Objective Dostarlimab+carboplatin-paclitaxel followed by dostarlimab maintenance demonstrated statistically significant and clinically meaningful benefits in progression-free and overall survival in the overall population of primary advanced/recurrent endometrial cancer versus chemotherapy alone in Part 1 of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial (NCT03981796). Part 2 evaluated the efficacy and safety of the addition of the poly(adenosine diphosphate-ribose) polymerase inhibitor niraparib to dostarlimab maintenance following dostarlimab+chemotherapy versus placebo maintenance following placebo+chemotherapy in primary advanced/recurrent endometrial cancer. Methods Patients were randomized 2:1 to dostarlimab+chemotherapy followed by niraparib+dostarlimab maintenance (niraparib+dostarlimab arm) or placebo+chemotherapy followed by placebo maintenance (control arm). Primary endpoint was progression-free survival in the overall and mismatch repair-proficient/micro-satellite stable populations. Overall survival (key secondary endpoint) and safety were assessed. Results In total, 291 patients were randomized (192 to niraparib+dostarlimab; 99 to control). With approximately 22 months of follow-up, the risk of progression or death was significantly reduced by 40% (hazard ratio 0.60, 95% confidence interval 0.43 to 0.82, p <.001) and 37% (hazard ratio 0.63, 95% confidence interval 0.44 to 0.91, p =.006) with niraparib+dostarlimab versus the control in the overall and mismatch repair-proficient/micro-satellite stable populations, respectively. At 36.2 months of follow-up, no overall survival benefit was observed with niraparib+dostarlimab versus the control (hazard ratio 1.2, 95% confidence interval 0.81 to 1.78).Grade ≥3 treatment-related adverse events occurred in 70.7% of patients in the niraparib+dostarlimab arm and 37.5% in the control arm; serious treatment-related adverse events occurred in 24.6% and 9.4%, respectively. Discontinuations due to adverse events occurred in 38.7% of patients in the niraparib+dostarlimab arm and 11.5% in the control arm. Conclusions While the addition of niraparib to dostarlimab maintenance showed a significant improvement in progression-free survival, there was no observed overall survival benefit. Dostarlimab+carboplatin-paclitaxel followed by dostarlimab maintenance remains the only regimen to demonstrate significant overall survival benefit versus carboplatin-paclitaxel alone in primary advanced/recurrent endometrial cancer.

Mucinous ovarian carcinoma (MOC) is an epithelial ovarian cancer subtype that is frequently misclassified as extraovarian mucinous metastasis (EOM) because of overlapping features. To address this diagnostic challenge, we perform genome-wide DNA methylation profiling of 58 MOCs, 38 EOMs, and 18 mucinous borderline ovarian tumors (mBOTs) collected from six institutions. Methylation analysis defines two mBOT groups, one epigenetically similar to normal ovary and one resembling MOC. Unsupervised clustering reveals two distinct MOC methylation subtypes with potential prognostic relevance in the internal cohort. Using these data together with 389 external profiles, we develop and validate a three-step machine-learning classifier that distinguishes MOC from EOM with 95.5% accuracy. External validation of this classifier on 21 MOCs and 24 EOMs yields an accuracy of 91.11% for differentiating MOC from EOM. These findings establish an epigenetic framework for mucinous ovarian tumors and provide a robust clinical classification tool.

