Pharma, and Oncoinvent AS; honoraria payment from Agenus, Aksebio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, Jazz Pharma, Karyopharm, MSD, Novartis, Novocure, Oncoinvent AS, Seagen, and Sotio AS; institutional travel support from Amgen, AstraZeneca, MSD, Roche, and Tesaro; and advisory board fees from Agenus, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals (2021), Eisai, F. Hoffmann–La Roche, Genmab, GSK, Immunogen, MSD, Novartis, Novocure, Seagen (2021), and Sotio AS. BJM reports consulting fees from Agenus, Akeso Bio, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, VBL, and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. AA reports advisory board fees from GSK and MSD. LJC reports institutional research funding from AbbVie, Advaxis, Agenus, Ajinomoto, Arcus Biosciences, Array BioPharma, AstraZeneca, BeiGene USA, BMS, Cerulean Pharma, Clovis Oncology, Deciphera Pharma, Eisai, EMD Serono, Ergomed Clinical Research, Exelixis, Genentech/Roche, Genmab, GSK, Hoffman–LaRoche, Immunogen, Incyte Corporation, Iovance Biotherapeutics, InVentiv Health Clinical, Jansen R&D, Karyopharm, Leap Therapeutics, Ludwig Institute of Pharmaceuticals, Merck, Mersana Therapeutics, Novocure, OncoQuest, OvaGene, Pfizer, PharmaMar, PRA International, Precision Therapeutics, Regeneron, Sanofi, Seattle Genetics, Serono, Stemcentrx, Sumitomo Dainippon Pharma Oncology, Sutro Biopharma, Tesaro (GSK), TRACON Pharm, and Verastem; personal advisory board fees from A28 Therapeutics, Celsion Corporation, Corcept Therapeutics, Elevar Therapeutics, GSK, Immunogen, InxMed, Luzsana Biotechnology, Myriad Genetics, Onconova, Rubius Therapeutics, Sorrento Therapeutics, Toray Industries, and VBL Therapeutics; and member of the data monitoring committee for Corcept Therapeutics. RS reports support for attending meetings from MSD and advisory board fees from Clovis Oncology, GSK, and MSD. TJH reports personal consulting fees from Aadi, AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genelux, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen; participation on a data safety monitoring board or advisory board for Corcept; and leadership role on the GOG Foundation Board and president of GOG Partners. PF reports payment or honoraria and payment for expert testimony from AstraZeneca, Clovis, Daiichi, GSK, and Novartis and support for attending meetings from AstraZeneca, Daiichi, GSK, and Novartis. BP reports institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Duality Bio, Eisai, Genentech/Roche, Karyopharm, Merck, Mersana, Seagen, Sutro Biopharma, Takeda Pharmaceuticals, Tesaro/GSK, Toray, and VBL Therapeutics; consulting fees from AstraZeneca, BioNtech, Clovis Oncology, Eisai, GOG Foundation, Lily, Merck, Mersana, Seagen, Sutro Biopharma, Tesaro/GSK, Onconova, and Toray; and travel support from GSK and BioNtech. EIB reports honoraria from AstraZeneca, GSK, and Merck; consulting or advisory roles at AstraZeneca and GSK; institutional research funding from AstraZeneca, Bayer, Clovis, Eisai, GSK, Merck, and Resolve; travel support from AstraZeneca; and relationship with medical director of the North Eastern German Society of Gynecological Oncology (NOGGO). CM reports advisory role fees from AstraZeneca, Clovis, GSK, ImmunoGen, and Merck. AY reports a GEICO grant by GSK. RGM reports personal fees from Fujirebio Diagnostics and research funding from Angle plc. PV reports payment of honoraria to self from MSD, Novartis, and Roche. NR-J reports advisory board fees from Eisai. WY and JH are employees of GSK. AG-M reports fees for different educational or advisory-related activities from Alkermes, Amgen, AstraZeneca, Clovis, Eisai, Genmab, GSK, Hedera Dx, Immunogen, Illumina, Karyopharm, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Regeneron, Roche, Seagen, Sotio, Sutro, Takeda, and Tubulis., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: There is a need for diagnostic tests for screening, triaging and staging of epithelial ovarian cancer (EOC). Glycoproteomics of blood samples has shown promise for biomarker discovery., Methods: We applied glycoproteomics to serum of people with EOC or benign pelvic masses and healthy controls. A total of 653 