Faculty Bibliography

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/BACKGROUND:ClinicalTrials.gov NCT03981796.

The presented retrospective analysis suggests, to the best of our knowledge for the first time, a potential significant interaction between statins and niraparib in clinical settings. Nevertheless, further investigations are required to gain a better understanding of the potential clinical benefit.

BACKGROUND:Evidence is limited in gynecologic cancers on best practices for clinical trial screening, but the risk of ineffective screening processes and subsequent under-enrollment introduces significant cost to patient, healthcare systems, and scientific advancement. Absence of a defined screening process makes determination of who and when to screen potential patients inconsistent allowing inefficiency and potential introduction of biases. This is especially germane as generative artificial intelligence (AI), and electronic health record (EHR) integration is applied to trial screening. Though often a requirement of cooperative groups such as the Cancer therapy Evaluation Program (CTEP), and/or the Commission on Cancer (CoC), there are no standard practice guidelines on best practices regarding screening and how best to track screening data. DEVELOPMENT OF MANUSCRIPT/UNASSIGNED:The authors provided a review of current clinical trial screening practices and the effect on enrollment and trial activation across a variety of disease and practice sites. Established clinical trial screening practices and evidence supporting emerging strategies were reviewed and reported. Due to lack of published literature in gynecologic oncology, authors sought to survey the members of current rostered GOG sites to provide perspectives on clinical trial screening practices. Survey results showed a variety of screening practices. Most respondents participate in some type of manual screening process, where approximately 13 % also report incorporating AI or EHR integration. Over half (60 %) of sites track screening data to use for feasibility when opening new trials. The rapid increase in generative AI, EHR integration, and site agnostic screening initiatives could provide a significant opportunity to improve screening efficiency, translating to improved enrollment, but limitations and barriers remain.

Findings from clinical trials have led to advancement of care for patients with gynecologic malignancies. However, restrictive inclusion of patients into trials has been widely criticized for inadequate representation of the real-world population. Ideally, patients enrolled in clinical trials should represent a broader population to enhance external validity and facilitate translation of outcomes across all relevant groups. Specifically, there has been a systematic lack of data for underrepresented groups, with many studies failing to report or differentiate study participants based on sociodemographic domains, such as race and ethnicity. As such, the impact of treatment in these underrepresented groups is poorly understood, and clinical outcomes according to various sociodemographic factors are infrequently assessed. Inclusion of diverse trial participants, with different racial and ethnic background, is essential for the understanding of factors that may impact clinical outcomes. Therefore, we conducted a multi-national meeting of clinical trial groups and industry with the goal of increasing equity, diversity, and inclusion in gynecologic cancer clinical trials and to address barriers to recruitment, participation, and harmonization of data collection and reporting. These Gynecologic Cancer Intergroup (GCIG) statements present recommendations and strategies for the gynecologic cancer research community to improve equity, diversity, and inclusion in gynecologic cancer clinical trials.

Findings from clinical trials have led to advancement of care for patients with gynecologic malignancies. However, restrictive inclusion of patients into trials has been widely criticized for inadequate representation of the real-world population. Ideally, patients enrolled in clinical trials should represent a broader population to enhance external validity and facilitate translation of outcomes across all relevant groups. Specifically, there has been a systematic lack of data for underrepresented groups, with many studies failing to report or differentiate study participants based on sociodemographic domains, such as race and ethnicity. As such, the impact of treatment in these underrepresented groups is poorly understood, and clinical outcomes according to various sociodemographic factors are infrequently assessed. Inclusion of diverse trial participants, with different racial and ethnic background, is essential for the understanding of factors that may impact clinical outcomes. Therefore, we conducted a multi-national meeting of clinical trial groups and industry with the goal of increasing equity, diversity, and inclusion in gynecologic cancer clinical trials and to address barriers to recruitment, participation, and harmonization of data collection and reporting. These Gynecologic Cancer Intergroup (GCIG) statements present recommendations and strategies for the gynecologic cancer research community to improve equity, diversity, and inclusion in gynecologic cancer clinical trials.

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/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.

BACKGROUND:Pembrolizumab plus chemotherapy provides clinically meaningful benefit as first-line therapy for advanced (locoregional extension and residual disease after surgery)/metastatic/recurrent mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) endometrial cancer, with greater magnitude of benefit in the dMMR phenotype. We evaluated the addition of pembrolizumab to adjuvant chemotherapy (with/without radiation therapy) among patients with newly diagnosed, high-risk endometrial cancer without any residual macroscopic disease following curative-intent surgery. METHODS:We included patients with histologically confirmed high-risk [International Federation of Gynecology and Obstetrics (FIGO) stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology] endometrial cancer following surgery with curative intent and no evidence of disease postoperatively, with no prior radiotherapy or systemic therapy. Patients were randomised to pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for six cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo every 6 weeks (Q6W) for six cycles per treatment assignment. Radiotherapy was at the investigator's discretion. The primary endpoints were investigator-assessed disease-free survival (DFS) and overall survival in the intention-to-treat population. RESULTS:A total of 1095 patients were randomised (pembrolizumab, n = 545; placebo, n = 550). At this interim analysis (data cut-off, 4 March 2024), 119 (22%) DFS events occurred in the pembrolizumab group and 121 (22%) occurred in the placebo group [hazard ratio 1.02, 95% confidence interval (CI) 0.79-1.32; P = 0.570]. Kaplan-Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. The hazard ratio for DFS was 0.31 (95% CI 0.14-0.69) in the dMMR population (n = 281) and 1.20 (95% CI 0.91-1.57) in the pMMR population (n = 814). Grade ≥3 adverse events (AEs) occurred in 386 of 543 (71%) and 348 of 549 (63%) patients in the pembrolizumab and placebo groups, respectively. No treatment-related grade 5 AEs occurred. CONCLUSIONS:Adjuvant pembrolizumab plus chemotherapy did not improve DFS in patients with newly diagnosed, high-risk, all-comer endometrial cancer. Preplanned subgroup analyses for stratification factors suggest that pembrolizumab plus chemotherapy improved DFS in patients with dMMR tumours. Safety was manageable. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov, NCT04634877; EudraCT, 2020-003424-17. RESEARCH SUPPORT/UNASSIGNED:Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Mismatch repair-deficient (dMMR) endometrial cancer is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase 3 ENGOT-en11/GOG-3053/KEYNOTE-B21 study (NCT04634877) in newly-diagnosed, high-risk endometrial cancer after surgery with curative intent. Patients were randomized to pembrolizumab 200mg or placebo (6 cycles) plus carboplatin-paclitaxel (4-6 cycles) Q3W, then pembrolizumab 400mg or placebo Q6W (6 cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary endpoint. No formal hypothesis testing was performed for subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, hazard ratio for DFS favored pembrolizumab (0.31; 95%CI, 0.14-0.69); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95%CI, 84.4%-96.4%) and 80.2% (95%CI, 70.8%-86.9%), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis based on the study's stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.