TPS5641 Background: Uterine serous carcinoma and uterine carcinosarcoma are rare, high-risk uterine cancer subtypes that overexpress HER2 in up to 40% and 10% of cases, respectively. Phase II data demonstrated a benefit in adding trastuzumab in HER2 positive advanced and recurrent uterine serous carcinoma. Dual anti-HER2 therapy has the potential for further improvement in survival. Methods: This is a non-blinded, three-arm randomized phase II/III study. The primary objective is to evaluate the efficacy of trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA) or a fixed dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive uterine serous carcinoma or carcinosarcoma. The primary outcome of the phase II component is PFS. Depending on the phase II results, the study will progress to a phase III study of either two or three study arms. Patients in the control arm (Arm 1) receive carboplatin and paclitaxel every 3 weeks for 6 cycles. Patients on Arm 2 receive carboplatin and paclitaxel with trastuzumab and hyaluronidase-oysk every 3 weeks for 6 cycles plus one year of maintenance trastuzumab and hyaluronidase-oysk. Patients enrolled on Arm 3 receive carboplatin and paclitaxel with trastuzumab, pertuzumab, and hyaluronidase-zzxf every 3 weeks for 6 cycles plus one year of maintenance trastuzumab, pertuzumab, and hyaluronidase-zzxf . Those with an ongoing partial response may continue maintenance therapy for up to three years. Patients are eligible if they are diagnosed with chemo-naïve, non-recurrent stage IA-IVB myoinvasive uterine serous or carcinosarcoma. All tumors must be HER2 positive as defined by the ASCO/CAP Breast Cancer 2018 guidelines (testing performed locally). Tumors may also be HER2 positive based on next generation sequencing testing. Patients may have measurable, non-measurable, or no measurable disease and may have a plan for vaginal brachytherapy . Key exclusion criteria include severe heart disease or interstitial lung disease. The phase II portion of this study is open and enrolling. Clinical trial information: NCT05256225 .

OBJECTIVE:To determine the efficacy and safety of darolutamide, exemestane, and leuprolide acetate in recurrent adult-type ovarian granulosa cell tumor (AGCT). METHODS:This single-arm Phase II cooperative group study included patients with recurrent AGCT who had progressed on a prior aromatase inhibitor. The treatment regimen consisted of darolutamide 600 mg by mouth twice daily, exemestane 25 mg by mouth once daily, and leuprolide acetate 7.5 mg by intramuscular injection every four weeks. Patient accrual occurred from January 2024 to April 2024 with sample size determined using Simon's Optimal two-stage design. The primary measure of efficacy was objective response rate (ORR) measured by Response Evaluation Criteria in Solid Tumors 1.1. Secondary objectives included duration of response, progression-free survival (PFS), overall survival (OS), and safety of the treatment regimen. RESULTS:Seventeen patients were enrolled to complete target accrual of the first stage. Of the 16 evaluable patients, there was one partial response (ORR = 6.25%). The trial did not continue to the second stage as it did not meet its prespecified endpoint. Ten patients (62.5%) were confirmed to have stable disease and five patients (31.25%) were confirmed to have progressive disease. Median PFS was 8.5 months (95% CI: 3.1 months - 12.0 months). Median OS was not reached. There were no grade 4 or grade 5 adverse events attributable to the treatment regimen. CONCLUSIONS:Though the trial did not meet its primary endpoint, there was one partial response to the treatment regimen. Clinically meaningful PFS was demonstrated. Clinical Trial Registration Number NCT06169124.

PURPOSE:Determine if molecular classification using mismatch repair (MMR) and p53 protein expression predicts recurrence-free survival (RFS) and overall survival (OS) in endometrial cancer (EC) patients treated with chemotherapy and radiation (CRT) versus chemotherapy (CT). METHODS:GOG-0258, a phase III randomized trial (NCT00942357), compared CRT to CT. Immunohistochemistry assessed MMR and p53 status. Kaplan-Meier curves and adjusted Cox models analyzed survival outcomes by molecular subtype. RESULTS:ECs classified as deficient MMR (dMMR) (27 %), p53 abnormal (p53abn) (24 %), and p53 wild type (p53wt) (49 %). p53abn were more frequent in patients that were older, Black, and had serous histology (p < 0.001). Median follow up was 113 months. Five-year RFS and OS were worse with p53abn (29 % [Hazard Ratio (HR) = 3.39 (95 % Confidence Interval (CI): 2.34-4.91)] and 39 % [HR = 4.64 (95 % CI: 3.16-6.79)] compared to those with p53wt (referent) (p < 0.001). The five-year RFS and OS for dMMR cancers were (58 % [HR = 1.30 (95 % CI: 0.85-1.97)] and 77 % [HR = 1.53 (95 % CI: 0.99-2.36)] compared to those with p53wt (69 % and 85 %). After adjusting for age, gross residual disease, and treatment, p53wt improved RFS with CRT compared to CT in an exploratory analysis (77 % vs 60 %; HR = 0.54 (95 % CI: 0.32-0.94). The 5-year and 10-year OS rates were similar in CRT compared to CT in all subgroups. CONCLUSION:Molecular classification appears to be predictive and prognostic, with worse survival in those with p53abn tumors. In an exploratory analysis, p53wt appears to predict improved RFS, favoring CRT over CT. There was no difference in treatment efficacy based on molecular subtype for OS.

