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INTRODUCTION: We aimed to evaluate real-life experiences with the re-challenge of poly(ADP-Ribose)Polymerase (PARP) inhibitors (PARPi) after a prior PARPi therapy in patients with recurrent EOC. METHODS: A retrospective descriptive study was conducted at a tertiary care center of excellence for ovarian cancer. Demographic, pathological, and therapeutic data were collected for patients with recurrent epithelial ovarian cancer who were re-treated with PARPi in their therapy course. RESULTS: Twenty-nine patients were included in the study. Twenty-six patients received the second PARPi as maintenance therapy after two different lines of therapy and three patients received the second PARPi as upfront therapy after progression. Most of the patients (57.7%) were exposed to first PARPi after a second-line therapy. The median progression-free survival under the first and second PARPi therapy was estimated at 15 and 7 months respectively. PFS under the second PARPi after platinum-based chemotherapy was better after a complete remission with a median PFS of 8.5 months, compared to patients with partial remission (5.5 months). A better PFS was noted in case of negative BRCA status under the second PARPi therapy (median PFS of 7.4 vs. 4.5 months, p = 0.11). The second PARPi therapy was mainly discontinued due to disease progression (84.6% of the cases). Discontinuation of treatment with the second PARP due to toxicity was needed in one case who developed a myelodysplastic syndrome. CONCLUSION: Real-life data support prospective evidence that patients with recurrent EOC may derive benefit of the re-treatment with PARPi in case of clear response to the last platinum-based therapy. ispartof: GYNECOLOGIC ONCOLOGY REPORTS vol:40 ispartof: location:Netherlands status: published

Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). Results: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non–BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. Conclusions: The newly trained classifiers detected most BRCA-mutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like.

The diagnostic evaluation of homologous recombination deficiency (HRD) is central to define targeted therapy strategies for patients with ovarian carcinoma. We evaluated HRD in 514 ovarian carcinoma samples by next-generation sequencing of DNA libraries, including BRCA1/BRCA2 and 26,523 single-nucleotide polymorphisms using the standardized Myriad HRD assay, with the predefined cut point of ≥42 for a positive genomic instability score (GIS). All samples were measured in the central Myriad laboratory and in an academic molecular pathology laboratory. A positive GIS was detected in 196 (38.1%) of tumors, whereas 318 (61.9%) were GIS negative. Combining GIS and BRCA mutations, a total of 200 (38.9%) of the 514 tumors were HRD positive. A positive GIS was significantly associated with high-grade serous histology (P 0.000001), grade 3 tumors (P = 0.001), and patient age60 years (P = 0.0003). The concordance between both laboratories for the GIS status was 96.9% (P 0.000001), with a sensitivity of 94.6% and a specificity of 98.4%. Concordance for HRD status was 97.1% (499 of 514 tumors). The percentage of HRD-positive tumors in our real-life cohort was similar to the proportion observed in the recently published PAOLA-1 trial, with high concordance between central and local laboratories. Our results support introduction of the standardized HRD assay in academic molecular pathology laboratories, thus broadening access to personalized oncology strategies for patients with ovarian cancer worldwide.

Simple Summary Advanced epithelial ovarian cancer has a poor prognosis, but targeted therapies have been developed and are providing new hope. We reviewed recent results with PARP inhibitors as treatment and/or maintenance therapy following chemotherapy in newly diagnosed advanced ovarian cancer. Data confirm the benefit of PARP inhibitors in this setting, especially in subgroups with genomic instability. We describe the implications of these trial results for clinical practice, focusing on the need for a personalized treatment approach based on biomarker profile and other factors, including tolerability, cost considerations, and physician and patient preference. We have developed a systemic treatment algorithm for newly diagnosed advanced ovarian cancer, intended as a tool for clinicians to aid decision making in their daily practice. We also consider areas of future research, such as exploring further options for patients whose disease relapses following PARP inhibitor treatment. Abstract Recent data have demonstrated substantial efficacy with poly (ADP-ribose) polymerase (PARP) inhibitors as treatment and/or maintenance therapy in patients with newly diagnosed advanced epithelial ovarian cancer (EOC). Here, we review efficacy and safety results from four recent Phase III trials in newly diagnosed EOC: SOLO1 (olaparib), PAOLA-1 (olaparib in combination with bevacizumab), PRIMA (niraparib), and VELIA (veliparib). The implications of these data for current clinical practice and areas for future research are discussed, including ongoing studies of targeted agents in the newly diagnosed setting. Data from SOLO1, PAOLA-1, PRIMA, and VELIA confirm the benefit of PARP inhibitors (olaparib, niraparib, veliparib) for women with newly diagnosed EOC. The greatest benefit was seen in patients with a BRCA1 and/or BRCA2 mutation or in the homologous recombination deficiency (HRD)-test positive subgroup. These four well-conducted studies have generated practice-changing data. However, deciding how to apply these results in clinical practice is challenging, and substantial differences in trial design impede cross-trial comparisons. Recent PARP inhibitor approvals (olaparib, niraparib) in the newly diagnosed EOC setting have provided new maintenance treatment options for a broader patient population. The results of these studies call for personalized medicine based on biomarker profile and other factors, including tolerability, cost considerations, and physician and patient preference. Important areas for future research include appropriate use of both BRCA mutation and HRD testing to inform magnitude of PARP inhibitor benefit as well as exploring further options for patients who are HRD-test negative and for those who become PARP inhibitor resistant.