analytes were quantified and assessed in multivariable models, which were tested in an independent cohort. Additionally, we analyzed glycosylation patterns in serum markers and in tissues., Results: We identified a biomarker panel that distinguished benign lesions from EOC with sensitivity and specificity of 83.5% and 90.1% in the training set, and of 86.7 and 86.7% in the test set, respectively. ROC analysis demonstrated strong performance across a range of cutoffs. Fucosylated multi-antennary glycopeptide markers were higher in late-stage than in early-stage EOC. A comparable pattern was found in late-stage EOC tissues., Conclusions: Blood glycopeptide biomarkers have the potential to distinguish benign from malignant pelvic masses, and early- from late-stage EOC. Glycosylation of circulating and tumor tissue proteins may be related. This study supports the hypothesis that blood glycoproteomic profiling can be used for EOC diagnosis and staging and it warrants further clinical evaluation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: The treatment for high risk or recurrent gestational trophoblastic neoplasia (GTN) is a highly toxic multi-agent chemotherapy. For patients with progressive or recurrent GTN, checkpoint inhibitors have demonstrated anti-tumor activity; however, identification of novel therapies for GTN remain an unmet need. Therefore, we sought to characterize the molecular landscape of GTN to identify potential therapeutic targets., Methods: GTN samples were analyzed using a combination of molecular - next-generation sequencing (NGS) or whole exome sequencing (WES)- and protein- Immunohistochemistry (IHC) analyses. GTN samples encompassed complete moles, choriocarcinoma, epithelioid trophoblastic tumors (ETT), and placental site trophoblastic tumors (PSTT)., Results: We analyzed 30 cases of GTN including 15 choriocarcinoma, 7 ETT, 5 PSTT, 1 invasive mole and 2 mixed histologies. The median age was 41.5. GTN samples were found to be PD-L1 positive (92.3%), tumor mutational burden (TMB) low (92.8%), and microsatellite stable (MSS) (100%). Forty-six percent of choriocarcinoma specimens contained a genomic alteration including TP53 (33%) and homologous recombination repair (HRR) (13%) genes. Alterations in RTK-RAS pathway signaling was present in 40% of ETT cases., Conclusions: The high rate of PD-L1 positivity in this real-world database and reported in prior literature support continued clinical trial development evaluating immunotherapy for treatment of GTN. Other potential targeted treatments identified include Wee1, PARP and MEK inhibitors based on molecular alterations in TP53, HRR genes, and RTK-RAS pathways respectively., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Leah McNally: None. Sharon Wu: employee of Caris Life Sciences. Kurt Hodges: employee of Caris Life Sciences. Matt Oberley: employee of Caris Life Sciences. John J Wallbillich: None. Nathaniel L Jones: None. Thomas J Herzog: Scientific Advisory Boards &/or Honorarium: Aadi Bioscience, Astra Zeneca, Caris, Clovis, Eisai, Epsilogen, Genentech, GSK, J&J, Merck, Mersana, Novocure, Seattle Genetics. Premal H Thaker: Grants to institution from: Merck and GSK. Scientific Advisory Boards: AstraZeneca, GlaxoSmithKline, Immunon, Immunogen, SeaGen, Novocure, Mersana, Verastem, Zentalis. Angeles Alvarez Secord: Duke receives Clinical trial grant funding from AbbVie, Aravive, AstraZeneca, Clovis, Eisai, Ellipses Pharma, GSK, I-MAB Biopharma, Immunogen, Merck, Oncoquest, Roche/Genentech, Seagen, Inc., Theradex, VBL, Zentalis, and the National Cancer Trial Network. Advisory Boards (uncompensated) for AstraZeneca, Clovis, Gilead, GSK, Immunogen, Imvax, Merck, Mersana, Natera, Onconova, Oncoquest. Participation on Steering Committees (uncompensated): Aravive (AxXelerate); Roche/Genentech (AtTEND trial); VBL (OVAL trial); and Oncoquest (GOG-3035/FLORA-5). SGO Board of Directors, GOG Foundation Board of Directors, AAOGF Board of Trustees. Marilyn Huang: University of Miami received clinical grant funding fromMerck, Jansen; Scientific advisory board: Clovis, Seattle Genetics, Eisai, Immunogen, VB111, Tesaro/GSK, Voluntis/Aptar Digital Health., (Published by Elsevier Inc.)