PURPOSE Constitutional epimutations arise early in development and are present across normal tissues, including peripheral blood. Constitutional BRCA1 promoter methylation has emerged as a risk factor for BRCA1 -associated cancers, such as ovarian cancer (OC), and may serve as a biomarker for OC risk. This study retrospectively evaluated the clinical relevance of constitutional BRCA1 promoter methylation in 473 patients with OC enrolled in the observational AGO-TR1 study (ClinicalTrials.gov identifier: NCT02222883 ). MATERIALS AND METHODS BRCA1 promoter methylation was quantified by the methylation-specific real-time polymerase chain reaction using whole blood-derived DNA from 476 female controls and 473 patients with OC along with 473 corresponding tumor-derived DNA samples. Methylation levels ≥1.0% were considered methylation-positive. RESULTS BRCA1 promoter methylation in blood-derived DNA was detected in 42 of 473 patients with OC and in 26 of 476 controls (8.9% v 5.5%; odds ratio [OR], 1.69 [95% CI, 1.02 to 2.80], P = .0432), with the strongest association observed with methylation levels ≥10% (OR, 6.17 [95% CI, 1.37 to 27.72], P = .018). Patients with BRCA1 promoter methylation in blood-derived DNA were diagnosed at a younger median age than those without (54.0 v 60.0 years, P = .018). Constitutional BRCA1 promoter methylation was less frequent in patients carrying pathogenic germline variants in OC predisposition genes than in noncarriers (4.1% v 10.5%; OR, 0.37 [95% CI, 0.14 to 0.96], P = .04) and showed no association with a family history of cancer or platinum-based chemotherapy before blood draw. BRCA1 promoter methylation in blood-derived DNA was correlated with tumor BRCA1 promoter methylation ( P < .001). Tumor BRCA1 promoter methylation was observed in 64 of 473 samples (13.5%), half (32 of 64) of which were attributable to constitutional BRCA1 promoter methylation also detectable in the blood. CONCLUSION Constitutional BRCA1 promoter methylation accounts for a substantial proportion of OCs and represents a robust biomarker for individual OC risk.

5595 Background: Low-grade serous ovarian cancer (LGSOC), a rare ovarian malignancy, exhibits a very limited responsiveness to chemotherapy. There is a pressing need for new therapeutic combinations with modern agents to enhance response rates and prognosis in this patient subgroup. Immune checkpoint inhibitors offer a promising pathway, having shown effectiveness in various malignant diseases, including selected cases of ovarian cancer. If our trial should show pembrolizumab effectivity in LGSOC, it would be a signal and impulse for future clinical studies in this rare disease. Methods: This multi-center, single-arm phase II study evaluates pembrolizumab in combination with platinum-based chemotherapy (carboplatin plus pegylated liposomal doxorubicin [PLD] or carboplatin plus gemcitabine) and as maintenance therapy in recurrent LGSOC. Eligible patients include those with disease progression or recurrence ≥6 months post prior platinum-based therapy and ECOG performance status 0-1. The primary endpoint is the 12-month progression-free survival (PFS) rate. Secondary endpoints include response rate (RR), PFS and ORR based on Ki67 expression. Using Simon’s two-stage design, 33 patients were enrolled. Success is defined as ≥11 patients achieving 12-month PFS. Assuming a true PFS rate of 40%, the study has 5% type I error and 80% power. Results: Data from 33 patients were evaluated. At data cut-off, 12 patients were progression free at 12-months (median PFS 15.5 months) while 19 patients progressed or died within 12 months (median PFS 5.6 months). Overall PFS median was 8.4 months. Comparing the subgroups of pre-treatment Ki67 expression <3.6% vs. ≥ 3.6%, the median PFS was 5.1 vs. 8.8 months. Four patients remain on pembrolizumab treatment; two of these have not yet reached the 12-month PFS endpoint. Median patient age was 52 years (range: 37-81), with ECOG performance status 0 in 30 patients (90.9%). Most patients had one prior chemotherapy line (61.1%; range: 1-5). Chemotherapy regimens included carboplatin + PLD (75.8%) and carboplatin + gemcitabine (24.2%). SAEs were reported in 22 patients (66.7%), with 11 (33.3%) considered treatment-related. Conclusions: The study achieved its primary objective in terms of the 12-months PFS and thus suggests efficacy of pembrolizumab in patients with platinum-sensitive recurrent LGSOC. Clinical trial information: 2023-508155-40-00.

BACKGROUND:Antibody-drug conjugates (ADCs) are approved for use in treating certain types of cancer and are now in clinical development for many others, as they are therapeutically effective. Some of these agents commonly cause ocular side effects, typically manifesting themselves as blurred vision or a foreign-body sensation. METHODS:For this narrative review of the literature, we carried out a database search and a cross-reference search at the German Federal Institute for Drugs and Medical Devices (BfArM) to identify publications on the diagnosis, prevention, and treatment of ocular side effects associated with ADCs. RESULTS:Of the 13 ADCs that have been approved to date, 4 cause ocular side effects in 5% to 89% of patients. Ocular side effects are severe in up to 43% of the cases in which they occur. Appropriate prophylactic measures must be taken to limit their frequency and intensity; these include not wearing contact lenses, using lubricating eye drops multiple times a day, and cooling the eyes during the administration of treatment. Severe ocular side effects can arise despite such measures and require treatment by a specialist. Ocular side effects can be managed successfully by rapid detection and adequate evaluation of their extent followed by proper treatment, thereby enabling the patient's cancer to be treated appropriately. CONCLUSION:Interdisciplinary collaboration between oncologists and ophthalmologists must be well-coordinated to ensure effective oncological treatment.