Annals of surgical oncology 28(11), 6696-6704 (2021). doi:10.1245/s10434-021-09744-y, Published by Springer, Berlin [u.a.]

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan–Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81–0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36–0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.

Background Predictive models based on radiomics features are novel, highly promising approaches for gynaecological oncology. Here, we wish to assess the prognostic value of the newly discovered Radiomic Prognostic Vector (RPV) in an independent cohort of high-grade serous ovarian cancer (HGSOC) patients, treated within a Centre of Excellence, thus avoiding any bias in treatment quality. Methods RPV was calculated using standardised algorithms following segmentation of routine preoperative imaging of patients (n = 323) who underwent upfront debulking surgery (01/2011-07/2018). RPV was correlated with operability, survival and adjusted for well-established prognostic factors (age, postoperative residual disease, stage), and compared to previous validation models. Results The distribution of low, medium and high RPV scores was 54.2% (n = 175), 33.4% (n = 108) and 12.4% (n = 40) across the cohort, respectively. High RPV scores independently associated with significantly worse progression-free survival (PFS) (HR = 1.69; 95% CI:1.06–2.71; P = 0.038), even after adjusting for stage, age, performance status and residual disease. Moreover, lower RPV was significantly associated with total macroscopic tumour clearance (OR = 2.02; 95% CI:1.56–2.62; P = 0.00647). Conclusions RPV was validated to independently identify those HGSOC patients who will not be operated tumour-free in an optimal setting, and those who will relapse early despite complete tumour clearance upfront. Further prospective, multicentre trials with a translational aspect are warranted for the incorporation of this radiomics approach into clinical routine.

BackgroundThe impact of comprehensive pelvic and para-aortic lymphadenectomy on survival in patients with stage I or II endometrial cancer with a high risk of recurrence is not reliably documented. The side effects of this procedure, including lymphedema and lymph cysts, are evident.Primary ObjectiveEvaluation of the effect of comprehensive pelvic and para-aortic lymphadenectomy in the absence of bulky nodes on 5 year overall survival of patients with endometrial cancer (International Federation of Gynecology and Obstetrics (FIGO) stages I and II) and a high risk of recurrence.Study HypothesisComprehensive pelvic and para-aortic lymphadenectomy will increase 5 year overall survival from 75% (no lymphadenectomy) to 83%, corresponding to a hazard ratio of 0.65.Trial DesignOpen label, randomized, controlled trial. In arm A, a total hysterectomy plus bilateral salpingo-oophorectomy is performed. In arm B, in addition, a systematic pelvic and para-aortic lymphadenectomy up to the level of the left renal vein is performed. For all patients, vaginal brachytherapy and adjuvant chemotherapy (carboplatin/paclitaxel) are recommended.Major Inclusion CriteriaPatients with histologically confirmed endometrial cancer stages pT1b–pT2, all histological subtypes, and pT1a endometrioid G3, serous, clear cell, or carcinosarcomas can be included when bulky nodes are absent. When hysterectomy has already been performed (eg, for presumed low risk endometrial cancer), study participation is also possible.Exclusion CriteriaPatients with pT1a, G1 or 2 of type 1 histology or uterine sarcomas (except for carcinosarcomas), endometrial cancers of FIGO stage III or IV (except for microscopic lymph node metastases) or visual extrauterine disease.Primary EndpointOverall survival calculated from the date of randomization until death.Sample Size640 patients will be enrolled in the study.Estimated Dates for Completing Accrual and Presenting ResultsAt present, 252 patients have been recruited. Based on this, accrual should be completed in 2025. Results should be presented in 2031.Trial RegistrationNCT03438474.