Purpose: To evaluate the addition of ofranergene obadenovec (ofra-vec, VB-111), a novel gene-based anticancer targeted therapy, to once a week paclitaxel in patients with recurrent platinum-resistant ovarian cancer (PROC)., Methods: This placebo-controlled, double-blind, phase III trial (ClinicalTrials.gov identifier: NCT03398655) randomly assigned patients with PROC 1:1 to receive intravenous ofra-vec every 8 weeks with once a week IV paclitaxel or placebo with paclitaxel until disease progression. The dual primary end points were overall survival (OS) and progression-free survival (PFS) as assessed by Blinded Independent Central Review., Results: Between December 2017 and March 2022, 409 patients were randomly assigned. The median PFS was 5.29 months in the ofra-vec arm and 5.36 months in the control arm, hazard ratio (HR) 1.03 (CI, 0.83 to 1.29; P = .7823). The median OS with ofra-vec was 13.37 months versus 13.14 months, HR 0.97 (CI, 0.75 to 1.27; P = .8440). Objective response rates (ORRs) per RECIST 1.1 were similar in both arms: 28.9% with ofra-vec versus 29.6% with control. In both treatment arms, response to CA-125 was a substantial prognostic factor for both PFS and OS. In the ofra-vec arm, the HR in CA-125 responders compared with that in nonresponders for PFS was 0.2428 (CI, 0.1642 to 0.3588), and for OS, the HR was 0.3343 (CI, 0.2134 to 0.5238). Safety profile was characterized by common transient flu-like symptoms such as fever and chills., Conclusion: The addition of ofra-vec to paclitaxel did not improve PFS or OS. The PFS and ORR in the control arm exceeded the results that were anticipated on the basis of the AURELIA chemotherapy control arm. CA-125 response was a substantial prognostic biomarker for PFS and OS in patients with PROC treated with paclitaxel.

Objective: Progression-free survival is an established clinically meaningful endpoint in ovarian cancer trials, but it may be susceptible to bias; therefore, blinded independent centralized radiological review is often included in trial designs. We compared blinded independent centralized review and investigator-assessed progressive disease performance in the PRIMA/ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy., Methods: PRIMA/ENGOT-ov26/GOG-3012 was a randomized, double-blind phase 3 trial; patients with newly diagnosed stage III/IV ovarian cancer received niraparib or placebo. The primary endpoint was progression-free survival (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), determined by two independent radiologists, an arbiter if required, and by blinded central clinician review. Discordance rates between blinded independent centralized review and investigator assessment of progressive disease and non-progressive disease were routinely assessed. To optimize disease assessment, a training intervention was developed for blinded independent centralized radiological reviewers, and RECIST refresher training was provided for investigators. Discordance rates were determined post-intervention., Results: There was a 39% discordance rate between blinded independent centralized review and investigator-assessed progressive disease/non-progressive disease in an initial patient subset (n=80); peritoneal carcinomatosis was the most common source of discordance. All reviewers underwent training, and as a result, changes were implemented, including removal of two original reviewers and identification of 10 best practices for reading imaging data. Post-hoc analysis indicated final discordance rates between blinded independent centralized review and investigator improved to 12% in the overall population. Median progression-free survival and hazard ratios were similar between blinded independent centralized review and investigators in the overall population and across subgroups., Conclusion: PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize blinded independent centralized review and investigator concordance using early, specialized, ovarian-cancer-specific radiology training to maximize validity of outcome data., Competing Interests: Competing interests: TJH has served on advisory boards (Aravive, AstraZeneca, Caris, Clovis Oncology, Eisai, Epsilogen, GSK, Immunogen, Johnson & Johnson, Merck, Roche Genentech, Seagen) and as a consultant for Abbvie. SAW reports consulting fees (GSK and BioClinica). MRM reports personal fees and other (Karyopharm Therapeutics, Sera Prognostics, Roche); institutional grants and no financial interest (Apexigen, AstraZeneca, Deciphera, GSK, Ultimovacs); personal fees and invited speaker (AstraZeneca, GSK); personal fees and advisory boards (AstraZeneca, Biocad, Boehringer Ingelheim, GSK, Karyopharm, Merck, Mersana, ImmunoGen, Clovis Oncology, Roche, Zailab); personal fees, stocks and a member of board of directors (Karyopharm). BP reports research funding (AstraZeneca, Celgene, Celsion, Clovis, Genentech, SeaGen, GSK, Merck, Mersana, SeaGen, Takada, Toray) and consulting fees (AstraZeneca, Celsion, Eisai, GSK, GOG Foundation, Immunogen, Inxmed, Lily, Merck, Mersana, SeaGen, Toray). IV reports consulting fees (Agenus, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Exelixis, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncoXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, Zentalis), travel grants (Karyopharm, Genmab, Novocure), and contracted research grants (Amgen, Roche, Oncoinvent AS). WSG reports advisory board and speaker fees (GSK). IAM, WY, and DG are employees of GSK. JAH is an employee of GSK and reports stocks in GSK. AGM reports personal fees for educational/advisory-related activities (Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GSK, Immunogen, Mersana, MSD, Novocure, Oncoinvent, PharmaMar, Roche, SOTIO, Takeda). BJM reports consulting fees (Acrivon, Adaptimmune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Eisai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyoparm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, GSK, US Oncology Research, VBL, Verstem, Zentalis); speakers honoraria (AstraZeneca, Clovis, Eisai, Merck, Myriad, Roche/Genentech, GSK); investigator honoraria (Gradalis)., (© IGCS and ESGO 2023. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Objective: This multi-center cohort study assessed associations between race, TP53 mutations, p53 expression, and histology to investigate racial survival disparities in endometrial cancer (EC)., Methods: Black and White patients with advanced or recurrent EC with Next Generation Sequencing data in the Endometrial Cancer Molecularly Targeted Therapy Consortium database were identified. Clinicopathologic and treatment variables were summarized by race and compared. Overall survival (OS) and progression-free survival (PFS) among all patients were estimated by the Kaplan-Meier method. Cox proportional hazards models estimated the association between race, TP53 status, p53 expression, histology, and survival outcomes., Results: Black patients were more likely than White patients to have TP53-mutated (N = 727, 71.7% vs 49.7%, p < 0.001) and p53-abnormal (N = 362, 71.1% vs 53.2%, p = 0.003) EC. Patients with TP53-mutated EC had worse PFS (HR 2.73 (95% CI 1.88-3.97)) and OS (HR 2.20 (95% CI 1.77-2.74)) compared to those with TP53-wildtype EC. Patients with p53-abnormal EC had worse PFS (HR 2.01 (95% CI 1.22-3.32)) and OS (HR 1.61 (95% CI 1.18-2.19)) compared to those with p53-wildtype EC. After adjusting for TP53 mutation and p53 expression, race was not associated with survival outcomes. The most frequent TP53 variants were at nucleotide positions R273 (n = 54), R248 (n = 38), and R175 (n = 23), rates of which did not differ by race., Conclusions: Black patients are more likely to have TP53-mutated and p53-abnormal EC, which are associated with worse survival outcomes than TP53- and p53-wildtype EC. The higher frequency of these subtypes among Black patients may contribute to survival disparities., Competing Interests: Declaration of Competing Interest Dr. Alvarez Secord discloses that her institution has received clinical trial grant funding from AbbVie, Aravive, Astra Zeneca,Clovis, Eisai, Ellipses Pharma, Tesaro/GSK, I-MAB Biopharma, Immunogen, Merck, OncoQuest, Roche/Genentech, Seagen Inc., VBL Therapeutics, and National Cancer Trial Network to support her effort. She has participated in Advisory Boards (all uncompensated) for AbbVie, Aravive, AstraZeneca, Clovis, GSK/Tesaro, Immunogen, Imvax, Merck, Mersana, Natera, Onconova, OncoQuest, and Regeneron; and Clinical Trial Steering Committees (all uncompensated) for the AXLerate trial (Aravive), AtTEnd trial (Hoffman-LaRoche), Oval Trial (VBL Therapeutics), FLORA-5 trial (CanariaBio), and QPT-ORE-004 (CanariaBio) within the past 36 months. Dr. Strickland discloses he has received consulting fees from Foundation Medicine, Inc., Almac Pharmaceuticals, and Oncoquest Pharmaceuticals. He has received stock or stock options from LapCorp and has other financial interests in LabCorp. Dr. Pothuri discloses she has received research funding from Tesaro/GSK, Clovis Oncology, Merck, Genentech, AstraZeneca, Mersana, Karyopharm, Celsion, Sutro, Takeda, Immunogen, Incyte, Seagen, Toray, VBL Therapeutics, and Onconova. She has received consulting fees from Tesaro/GSK, Merck, AstraZeneca, Eli Lilly, Sutro, Seattle Genetics, Eisai, Natera, and GOG Partners. She has received speaker fees from PeerView and OncLive. She has participated in Advisory Boards for Tesaro/GSK, Eli Lily, Merck, Seattle Genetics, Eisai, AstraZeneca, and GOG Foundation. Dr. Bae-Jump discloses she has received research grant funding from Chimerix, Genentech, Merck, and Epirium. She has received consulting or advisory fees from Eisai. Dr. Thaker discloses her institution has received research grant funding from Merck and GSK. She has participated in advisory boards for GSK, Clovis Oncology, Astra Zeneca, Seagen, Mersana, Immunogen, Verastem, Immunon, Aadi Pharmaceuticals, R-Pharm, Merck, and Novocure. She has participated in data safety monitoring boards (uncompensated) for Iovance, Novocure, and Immunon. Dr. Arend discloses she has consulting or advisory role at Merck, Seagen, Sutro, GSK, VBL Therapeutics, Kiyatec; and research support from Immunogen, GSK, GOG Foundation, Champions Oncology, Exelixis, and Merck. Dr. Ko discloses she has received research grants from the Foundation for Women's Cancer, Feath Therapeutics, National Institutes of Health, National Cancer Institute, Penn Optum Labs, Department of Health and Human Services, and the Winn Bristow Meyers Squibb Diversity in Clinical Trials Award. She serves as a Society of Gynecologic Oncology committee chair. Dr. Jackson discloses she has received speaker fees from OncLive and served as a consultant to Ethicon. She has participated in Advisory Boards for AstraZeneca, Seagen, and Sutro. Dr. Corr discloses he has received research support from Clovis and Immunogen. He has participated in Advisory Boards for GSK, Gilead, Immunogen, Zentalis, Merck, and Imvax. Dr. Wright discloses his institution has received research grant funding from Merck. He received royalties from UpToDate and payment for expert testimony from Medicolegal Consulting Gynecologic Cancer. He serves as a journal editor for American College of Obstetricians and Gynecologists. Dr. Lightfoot discloses she has participated in an Advisory Board for GSK. Dr. Washington discloses she has received the Robert A Winn Career Development Award and ACS iRG URM Grant to