BACKGROUND:Malignant ovarian germ cell tumours (MOGCT) are rare tumours that disproportionally affect younger women. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) study group has established a clinico-pathological database (Current Ovarian geRm cell and SEx cord stromal Tumour Treatment strategies, CORSETT) to provide an overview of the current treatment strategies and survival of MOGCT patients. METHODS:Twenty German centres provided mixed retro- and prospective data of patients with tumour specimens treated between 2001 and 2014. A second opinion pathology board reviewed the tumour specimens. Descriptive analyses of the treatment strategies and fertility outcomes were conducted. Kaplan-Meier curves were plotted for disease-free and overall survival data. RESULTS:Seventy-seven MOGCT patients were included, 36 malignant dysgerminoma (MD), 21 malignant teratoma (MT) and 20 mixed MOGCT (MM) patients. Patients had a median age of 28 (MD), 38 (MT) and 33 (MM) years and fertility-sparing surgery (FSS) was offered in most (83% MD, 81% MT and 75% MM) patients. Final FIGO stage I disease was diagnosed in 78% (MD), 81% (MT) and 60% (MM) and adjuvant systemic treatment was given to 56% (MD), 53% (MT) and 70% (MM) patients. After a median observation time of 78.2 months, 5% (MD), 14% (MT) and 45% (MM) experienced disease recurrence. Overall survival was excellent in all groups (100% MD, 100% MT and 95% MM). DISCUSSION:In this descriptive analysis, FSS was the surgical method of choice for patients with MOGCT in AGO centres without negative impact on OS. MOGCTs appeared however as a heterogeneous group of tumours with particularly high recurrence rates for patients with MM.

5506 Background: Mirvetuximab soravtansine (MIRV) has demonstrated single agent activity in patients with platinum-resistant ovarian cancer with FRα high expression. However, its activity and safety in combination with carboplatin has not been defined in platinum eligible patients so far. Methods: Randomized phase II trial comparing 6 cycles of carboplatin AUC5+MIRV 6 mg/kg AIBW every 3 weeks followed by MIRV versus 6 cycles of carboplatin combined with either paclitaxel, gemcitabine or pegylated liposomal doxorubicin followed by maintenance PARP inhibitor (PARPi) if applicable. All histologic subtypes were eligible with a platinum-free interval >3 months and FRα high expression (≥75% with PS2+ scoring) confirmed by central laboratory. Prior PARPi therapy in BRCAmut patients was mandatory. Strata were BRCA-Status, TFIp and number of prior lines of chemotherapy. The primary endpoint was PFS. Results: In total, 145 patients were randomized. Of them, 112/145 (77.2%) patients had received prior bevacizumab and 97/145 (66.9%) had prior PARPi, 15.2% were BRCAmut. In the standard arm, 39.15% received PARPi as maintenance. Median PFS in the standard arm was 9.79 months versus 9.53 months in the experimental arm (p=0.996; HR=1.00; 95% CI: 0.68; 1.46). Conclusions: MIROVA/AGO-OVAR 2.34 is the first randomized trial evaluating the activity and safety of the combination of carboplatin with an antibody-drug conjugate in the setting of platinum-eligible relapsed ovarian cancer. The primary endpoint regarding improvement of PFS was not met. Further analysis will be presented. Clinical trial information: NCT04274426 .