Previously, we developed breast cancerThe detection rate of theThe newly trained classifiers detected most

Summary Background Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody–drug conjugate, in this patient population. Methods This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396. Findings 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1–13·0). The confirmed objective response rate was 24% (95% CI 16–33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes. Interpretation Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer. Funding Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.

Objective To evaluate the prevalence of low anterior resection syndrome (LARS) in patients with debulking surgery for primary advanced epithelial ovarian cancer and to identify potential risk factors for development of LARS. Methods We reviewed data on 552 consecutive patients with primary epithelial ovarian cancer (EOC), who underwent upfront or interval cytoreductive surgery including low anterior resection at two different academic institutions (Kliniken-Essen-Mitte, Germany, and Medical University of Vienna, Austria). Intestinal dysfunction was assessed by the validated LARS-questionnaire via telephone call. We performed descriptive statistics and a binary logistic regression model to evaluate risk factors for LARS. Results In total, 341 patients were eligible and 206 (60.4%) were successfully contacted and provided complete information. Major LARS was observed in 78 (37.9%) patients, minor LARS in 44 (21.4%) patients, and no LARS in 84 (40.8%) patients. The prevalence rate of major LARS was not influenced by time interval between surgery and LARS assessment, type of cytoreductive surgery, and recurrent disease at the time of assessment. In multivariate analyses, number of anastomosis was independently associated with an increased risk for presence of major LARS (OR 3.76 [1.95–7.24]). In the present cohort, 25.2% patients had more than one bowel anastomosis. Conclusions LARS in general and major LARS in particular seem to be a frequent long-term complication after debulking surgery including low anterior resection in primary advanced EOC patients. Particularly EOC patients with more than one bowel anastomosis during surgery seem to be at an increased risk for major LARS.

Objective. To analyze the safety and efficacy of niraparib in patients aged >= 70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial. Methods. The trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors. Results. Patients aged >= 70 years in the gBRCAmut cohort receiving niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged >= 70 years receiving niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the niraparib arm was 17.3 months in patients >= 70 years and 17.2 months in patients = 70 years population. The most common grade >= 3 AEs in patients >= 70 years were hematologic: thrombocytopenia event (34.4%), anemia event (13.1%), and neutropenia event (16.4%). Conclusions. For patients >= 70 years of age receiving niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of niraparib should be considered in this population., TESARO, Inc.

Background Cardiophrenic lymph nodes (CPLN) define FIGO stage IVB disease. We evaluate the pattern of CPLN metastases, their prognostic impact and the potential role of CPLN resection in patients with epithelial ovarian cancer (EOC). Methods Analysis of 595 consecutive patients with EOC treated in the period 01/2011–05/2016. CT scans were re-reviewed by two radiologists. Positive CPLN were defined as ≥5 mm in the short-axis diameter. The role of CPLN resection was evaluated in a case-control matched-pair analysis. Results Of 595 patients 458 had FIGO stage IIIB-IV disease. We excluded patients undergoing interval surgery (n = 54), without debulking surgery (n = 32) and without sufficient pre-operative imaging (n = 22), resulting in a study cohort of 350 patients. Of these, 133 (37.9%) had negative CPLN and 217 (62.0%) had radiologically positive CPLN. In patients with postoperative residual tumor, enlarged CPLN had no impact on survival. In patients with complete resection (n = 223), 98 (44.0%) had negative CPLN and a 5-year OS of 69% and a 5-year PFS of 41%; in contrast, in the 125 patients (56.0%) with positive CPLN, 5-year OS was 30% and 5-year PFS was 13%. In 52 patients we resected CPLN. The matched-pair case-control analysis did not demonstrate any significant impact on survival of CPLN resection. Conclusion CPLN metastases are associated with impaired PFS and OS in patients with macroscopically completely resected tumor. Intraabdominal residual tumor has a greater prognostic impact than positive CPLN. The impact of the resection of CPLN remains unclear.

