Faculty Bibliography

Dostarlimab in combination with carboplatin-paclitaxel was approved for primary advanced or recurrent endometrial cancer (pA/rEC). The first interim analysis (IA1) of RUBY Part 1 (NCT03981796) showed no significant exposure-response (ER) relationship for progression-free survival or for the five most common dostarlimab-related adverse events (AEs), except rash. Herein, we report the ER relationship between dostarlimab exposure and overall survival (OS) and between dostarlimab exposure and dostarlimab-related AEs. Population pharmacokinetic model was based on IA1, and the predicted exposure metrics from Cycle 1 were used to perform ER analysis at the second interim analysis (IA2). AE analysis was completed for three periods: Cycles 1-6 (chemotherapy phase), Cycle 7 and beyond (monotherapy phase), and all cycles. Included in the OS analysis were 232 patients treated with dostarlimab + carboplatin-paclitaxel. Cox regression of OS showed no significant ER relationship based on dostarlimab Cycle 1 exposure, except for rash and arthralgia. The increase in predicted probabilities for rash and arthralgia for patients with high versus low exposure was limited, ranging from 5.6% to 10.4% for rash and 4.3% to 17.7% for arthralgia (deemed not clinically relevant). These data support the risk/benefit profile at the selected dose of dostarlimab + carboplatin-paclitaxel as standard of care in patients with pA/rEC.

OBJECTIVE:Under-representation of key population groups limits the generalizability, applicability, and equity of evidence generated by gynecologic oncology trials. Building on the Gynecologic Cancer InterGroup Barcelona consensus, this initiative aimed to translate the principles of diversity into a structured, practice-oriented Code of Conduct spanning all phases of clinical research. METHODS:As the third step in an iterative Gynecologic Cancer InterGroup consensus process, a Code of Conduct was developed and formally adopted at the Gynecologic Cancer InterGroup Berlin Meeting. All 33 Gynecologic Cancer InterGroup member groups appointed delegates. Preparatory work included a comprehensive literature review, structured meetings of an interdisciplinary scientific committee, and the NOGGO-GCIG-IDEA survey on equity, diversity, and inclusion. A plenary session included individuals with lived experience, clinicians, and researchers from multiple continents. Statements were drafted in focused working groups and refined to consensus. RESULTS:The resulting Code of Conduct provides actionable guidance across 12 domains: transparent inclusion criteria; standardized data collection, analysis, and reporting; ethnicity considerations; patient-centered communication and consent; reducing the burden of participation; ethics and scientific integrity; data and biospecimen sharing; governance, accountability, and oversight; global collaboration and capacity building; post-trial responsibilities; authorship, acknowledgment, and dissemination; and implementation and continuous improvement. Harmonized collection of diversity variables is recommended to enable international comparison. CONCLUSION/CONCLUSIONS:Diversity is a prerequisite for scientific validity and clinical relevance rather than an optional consideration. By embedding diversity into every phase of research, the Gynecologic Cancer InterGroup Code of Conduct provides a framework to generate robust, generalizable, and inclusive evidence for the global gynecologic oncology community. The Code is endorsed by the European Society of Gynaecological Oncology and the International Federation of Gynecology and Obstetrics and will be reviewed biennially.

OBJECTIVE:We assessed the underlying etiology of MMR deficiency (dMMR), genetic (germline/somatic) versus epigenetic hMLH1, and associations between response rate, and survival outcomes in patients with advanced and recurrent dMMR endometrial adenocarcinoma treated with immune checkpoint inhibitors. METHODS:The Endometrial Cancer Molecularly Targeted Therapy Consortium (ECMT2) database was used to identify patients with mismatch repair deficient (dMMR) tumors treated with pembrolizumab or dostarlimab from 2016 to 2023. Cases were categorized into two groups- germline Lynch Syndrome mutation (gLS) and somatic Lynch Syndrome mutation (sLS), or MLH1 promoter hypermethylation (hMLH1). Clinical and pathologic data included patient demographics, tumor characteristics, recurrence date, survival, and treatment. RESULTS:A total of 133 patients were included: gLS/sLS (n = 34, 25.6%) or hMLH1 (n = 99, 74.4%). Demographic and tumor characteristics, including stage at diagnosis and histology were similar between groups. The response rate was 57.1% for the entire cohort [55.9% gLS/sLS, 57.6% hMLH1; (p = 0.90)]. The survival outcomes were not significantly different in the gLS/sLS and hMLH1 groups [2-year progression-free survival: 68.0% and 59.0% (p = 0.77); 2-year overall survival: 70.9% and 62.2% (p = 0.55)], respectively. CONCLUSION/CONCLUSIONS:Our findings suggest that response to immune checkpoint inhibitors and survival outcomes are not associated with different mechanisms of dMMR.

OBJECTIVE:To report updated patient-reported (PRO) health-related quality of life (HRQOL) findings and evaluate the effect of disease progression on HRQOL using data from the final analysis of the PRIMA/ENGOT-OV26/GOG-3012 trial. METHODS:Patients were randomized 2:1 to niraparib first-line maintenance or placebo. Longitudinal HRQOL was a prespecified secondary endpoint assessed via European Organisation for Research and Treatment of Cancer QOL-Core Questionnaire (EORTC QLQ-C30) and -Ovarian Cancer module (EORTC QLQ-OV28), Functional Assessment of Cancer Therapy Ovarian Cancer Symptom Index (FOSI), and EuroQol 5-dimension 5-level questionnaire with visual analog scale (EQ-VAS). Post hoc analyses evaluated least-squares mean change from baseline or last on-treatment visit before disease progression (clinical cutoff: April 8, 2024). RESULTS:Questionnaire completion rates exceeded 89% through cycle 24 and were 80% at end of treatment. Early differences in gastrointestinal symptom scores between arms resolved over time, and no differences in overall HRQOL were observed. Disease progression reduced overall HRQOL across arms, with marked reductions in EORTC QLQ-C30 overall HRQOL, FOSI, and EQ-VAS scores that never recovered to pre-progression levels. Progression also resulted in sustained deterioration across all EORTC QLQ-C30 and QLQ-OV28 functional scales and worsening symptom scores, particularly for fatigue, dyspnea, pain, and appetite loss. Similar results were observed when patients were evaluated by homologous recombination deficiency status. CONCLUSION/CONCLUSIONS:In the final PRIMA PRO analysis, results confirmed that niraparib first-line maintenance did not negatively affect HRQOL versus placebo. Disease progression caused sustained HRQOL deterioration across arms, emphasizing the clinical importance of extending progression-free survival to preserve patient HRQOL. CLINICAL TRIAL REGISTRATION NUMBER/BACKGROUND:NCT02655016.

PURPOSE/OBJECTIVE:amp prevalence, molecular subtype, and histologic associations, as well as prognostic impact across diverse genetic ancestries using a large clinicogenomic database (CGDB). METHODS:amp prevalence, histologic and molecular correlations, and associations with OS were examined. RESULTS: CONCLUSION/CONCLUSIONS:

OBJECTIVE:To determine the association between molecular classification and response in patients with endometrial intra-epithelial neoplasia or endometrial cancer treated with a levonorgestrel intra-uterine device. METHODS:Eligible patients were treated with a levonorgestrel intra-uterine device for endometrial intra-epithelial neoplasia or endometrial cancer for at least 6 months. Immunohistochemistry for MLH1, MSH2, MSH6, PMS2, and p53 was performed. Specimens were categorized using a modified Proactive Molecular Risk Classifier for Endometrial Cancer algorithm as deficient mismatch repair, p53 abnormal, or p53 wild-type. A subset underwent single-gene POLE sequencing. Best response was recorded as pathologic complete response, partial response, stable disease, or progressive disease. Kruskal-Wallis tests and Fisher exact tests were used for statistical analysis. RESULTS:There were 143 patients, including 83 with endometrial intra-epithelial neoplasia and 60 with endometrial cancer. Fertility preservation was desired in 35.7%, 53.8% had significant medical co-morbidities precluding hysterectomy, and 10.5% had levonorgestrel intra-uterine device placement for other indications, including patient preference, placement during the coronavirus disease 2019 pandemic, and logistical considerations for other cancer diagnoses. Molecular characterization showed 90.9% p53 wild-type, 7.0% deficient mismatch repair, and 2.1% p53 abnormal. Only 4.4% of specimens with sequencing had a POLE mutation (2 of 45). The overall response rate was 86.7% (endometrial cancer: complete response 38.3%, partial response 36.7%; endometrial intra-epithelial neoplasia: complete response 67.5%, partial response 27.7%). In patients with endometrial cancer, the response rate was 75% (45 of 60), varying by molecular sub-group: 50% in the p53 abnormal group (1 of 2) and 50% in the deficient mismatch repair group (5 of 10). Only 1 patient with endometrial intra-epithelial neoplasia had p53 abnormal expression; the remaining patients had intact MMR expression and p53 wild-type. CONCLUSIONS:The complete response to levonorgestrel intra-uterine device therapy was lower than expected for endometrial intra-epithelial neoplasia. Response rates varied by molecular classification, with worse outcomes observed in deficient mismatch repair and p53 abnormal sub-types. Although limited by sample size, these findings suggest that levonorgestrel intra-uterine device therapy may not be sufficient for all molecular sub-groups.