Introduction. Early reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO -1 inhibitor epacadostat in patients with recurrent OCCC. Methods. This single arm, two-stage, phase 2 trial included those with measurable disease and 1-3 prior regimens. Patients received intravenous pembrolizumab 200 mg every 3 weeks and oral epacadostat 100 mg twice a day. Primary endpoint was overall response rate (ORR), secondary endpoints were toxicity, progression -free survival (PFS) and overall survival (OS). The study was powered to detect an absolute 25% increase in response (15% to 40%). Results. Between September 28, 2018 and April 10, 2019,14 patients enrolled at first stage. Rate of accrual was 2.3 patients per month. Median age was 65 years (44-89), 10 (71.4%) had >= 2 prior regimens. ORR was 21% (95% 5-51%) within 7 months of study entry with 3 partial responses, and 4 had stable disease (disease control rate 50%). Median PFS was 4.8 months (95% CI: 1.9-9.6), OS 18.9 months (95% CI: 1.9 -NR). Most common grade >= adverse events were electrolyte abnormalities and gastrointestinal pain, nausea, vomiting, bowel obstruction. July 2019, the study reached the pre-specified criteria to re-open to second stage; however, the study closed maturely in February 2021 due to insufficient drug supply. Conclusions. Pembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with (c) 2024 Elsevier Inc. All rights reserved.

PURPOSE Pelvic recurrence is a frequent pattern of relapse for women with endometrial cancer. A randomized trial compared progression-free survival (PFS) after treatment with radiation therapy alone as compared with concurrent chemotherapy. MATERIALS AND METHODS Between February 2008 and August 2020, 165 patients were randomly assigned 1:1 to receive either radiation treatment alone or a combination of chemotherapy and radiation treatment. The primary objective of this study was to determine whether chemoradiation therapy was more effective than radiation therapy alone at improving PFS. RESULTS The majority of patients had low-grade (1 or 2) endometrioid histology (82%) and recurrences confined to the vagina (86%). External beam with either the three-dimensional or intensity modulated radiation treatment technique was followed by a boost delivered with brachytherapy or external beam. Patients randomly assigned to receive chemotherapy were treated with once weekly cisplatin (40 mg/m2). Rates of acute toxicity were higher in patients treated with chemoradiation as compared with radiation treatment alone. Median PFS was longer for patients treated with radiation therapy alone as compared with chemotherapy and radiation (median PFS was not reached for RT v 73 months for chemoradiation, hazard ratio of 1.25 (95% CI, 0.75 to 2.07). At 3 years, 73% of patients treated definitively with radiation and 62% of patients treated with chemoradiation were alive and free of disease progression. CONCLUSION Excellent outcomes can be achieved for women with localized recurrences of endometrial cancer when treated with radiation therapy. The addition of chemotherapy does not improve PFS for patients treated with definitive radiation therapy for recurrent endometrial cancer and increases acute toxicity. Patients with low-grade and vaginal recurrences who constituted the majority of those enrolled are best treated with radiation therapy alone.