5560 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, maintenance olaparib + bevacizumab (bev) provided a significant progression-free survival (PFS) benefit vs placebo (pbo) + bev in patients (pts) with newly diagnosed advanced ovarian cancer in response to platinum-based chemotherapy. Subgroup analyses revealed a substantial PFS benefit in homologous recombination deficiency (HRD)-positive (including BRCA1/2 mutation) pts, leading to US/EU labels for this combination. Preliminary analyses reported that olaparib did not alter global health-related quality of life (G-HQoL; Ray-Coquard I et al. NEJM 2019). We analyzed HQoL by domains and molecular subgroups and explored the impact of disease progression (DP) on HQoL in the 1L setting. Methods: Eligible pts with newly diagnosed advanced (FIGO stage III–IV) HGOC were randomized 2:1 to maintenance olaparib + bev or pbo + bev. Pts completed European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 HQoL questionnaires at baseline and every 12 weeks for 2 years’ follow-up, irrespective of DP. The minimal important difference for clinically relevant change was fixed at 10 points. Longitudinal data were analyzed by mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD). Analyses were in the intent-to-treat population and HRD-positive subgroup. HQoL analyses at DP (± 60 days) were explored. Results: 806 pts were randomized to olaparib + bev (n=537) or pbo + bev (n=269). 465 pts had DP over 2 years’ follow-up. Compliance to HQoL questionnaires was high at baseline (95%) and over time (>70%). MMRM models by HQoL domain did not reveal a clinically relevant difference between treatment arms over time. TUDD of G-HQoL did not differ between arms (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.72–1.07). In the HRD-positive subgroup (n=372), we observed no difference by HQoL domain between treatment arms. Interestingly, TUDD of G-HQoL was statistically significantly in favor of olaparib + bev compared with pbo + bev (HR 0.70, 95% CI 0.52–0.93). We also observed a clinically significant deterioration in emotional (mean change −12.30 points, 95% CI −16.46 to −8.13) and social (−11.17 points, 95% CI −16.21 to −6.12) functioning in both treatment arms at DP, among 103 pts with HQoL questionnaires at DP. Conclusions: The substantial PFS benefit provided by maintenance olaparib + bev in the newly diagnosed setting was achieved without detrimental effect on HQoL domains, even with longer TUDD of G-HQoL in the HRD-positive subgroup. Use of an effective maintenance therapy (ie one with a significant PFS benefit) in HGOC patients in the 1L setting is likely to delay the clinically significant deterioration in emotional and social functioning we identified in patients at DP across PAOLA-1 treatments arms. Clinical trial information: NCT02477644.

TPS5618 Background: Despite radical primary surgery and carboplatin/paclitaxel-based chemotherapy in combination with anti-angiogenic bevacizumab and/or PARP inhibitors (PARPi), most patients (pts) with advanced ovarian cancer (OC) will relapse. Following the implementation of these targeted therapies to first-line treatment, repeated use of bevacizumab and/or PARPi is often not approved nor has conclusively been proven efficacious for all pts with recurrent OC. New combination partners for platinum-based chemotherapy remain important to improve outcome. The antibody-drug conjugate Mirvetuximab soravtansine (MIRV) is comprised of a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. Results from the phase III trial FORWARD I revealed in an exploratory analysis that pts with high FRα expression following PS2+ Scoring (cut off: ≥75% of tumor cells with FRα membrane staining and ≥ 2+ intensity) had significant progression-free survival (PFS) improvements with a hazard ratio of 0.55 compared to mono-chemotherapy (median PFS 5.6 vs 3.2 months, P=0.015) and high activity was most recently confirmed in the SORAYA trial with an overall response rate (ORR) of 32.4%. Preliminary data for the combination of MIRV with carboplatin exist from the Phase 1b FORWARD II trial, which resulted in an ORR of 71%, observed in 17 pts with a median PFS of 15 months, and an ORR of 80% in the FRα medium/high (>50% PS2+) subset of 10 pts. MIRV is well-tolerated with a manageable safety profile. Methods: Eligible pts for this multicenter, randomized, two-arm, open-label, comparative phase II trial must have recurrent, FRα high epithelial cancer of the ovary, fallopian tube or peritoneum and have measurable disease. Pts are eligible for platinum-based chemotherapy with a platinum-free interval of more than 3 months and had at least one prior chemotherapy, but are not candidates to receive bevacizumab for the current relapse. Pts can be included irrespective of wildtype BRCA1/2 mutation status, pts with a deleterious mutation are required to have received prior PARPi therapy. Following pre-screening for high FRα expression in FFPE tumor tissue according to PS2+ scoring, 136 pts are randomized (1:1) to: a) Control arm: Platinum-based combination chemotherapy (for 6 cycles) followed by PARPi if indicated or standard of care or b) Experimental arm: Carboplatin + MIRV 6 mg/kg adjusted ideal body weight (AIBW) IV d1 (6 cycles q21d) followed by MIRV monotherapy 6 mg/kg AIBW IV q21d until disease progression. The primary endpoint of PFS will be assessed by modified RECIST 1.1. Key secondary endpoints include overall survival, ORR, and quality of life. Enrollment started in September 2021. Clinical trial information: NCT04274426.