LBA5500 Background: Optimal timing of cytoreduction in non-frail patients (pts) with seemingly resectable stage IIIB-IVB ovarian, tubal, and peritoneal carcinoma (OC) remains controversial. Methods: TRUST is an international randomized multicenter phase III trial in pts with stage IIIB-IVB OC and good performance status (ECOG 0/1) comparing primary cytoreductive surgery (PCS) followed by 6 cycles of intravenous (iv) chemotherapy to 3 cycles of neoadjuvant iv chemotherapy (NACT) followed by interval cytoreductive surgery (ICS) and 3 further iv cycles. Maintenance treatment with bevacizumab and/or PARP inhibitors was allowed if selection criteria was similar for both arms. Pts were eligible for the study if preoperative clinical and radiologic assessment identified them as potential candidates for PCS. To ensure surgical quality, participating centers complied with an onsite surgery quality assurance audit, had adequate infrastructure, surgical proficiency (complete resection rates ≥50% in PCS) and sufficient volume (≥36 PCS/year). The intent to treat analysis population included all eligible pts with confirmed stage IIIB-IVB disease. The primary endpoint was overall survival (OS). Superiority was tested using a two-sided stratified log-rank test with significance level 0.05. Secondary endpoints were progression-free survival (PFS) and surgical complications. Results: A total of 688 eligible pts (median age: 63y; range: 32-83) underwent randomization: 345 were assigned to PCS and 343 to NACT/ICS. 91% had high-grade serous histology. Complete resection was achieved in 61.7%/62.9% of all randomized/all operated pts in the PCS group and 72%/76.6% in the ICS group. Median PFS was 22.2 months in the PCS group, and 19.7 months in the ICS group (HR 0.80 95%CI: 0.66-0.96; p=0.02). Median OS was 54.3 months in the PCS group and 48.3 months in the ICS group (HR 0.89 95%CI: 0.74-1.08; p=0.24). Pts with complete cytoreduction after PCS had the most favorable outcome, with a median PFS and OS of 27.9 and 67.0 months, respectively. A long-term benefit from PCS was seen in all analyzed subgroups. The benefit of PCS was most prominent in stage III pts (n=468): median PFS for PCS vs ICS, 26.3 vs 21.4 mos; median OS for PCS vs ICS, 63.7 vs 53.2 months. Major postoperative complication rates were acceptable, with a 30-day postoperative mortality rate of < 1% in both groups. Conclusions: In expert centers with proven surgical quality, PCS followed by iv chemotherapy resulted in a significantly longer median PFS and a numerically longer OS compared to NACT/ICS in non-frail OC pts. Although statistical significance in the primary endpoint was not reached, this is the first randomized trial to show a benefit of PCS over ICS. This benefit is likely to be associated with the high complete resection rate, reinforcing PCS as a standard of care in non-frail pts with seemingly resectable advanced OC. Clinical trial information: NCT02828618 .

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: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:NCT02655016.

Objective Endometrioid ovarian carcinoma (ENOC) is increasingly recognized as a distinct disease entity, yet treatment still largely parallels high-grade serous disease management. We aimed to assemble a large, well-annotated ENOC cohort allowing us to study real-world treatment patterns with special interest on lymph node (LN) metastasis in presumed early-stage disease. Methods ENOC cases from 22 centers across five countries underwent IHC-supported central pathology review. Standardized chart review captured patient characteristics, detailed surgical and adjuvant treatment data. Results A total of 721 centrally confirmed ENOC cases diagnosed between 1984 and 2020 was assembled. Median age was 55.6 years; 86.0% presented with pelvic-confined disease, and 45.1% had grade 1 tumors. Complete resection was achieved in 96.5% of pT1/2 and 62.6% of pT3 cases. LN surgery (LNS) was performed in 58.3% of presumed early-stage cases, revealing nodal metastases in 2.6%, occurring in 4/255 (1.6%) after sampling and 5/95 (5.3%) after systematic LNS. No nodal metastases were observed in grade 1 pelvic-confined tumors (0/171). Adjuvant chemotherapy was administered in 68.0% of FIGOI/II cases and 95.5% of advanced-stage disease. Multivariable analyses revealed grade (p = 0.0006), stage (p = 0.0030) and chemotherapy (p = 0.0219) as independent prognosticators. Conclusions This multinational initiative enabled detailed analyses in a large cohort of validated ENOC.According to our results, LNS may be safely omitted in patients with pelvic-confined G1 tumors, however, if LNS is deemed necessary, a systematic approach seems to result in higher detection rates. The findings presented herein may help to shape type-specific treatment, ultimately aiming to reduce not only ovarian carcinoma mortality but also treatment-associated morbidity.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), residual disease after primary surgery has limited prognostic effect in gBRCApv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2-deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA, RAD21 and MYC amplification define BRCA2-deficient HGSC with exceptionally short survival. Patients with BRCA1-deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1-deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.