5525 Background: NRG GY012 is a randomized, 3-arm phase II study, comparing olaparib (O) and the combination of cediranib and olaparib (CO) to the reference arm cediranib (C) for metastatic pre-treated, endometrial cancer (EC). The trial found a trend towards benefit for CO and no benefit for O compared to C. Archival tumor and prospective blood samples were collected for biomarker analysis. Methods: Targeted next-generation sequencing (BROCA-GO) was used to detect pathogenic variants (PV) and loss of heterozygosity (LOH) in DNA from paired blood and archival cancers. The LOH cut-off was identified at 11% for HRD based on testing ovarian cancers with known HRD. Plasma samples collected at baseline, cycle 2 day 1, and end-of-treatment were analyzed via multiplex ELISA for 25 angiogenic and inflammatory circulating protein biomarkers (Angiome); IL6 was of specific interest. Prognostic associations with PFS and OS were analyzed using proportional hazards models (PhM) stratified by histology and adjusted for treatment assignment. Predictive associations (PFS and OS) were analyzed using PhM stratified by histology and including main effects for both treatment assignment and biomarker group plus an interaction term. Results: In 97 patients (pts) with evaluable tumor, BROCA-GO identified 370 somatic PV; TP53 (61%) was the most commonly mutated gene. PV in homologous recombination repair (HRR) genes were identified in 5 cases (5%). Somatic PVs were identified in BRCA2, RAD51B and PALB2. 1 pt had a germline BRCA1 PV. 2 cases had somatic PV that might restore HRR: 1 case with a somatic BRCA2 PV had somatic PVs in CHD4 and TP53BP1; the TP53BP1 frameshift PV was present only in the recurrent and not primary cancer. LOH was available for 45 cases. LOH high occurred in 16 (35.6%) cases and was exclusive to EC with TP53 mutations (p=0.0003). LOH was not associated with outcome in any of the arms. For the circulating biomarker analysis (N=96), median IL-6 was 4pg/ml. IL-6 levels >4pg/ml were associated with increased risk of progression (HR: 1.59; 95% CI: (1.04-2.42); p-value=0.032). In predictive analyses, pts with IL-6 > 4 pg/ml receiving C or C+O had increased PFS (3.8 mo vs 1.9 mo) and OS (11.9 mo vs 5.7 mo) compared to pts receiving O, the interaction p value did not reach statistical significance. Conclusions: LOH high status was not associated with outcome to O. There were too few cases with HRR PVs to determine their relationship to PARPi response. The restriction of LOH high to cancers with TP53 mutation may suggest that genomic LOH in ECs correlates better with aneuploidy than with HRR function indicating that at least some biomarkers of PARPi response vary between tumor types. IL-6 levels were prognostic of PFS but were not predictive of either OS or PFS for pts receiving C compared to pts receiving O in this small study. Further analysis of the complete Angiome and integration with the BROCA-GO dataset are ongoing. Clinical trial information: NCT03660826 .

PURPOSE:This paper reports the efficacy of the poly (ADP-ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer. METHODS:This was open-label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned (1:1:1), stratified by histology (serous vs. other) to receive cediranib alone (reference arm), olaparib, or olaparib and cediranib for 28-day cycles until progression or unacceptable toxicity. The primary end point was progression-free survival in the intention-to-treat population. Homologous repair deficiency was explored using the BROCA-GO sequencing panel. RESULTS:A total of 120 patients were enrolled and all were included in the intention-to-treat analysis. Median age was 66 (range, 41-86) years and 47 (39.2%) had serous histology. Median progression-free survival for cediranib was 3.8 months compared with 2.0 months for olaparib (hazard ratio, 1.45 [95% CI, 0.91-2.3] p = .935) and 5.5 months for olaparib/cediranib (hazard ratio, 0.7 [95% CI, 0.43-1.14] p = .064). Four patients receiving the combination had a durable response lasting more than 20 months. The most common grade 3/4 toxicities were hypertension in the cediranib (36%) and olaparib/cediranib (33%) arms, fatigue (20.5% olaparib/cediranib), and diarrhea (17.9% cediranib). The BROCA-GO panel results were not associated with response. CONCLUSION:The combination of cediranib and olaparib demonstrated modest clinical efficacy; however, the primary end point of the study was not met. The combination was safe without unexpected toxicity.

Figure S5 shows circulating cytokine analysis of each patient from baseline, post-CRT and post-ipilimumab time points.