support her research. She has received payment for her Great Debates presentation and support for travel from the NRG New Investigator Award. Dr. Herzog discloses he has received consulting fees from AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genelux, Genentech, GSK, Immunogen, Johnson & Johnson, Merck, Mersana, and Seagen. He has received travel support from Alkermes. He has served an Advisory Board for Corcept and in a leadership role for GOG Foundation. Dr. Salani discloses she has received speaker fees from Merck, Seagen, Regeneron, Eisai, Immunogen, and Mersana. She has received royalties or licensing fees from UpToDate. She serves on the International Gynecologic Cancer Society Executive Committee. Ms. Whelan, Ms. Dillon, Ms. Thomas, Mr. Smitherman, Ms. Powell, and Drs. Haight, Harsono, Ayoola-Adeola, Cosgrove, Newton, Podwika, and Borden have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

The definition of "platinum-resistant ovarian cancer" has evolved; it now also reflects cancers for which platinum treatment is no longer an option. Standard of care for platinum-resistant ovarian cancer is single-agent, non-platinum chemotherapy with or without bevacizumab, which produces modest response rates, with the greatest benefits achieved using weekly paclitaxel. Several recent phase 3 trials of pretreated patients with prior bevacizumab exposure failed to meet their primary efficacy endpoints, highlighting the challenge in improving clinical outcomes among these patients. Combination treatment with antiangiogenics has improved outcomes, whereas combination strategies with immune checkpoint inhibitors have yielded modest results. Despite extensive translational research, there has been a lack of reliable and established biomarkers that predict treatment response in platinum-resistant ovarian cancer. Additionally, in the platinum-resistant setting, implications for the time between the penultimate dose of platinum therapy and platinum retreatment remain an area of debate. Addressing the unmet need for an effective treatment in the platinum-resistant setting requires thoughtful clinical trial design based on a growing understanding of the disease. Recent cancer drug approvals highlight the value of incorporating molecular phenotypes to better define patients who are more likely to respond to novel therapies. Clinical trials designed per the Gynecologic Cancer InterGroup recommendations-which advocate against relying solely upon the platinum-free interval-will help advance our understanding of recurrent ovarian cancer response where platinum rechallenge in the platinum-resistant setting may be considered. The inclusion of biomarkers in clinical trials will improve patient stratification and potentially demonstrate correlations with biomarker expression and duration of response. With the efficacy of antibody-drug conjugates shown for the treatment of some solid and hematologic cancers, current trials are evaluating the use of various novel conjugates in the setting of platinum-resistant ovarian cancer. Emerging novel treatments coupled with combination trials and biomarker explorations offer encouraging results for potential strategies to improve response rates and prolong progression-free survival in this population with high unmet need. This review outlines existing data from contemporary clinical trials of patients with platinum-resistant ovarian cancer and suggests historical synthetic benchmarks for non-randomized trials., Competing Interests: RE reports receiving institution research support from AstraZeneca, Clovis Oncology, Eisai, Merck, and Novocure; and consulting and advisory fees from AstraZeneca; Cardiff Oncology; Clovis Oncology; Eisai; Elevar; Genentech/Roche; GSK/Tesaro; ImmunoGen, Inc; Merck; Mersana; and Myriad. KM reports advisory board