e17599 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) induce synthetic lethality in cells with homologous recombination deficiency (HRD). PARPi treatment revolutionized management of patients with cancer, particularly in types where HRD is common, such as ovarian and breast cancer. However, challenges in the implementation of available methods currently limit adoption of HRD testing in the clinics. Here we present the analytical performance evaluation of the Genomic Integrity Index (GII) (SOPHiA GENETICs SA). Methods: GII is a deep-learning based solution for identification of HRD positive tumors from low-pass whole genome sequencing (lpWGS) data (X1 fold coverage). The analytical performance of the GII was evaluated as positive (PPA), negative (NPA) and overall (OPA) percentage of agreement with the HRD status determined by Myriad myChoice CDx (Myriad Genetic Laboratories, Inc.; US FDA-approved). We generated whole genome sequencing libraries for DNA extracted from 139 ovarian cancer Formalin-Fixed Paraffin- Embedded samples, in 4 independent clinical laboratories. We sequenced to the equivalent of 1X coverage (̃10 million reads, 150 base paired end reads, Illumina) and performed HRD classification data using GII using manufacturer’s recommended thresholds. Results: The GII demonstrated high analytical concordance with Myriad myChoice CDx with 91.7% PPA, 95.5% NPA and 94.5% OPA (Table). The HRD status obtained by GII from a subset of positive and negative samples was 100% reproducible (n = 4) between runs. Conclusions: The HRD status obtained by GII is highly concordant with that obtained from standard method, supporting that GII allows accurate and reproducible detection of HRD from lpWGS data. LpWGS is amongst the most cost-effective and easy to implement genome profiling methods, making it uniquely suited for clinical applications. [Table: see text]

TPS5612 Background: Standard of care chemotherapy in patients (pts) with advanced ovarian cancer (AOC) is the combination of carboplatin and paclitaxel. Data from the PRIMA trial has shown a significant benefit in pts by the addition of a maintenance treatment (MT) with niraparib irrespective of BRCA or HRD-status in high-grade ovarian cancers (OC). The PAOLA-1 trial evaluated MT in pts with AOC with the combination of olaparib and bevacizumab and has also shown a significant benefit compared to bevacizumab monotherapy. However, it is unclear if a PARP-inhibitor (PARPi) MT monotherapy is sufficient or if the addition of bevacizumab is needed. Therefore, we investigate, if the treatment strategy of carboplatin / paclitaxel / bevacizumab / PARPi is superior to the treatment of carboplatin / paclitaxel / PARPi in an all-comer population. Methods: AGO-OVAR 28/ ENGOT-ov57 (NCT05009082; EudraCT Number: 2021-001271-16) is an Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group led, international, multicenter, randomized, prospective phase III trial within the ENGOT trial network. The trial population is composed of adult pts with newly diagnosed, advanced high-grade epithelial OC, primary peritoneal cancer or fallopian tube cancer FIGO III/IV (except FIGO IIIA2 without nodal involvement). All pts should have completed the first cycle of chemotherapy (carboplatin and paclitaxel) as part of Study Run-In-Period. Prior to day1 of cycle2, pts with a valid central tumor BRCA ( tBRCA) test result will be randomized 1:1 into either Arm1 and will receive 5 additional cycles of carboplatin and paclitaxel, q21d followed by niraparib for up to 3 years; or into Arm2 where pts will receive 5 additional cycles of carboplatin and paclitaxel plus bevacizumab, q21d followed by bevacizumab, q21d (for up to 1 year) and niraparib for up to 3 years. Patients who are scheduled for neoadjuvant chemotherapy and interval debulking surgery are also allowed to be included in the trial. The primary objective is progression free survival (PFS). Secondary objectives include but are not limited to: PFS according to tBRCA-status, overall survival, PFS2, safety and tolerability, and quality of life. The trial will start in Q1/2022 with First Patient First Visit expected in Q2/2022. It is planned to recruit 970 patients. Clinical trial information: NCT05009082.