TPS5629 Background: Identifying new approaches for the treatment of advanced endometrial cancer (EC) is a priority. A platform study design allows for a faster investigation of novel drug combinations. NRG-GY012 is an ongoing platform study investigating drug combinations with the PARP inhibitor olaparib (O) and the anti-angiogenic agent cediranib (C). Results from the first set of arms established improved PFS for combination cediranib/olaparib over C alone, but did not meet its prespecified statistical significance. In this second set of arms, based on preclinical data, we are investigating the combination of O with an AKT inhibitor (capivasertib), O with durvalumab and C with durvalumab compared to the reference arm of C alone. Methods: This is a multicenter randomized four arm study for patients with recurrent, metastatic or persistent EC. Patients are randomized 1:1:1:1 to cediranib PO 30 mg Daily; olaparib 300 mg PO BID and capivasertib 400mg 4 day on/3 off schedule; olaparib 300 mg PO BID and durvalumab 1500mg q28 days; or the combination of cediranib 20 mg PO Daily 5 days on/2 days and durvalumab 1500mg q28. All treatment cycles are 28 days. Primary endpoint is progression free survival (PFS). The study is powered to detect a doubling in median PFS from 3.6 (based on cediranib alone) to 7.2 months with 90% power, using a one-sided test with α = 0.05 per comparison. Forty patients will be enrolled per arm, with an interim futility analysis planned at 50% information time. Eligibility includes endometroid, serous, and mixed histology EC; at least 1 prior line of chemotherapy (no more than 2 lines for metastatic disease), prior endocrine or immunotherapy alone is allowed; prior treatment with lenvatinib and pembrolizumab is excluded. Archival tumor tissue and blood samples are being collected for translational studies. The study is open across the NRG network; 76 of a planned 168 patients are enrolled to date. Safety analysis at the time of 36 patients enrolled did not demonstrate any new safety signals and the study was approved to continue enrollment. Clinical trial information: NCT03660826 .

Figure S2 shows the association of T cell subsets and T cell activation status to ipilimumab dose level received.

Figure S3 shows the association of changes in circulating T cell memory subsets with clinical response.

Figure S4 shows the association of changes in immune biomarkers with overall survival

Figure S6 shows the association of circulating cytokine levels with objective clinical response.

IntroductionDetermine whether molecular classification using mismatch repair (MMR) and p53 protein expression predictsRFS in EC patients treated with chemotherapy and radiation (CRT) versus chemotherapy (CT).MethodsGOG-0258 was a phase III, randomized trial (NCT00942357) comparing CRT and CT with primary endpoint of RFS. Immunohistochemistry was performed to determine MMR and p53 status. Demographic variables were compared with chi-squared and Kruskal Wallis tests for categorical and continuous variables, respectively. Kaplan-Meier curves estimated RFS between sub-groups. Adjusted Cox proportional hazards models estimated hazard ratios and 95% confidence limits.ResultsUsing a modified ProMiSe algorithm, 27.4% of EC classified as dMMR, 49% p53wt, and 23.6% p53abn. p53abn tumors were more frequent in older (p<0.001ADD p-value) and Black (p<0.001ADD p-value) patients, and those with serous histology (p<0.001ADD p-value). In contrast, dMMR was more common in Non-Hispanic patients (ADD p-valuep=0.025) and endometrioid cancers (p<0.001ADD p-value). 5-year RFS was significantly worse for those with p53abn [28.8% vs 68.9% vs 57.5%; HR=3.39 (2.34–4.91); p<0.001] compared to p53wt (referent) and dMMR ECs. After adjusting for age, gross residual disease, and treatment,p53wt was associated with improved RFS in the CRT compared to CT group [77.2% vs 59.7%; HR=0.54 (0.32–0.94); p=0.02]. The 5-year RFS with CRT versus CT were similar for those with p53abn [29.3% vs 29.4%; 0.76 (0.46–1.24)] and dMMR [52.5% vs 63.7% (0.70–2.57)] ECs.Conclusion/ImplicationsMolecular classification is prognostic in EC, with worse RFS in p53abn tumors. In an exploratory analysis, p53wt appears to be predictive for treatment efficacy favoring CRT over CT. Further trials are warranted to confirm these findings.

Objectives The pelvis is a common site of recurrence for patients with endometrial cancers. A randomized trial was conducted to compare progression-free survival in patients treated with radiation therapy alone as compared to radiation therapy with concurrent cisplatin-based chemotherapy. Methods 165 Patients were accrued between February 2009 and August 2020. Women with recurrent endometrial carcinoma limited to the pelvis were eligible. The median time for follow up for vital status was 60 months. Results Most patients had grade 1 or 2 endometroid endometrial cancer (81%) and most recurrences were vaginal (86%). Radiation therapy was delivered to the pelvis with 3D or IMRT techniques followed by HDR or LDR interstitial or intracavitary brachytherapy. Chemotherapy was delivered with weekly cisplatin. Grade 4 or higher acute adverse event were reported in 8 participants in the chemotherapy and radiation arm as compared to 1 treated with radiation only. 68% of patients treated with radiation therapy were alive and progression-free as compared to 59.8% of those that received chemotherapy and radiation. Overall, patients treated with weekly cisplatin had a lower rate of PFS as compared to patients treated with radiation alone (stratified HR=1.40, 95% CI: 0.82–2.39, p=0.8919). Conclusions Results of this randomized trial suggest that the addition of chemotherapy does not improve, and may worsen, outcomes for patients treated with definitive radiation therapy for recurrent endometrial cancer. Those with low grade and vaginal apex recurrences may be best treated with radiation therapy alone.