participation for Addi; Alkermes; Aravive, Inc; AstraZeneca; Blueprint Pharma; Caris; Celsion Corporation; Clovis; Eisai Co, Ltd; Eli Lilly and Company; EMD Serono; Genentech, Inc/Roche; GlaxoSmithKline plc/Tesaro; I-MAB Biopharma Co, Ltd; ImmunoGen, Inc; InxMed Co, Ltd; Jiangsu Hengrui Pharmaceuticals Company Ltd; Merck & Co, Inc; Mereo Biopharma Group plc; Mersana Therapeutics, Inc; Myriad Genetics, Inc; Novartis Pharmaceuticals Corporation; Novocure GmbH; Onconova Therapeutics, Inc; OncXerna Therapeutics, Inc; Tarveda Therapeutics; VBL Therapeutics; and Verastem, Inc; research funding from Eli Lilly and Company; GlaxoSmithKline plc/Tesaro; Merck & Co, Inc; PTC Therapeutics; and Verastem, Inc; and employment by GOG Partners, NRG Ovarian Cancer Committee Chair, and employment by The GOG Foundation Inc uncompensated. BM reports receiving speaker and/or consultant fees from Acrivon; Adaptimmune; Amgen; Aravive; AstraZeneca; Bayer; Clovis; Eisai; Elevar; Genmab/Seagen; the GOG Foundation; Gradalis; Heng Rui; ImmunoGen, Inc; Laekna; MacroGenics; Merck; Mersana; Myriad; Novartis; Novocure; OncoC4; Panavance; Pieris; Pfizer; Roche/Genentech; Sorrento; TESARO/GSK; VBL; Verastem; and Zentalis; and consultant and/or investigator fees from US Oncology Research. TH reports advisory board participation for AstraZeneca; Caris; Clovis; Eisai Co, Ltd; Epsilogen Ltd; Genentech, Inc; GlaxoSmithKline plc; Johnson & Johnson; Merck & Co, Inc; Mersana Therapeutics, Inc; and Seagen Inc. CA reports nothing to disclose. DO reports receiving institutional funds from AbbVie; Advaxis; Agenus, Inc; Alkermes; Aravive, Inc; Arcus Biosciences, Inc; AstraZeneca; BeiGene USA, Inc; Boston Biomedical; Bristol Myers Squibb; Clovis Oncology; Deciphera Pharma; Eisai; EMD Serono, Inc; Exelixis; Genentech, Inc; Genmab; GlaxoSmithKline; GOG Foundation; Hoffmann-La Roche, Inc; ImmunoGen, Inc; Incyte Corporation; IOVANCE Biotherapeutics; Karyopharm; Leap Therapeutics, Inc; Ludwig Institute for Ca; Merck & Co, Inc; Merck Sharp & Dohme Corp; Mersana Therapeutics, Inc; NCI; Novartis; Novocure; NRG Oncology; OncoC4, Inc; OncoQuest, Inc; Pfizer, Inc; Precision Therapeutics, Inc; Prelude Therapeutics; Regeneron Pharmaceuticals, Inc; RTOG; Rubius Therapeutics; Seattle Genetics Seagen; Sutro Biopharma; SWOG; TESARO; and Verastem, Inc; and consultant and/or advisory board personal fees from AbbVie; Adaptimmune; Agenus, Inc; Arquer Diagnostics; Arcus Biosciences, Inc; AstraZeneca; Atossa Therapeutics; Boston Biomedical; Cardiff Oncology; Celcuity; Clovis Oncology; Corcept Therapeutics; Duality Bio; Eisai; Elevar; Exelixis; Genentech, Inc; Genelux; GlaxoSmithKline; GOG Foundation; Hoffmann-La Roche, Inc; ImmunoGen, Inc; Imvax; InterVenn; INXMED; IOVANCE Biotherapeutics; Janssen; Jazz Pharmaceuticals; Laekna; Leap Therapeutics, Inc; Luzsana Biotechnology; Merck & Co, Inc; Merck Sharp & Dohme Corp; Mersana Therapeutics, Inc; Myriad; Novartis; Novocure; OncoC4, Inc; Onconova; Regeneron Pharmaceuticals, Inc; Replimmune; R-PHARM US, LLC; Roche Diagnostics; Seattle Genetics Seagen; Sorrento; Sutro Biopharma; Tarveda Therapeutics; Toray; Trillium; Umoja; Verastem, Inc; VBL Therapeutics; Vincerx Pharma; Xencor; and Zentalis. RC reports research funding from AbbVie Inc; AstraZeneca; Clovis; Genmab A/S; ImmunoGen, Inc; Merck & Co, Inc; Mersana Therapeutics, Inc; Roche/Genentech, Inc; and Toray; and scientific steering committee participation with AbbVie Inc; Agenus Inc; Aravive, Inc; AstraZeneca; Clovis; Deciphera Pharmaceuticals, Inc; Epsilogen Ltd; Genentech, Inc; Genmab A/S/Seagen Inc; GlaxoSmithKline plc; ImmunoGen, Inc; Karyopharm Therapeutics Inc; Merck & Co, Inc; Mirati Therapeutics, Inc; Novocure GmbH; OncXerna Therapeutics, Inc; and Toray., (Copyright © 2023 Eskander, Moore, Monk, Herzog, Annunziata, O’Malley and Coleman.)