Endometrial cancer is the most common gynecologic malignancy in the United States, with rising incidence and high recurrence rates. Immune checkpoint inhibitors (ICIs) benefit patients with mismatch repair-deficient (dMMR) tumors, but options remain limited for those with mismatch repair-proficient (pMMR) disease. Homologous recombination deficiency (HRD), a genomic instability phenotype, has emerged as a therapeutic target. Poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPis) are being investigated in endometrial cancer, with studies exploring whether HRD predicts response, particularly in combination with ICIs or chemotherapy. This review examines HRD in endometrial cancer, focusing on its molecular basis, clinical implications, and emerging therapeutic strategies. HRD occurs in a sub-set of endometrial cancers, particularly non-endometrioid sub-types, and is linked to genomic instability and platinum sensitivity. The Cancer Genome Atlas (TCGA) molecular classification has improved understanding of HRD prevalence across sub-types. HRD testing remains challenging due to a lack of standardization, with current methods including genomic-scar assays, next-generation sequencing, and functional assays. Clinical trials, such as DUO-E and RUBY-2, suggest that PARPi combined with ICIs or chemotherapy may improve outcomes in pMMR tumors, whereas PARPi monotherapy offers limited benefits. Resistance to PARPi is common, driven by the restoration of homologous recombination repair, replication fork stabilization, and drug efflux. HRD is a promising biomarker and therapeutic target in endometrial cancer. Evidence supports the integration of PARPi for select populations, although further research is needed to refine testing, optimize patient selection, and overcome resistance. Future trials should prioritize predictive biomarkers and novel combinations to maximize the benefits of PARPi in HRD endometrial cancer.

This Society of Gynecologic Oncology review synthesizes updated data from pivotal trials of poly-ADP-ribose polymerase inhibitors (PARPi) in ovarian cancer. Multiple phase III trials established PARPi as effective maintenance therapy, demonstrating substantial progression-free survival across biomarker-defined subgroups, particularly for patients with BRCA-mutated and homologous recombination-deficient (HRD) ovarian cancer. However, mature overall survival analyses and safety signals prompted the US Food and Drug Administration to narrow indications, while the broader indications were maintained by the European Medicines Agency. We review the current FDA approvals that now prioritize patients with BRCA-mutated and HRD ovarian cancers, underscoring the importance of biomarker stratification and careful patient selection. We discuss the evolving regulatory landscape and potential mechanisms of PARPi resistance.

OBJECTIVE:To examine the association between malignant peritoneal cytology and survival outcomes in endometrial cancer. METHODS:This was an ancillary analysis of prospectively collected surgical-pathological data in the NRG Oncology / Gynecologic Oncology Group study on GOG-210 protocol. The study population included 2383 patients with stage I-III endometrial cancer from 2003 to 2011. Exposure was peritoneal cytology status: malignant peritoneal cytology (n = 215) or negative peritoneal cytology (n = 2168). Main outcome measures were recurrence-free survival and overall survival. Propensity score inverse probability treatment weighting was performed to balance the baseline clinico-pathological characteristics, followed by adjustment for adjuvant therapy. RESULTS:Malignant peritoneal cytology was associated with a 32% increased risk of recurrence (5-year rates, 72% versus 77%, hazard ratio 1.32, 95% confidence interval 1.03 to 1.69, P = 0.028) and 37% increased risk of all-cause mortality (78% versus 83%, hazard ratio 1.37, 95% confidence interval 1.06 to 1.78, P = 0.018) compared to negative peritoneal cytology. When controlling for adjuvant therapy, the association between malignant peritoneal cytology and survival was attenuated for both recurrence-free survival (adjusted-hazard ratio 1.16, 95% confidence interval 0.90 to 1.50, P = 0.24) and overall survival (adjusted-hazard ratio 1.22, 95% confidence interval 0.93 to 1.60, P = 0.16) without statistical significance. Peritoneal cytology status and adjuvant therapy type had a possible interaction on overall survival, and malignant peritoneal cytology was associated with decreased overall survival when radiotherapy was received as adjuvant therapy but not when chemotherapy was utilized (P-interaction = 0.059). CONCLUSION/CONCLUSIONS:The results of this prospective assessment suggest that malignant peritoneal cytology is a prognostic factor, if any, associated with a modest decrease in survival for endometrial cancer.