Background. Age and ethnicity are among several factors that influence overall survival (OS) in ovarian can-cer. The study objective was to determine whether ethnicity and age were of prognostic significance in women enrolled in a clinical trial evaluating the addition of bevacizumab to front-line therapy. Methods. Women with advanced stage ovarian, primary peritoneal, or fallopian tube cancer were enrolled in a phase III clinical trial. All women had surgical staging and received adjuvant chemotherapy with one of three reg-imens. Cox proportional hazards models were used to evaluate the relationship between OS with age and race/ ethnicity among the study participants. Results. One-thousand-eight-hundred-seventy-three women were enrolled in the study. There were 280 mi-nority women and 328 women over the age of 70. Women age 70 and older had a 34% increase risk for death when compared to women under 60 (HR = 1.34; 95% CI 1.16-1.54). Non-Hispanic Black women had a 54% de-creased risk of death with the addition of maintenance bevacizumab (HR = 0.46, 95% CI:0.26-0.83). Women of Asian descent had more hematologic grade 3 or greater adverse events and a 27% decrease risk of death when compared to non-Hispanic Whites (HR = 0.73; 95% CI: 0.59-0.90). Conclusions. Non-Hispanic Black women showed a decreased risk of death with the addition of bevacizumab and patients of Asian ancestry had a lower death rate than all other minority groups, but despite these clinically meaningful improvements there was no statistically significant difference in OS among the groups. (c) 2021 Published by Elsevier Inc.

BACKGROUND:The residual lifetime risk (RLR) of developing heart failure (HF) may have changed over time because of the increasing population burden of hypertension, obesity, and diabetes; greater survival after myocardial infarction; and a greater lifespan. OBJECTIVES:The authors assessed changes in the RLR for HF in two 25-year epochs (1965-1989 and 1990-2014). METHODS:We compared the RLR of HF at age 50 years (adjusting for competing risk of death) in the 2 epochs in Framingham Study participants overall and in the following strata: sex, body mass index, blood pressure, and diabetes. RESULTS:Mean life expectancy increased from 75.9 to 82.1 years in women and 72.5 to 78.1 years in men. We observed 624 HF events over 111,351 person-observations in epoch 1, and 875 HF events over 128,903 person-observations in epoch 2. The mean age at onset of HF increased across the epochs by 6.6 years (women) to 7.2 years (men). The RLR of HF at age 50 years increased across epochs from 18.86% to 22.55% (absolute increase 3.69; 95% CI: 0.90-6.49; P = 0.01) in women, and from 19.19% to 25.25% (absolute increase 6.06; 95% CI: 3.08-9.04; P < 0.001) in men. The increase in RLR of HF in the second epoch was consistent across strata with excess body mass index or higher blood pressure (relative increase of 28%-47%) and in participants without prior myocardial infarction (relative increase of 23%). CONCLUSIONS:The RLR of HF has increased in our community-based sample of White individuals over the last 5 decades, possibly caused by an increase in life expectancy.

Clinical trials typically collect longitudinal data, data that are collected repeated over time, such as laboratories, scans, or patient-reported outcomes. Due to a variety of reasons, this data can be missing, whether a patient stops attending clinical visits (ie, dropout) or misses assessments intermittently. Understanding the reasons for missing data as well as predictors of missing data can aid in determination of the missing data mechanism. The analysis methods used are dependent on the missing data mechanism and may make certain assumptions about the missing data itself. Methods for nonignorable missing data, which assumes that the missing data depend on the missing data itself, make stronger assumptions and include pattern-mixture models and shared parameter models. Missing data that are ignorable after adjusting for other covariates can be analyzed using methods that adjust for covariates, such as mixed-effects models or multiple imputation. Missing data that are ignorable can be analyzed using standard approaches that require complete case data, such as change from baseline or proportion of patients who declined at a specified time point. In clinical trials, truly ignorable data are rare, resulting in additional analysis methods required for proper interpretation of the results. Conducting several analyses under different assumptions, called sensitivity analyses, can determine the extent of the impact of the missing data.