Cruciferous vegetable consumption is associated with numerous health benefits attributed to the phytochemical sulforaphane (SFN) that exerts antioxidant and chemopreventive properties, among other bioactive compounds. Broccoli sprouts, rich in SFN precursor glucoraphanin (GRN), have been investigated in numerous clinical trials. Broccoli microgreens are similarly rich in GRN but have remained largely unexplored. The goal of this study was to examine SFN bioavailability and the microbiome profile in subjects fed a single serving of fresh broccoli microgreens. Eleven subjects participated in a broccoli microgreens feeding study. Broccoli microgreens GRN and SFN contents and stability were measured. Urine and stool SFN metabolite profiles and microbiome composition were examined. Broccoli microgreens had similar GRN content to values previously reported for broccoli sprouts, which was stable over time. Urine SFN metabolite profiles in broccoli microgreens-fed subjects were similar to those reported previously in broccoli sprouts-fed subjects, including the detection of SFN-nitriles. We also reported the detection of SFN metabolites in stool samples for the first time. A single serving of broccoli microgreens did not significantly alter microbiome composition. We showed in this study that broccoli microgreens are a significant source of SFN. Our work provides the foundation for future studies to establish the health benefits of broccoli microgreens consumption.

Objectives: To identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated ("Lynch-like") endometrial tumors and determine whether their molecular profiles can elucidate the differential outcomes., Methods: 1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons. Overall survival (OS) was depicted using Kaplan-Meier survival curves., Results: The endometrial cancer cohort comprised 89.2% patients with MLH1 hypermethylated tumors and 10.8% with MLH1 mutated tumors, with median ages of 67 and 60 years, respectively (p < 0.01). Patients with MLH1 hypermethylated tumors had significantly worse OS and trended toward worse OS following ICI treatment than patients with MLH1 mutated tumors. The immune microenvironment of MLH1 hypermethylated relative to MLH1 mutated was characterized by decreased PD-L1 positivity, immune checkpoint gene expression, immune cell infiltration, T cell inflamed scores, and interferon gamma (IFNγ) scores. MLH1 hypermethylation was also associated with decreased mutation rates in TP53 and DNA damage repair genes, but increased rates of JAK1, FGFR2, CCND1, and PTEN mutations, as well as increased ER and PR positivity., Conclusions: Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors., Competing Interests: Declaration of Competing Interest SW, JRR, AF, JX, MJO: Caris Life Sciences (employee salary, stock/stock options). PHT: DSM or Advisory Board: Iovance, AstraZeneca, GlaxoSmithKline, Clovis Oncology, Zentalis, Novocure, Seagen, Immunogen, R-Pharm, Aadi Pharmaceuticals, Caris Life Sciences, Merck, Immunon; Stock/Stock Options: Immunon. TJH: Consulting Fees: AstraZeneca, Caris Life Sciences, Clovis Oncology, Eisai, Genelux, Genentech, GlaskoSmithKline, Immunogen, J&J, Merck, Mersana, Seagen; Meeting Support: Alkermes; DSM or Advisory Board: Corcept; Leadership or Fiduciary Role: GOG-Foundation. MAP: Consulting Fees: GlaxoSmithKline/Tesaro, Merck, AstraZeneca, Clovis Oncology, Seagen, Eisai. BKE: Consulting Fees: GlaskoSmithKline, Merck, Signatera. RA: Consulting Fees: GlaskoSmithKline, Merck, Sutro, Seagen., (Copyright © 2023 Elsevier Inc. All rights reserved.)