TPS5613 Background: Low-grade serous ovarian cancer (LGSOC) represents a minority within the group of invasive epithelial ovarian malignancies. Recent analyses showed a very limited responsiveness to chemotherapy in LGSOC. Since bevacizumab many years ago, none other agents have been approved in LGSOC. There is a high demand of new therapy combinations with modern substances to improve the response rate and prognosis in this group of patients. Immune check-point inhibitors provide a new possibility which showed to be effective in different malignant diseases as well as in selected ovarian cancer patients. In this study, the standard chemotherapy is going to be combined with pembrolizumab in recurrent LGSOC cases with therapy free interval (TFI) over 6 months after last platinum-based chemotherapy. To the authors knowledge no comparable studies have been performed or planned. 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: PERCEPTION/NOGGO-ov44 (NCT04575961) clinical trial is a multi-center, single-arm phase 2 study to evaluate pembrolizumab therapy concomitant to platinum-based chemotherapy (carboplatin plus pegylated liposomal doxorubicin, carboplatin plus gemcitabine or carboplatin monotherapy) and as maintenance in recurrent low-grade serous ovarian cancer cases. LGSOC patients with progression or recurrence at least six months after most previous platinum-containing therapy and in good general performance (ECOG 0 or 1) are eligible to participate in this clinical trial. The primary objective is the 12 months progression free survival (PFS) rate. Secondary end-points include overall survival, response rate (RR), PFS and RR according to Ki67 expression levels, time to first subsequent therapy (TFST) and its response, safety and quality of life. The trial is planned according to Simon’s two-stage design with total sample size up to 33 patients. The null hypothesis is PFS-rate after 12 months of 20%. In the first phase 18 patients will be enrolled and if at least 5 patients show PFS after 12 months the study is going to be continued with an additional 15 patients. The trial is claimed successful, if at least 11 patients show PFS after 12 months. Assuming a true PFS-rate of 40%, this trial has 5% type I error rate and 80% power. Clinical trial information: NCT04575961.

5512 Background: SORAYA is a global single arm phase 3 study evaluating MIRV in patients (pts) with FRα high platinum-resistant ovarian cancer (PROC). MIRV is an antibody drug conjugate comprising a FRα-binding antibody, cleavable linker, and maytansinoid DM4, a potent tubulin-targeting agent. In this study, MIRV demonstrated activity in a broad population of PROC, regardless of number of prior lines of therapy or prior PARPi (Matulonis, SGO 2022). Here we describe details of response to treatment important for clinical decision making. Methods: SORAYA enrolled PROC pts with high FRα expression by immunohistochemistry (Roche FOLR1 Assay ≥ 75% of cells with PS2+ staining intensity) who had received 1-3 prior therapies, including required prior bevacizumab. Pts received intravenous MIRV at 6 mg/kg, adjusted ideal body weight, on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was confirmed objective response rate (ORR) per RECIST v1.1 by investigator (INV) and the key secondary endpoint was duration of response (DOR); additional endpoints included time to response, CA-125 response, safety and tolerability. Results: 106 pts were enrolled; 51% had 3 prior lines; 48% had 1-2 prior lines of therapy; 48% received prior PARPi. ORR by INV was 32.4% (95% confidence interval [CI]: 23.6%, 42.2%), including five complete responses. Median time to response was 1.5 mos (range 1.0 to 5.6) and 71% of pts demonstrated tumor reduction. At the time of the protocol specified primary analysis (16 Nov 2021), the median DOR was 5.9 mos (95% CI: 5.6, 7.7). With 15 responders remaining on MIRV, the DOR continues to evolve. In the 86 response-evaluable patients for CA-125 (by Gynecologic Cancer Intergroup criteria), responses were observed in 46.5% (95% CI: 35.7, 57.6). Updated data will be presented including depth and duration of responses and impact of dose modifications. The most common treatment-related adverse events (TRAE; all grade, grade 3+) included blurred vision (41%, 6%), keratopathy (36%, 9%), and nausea (29%, 0%). TRAEs led to dose delays in 32%, dose reductions in 19%, and discontinuations in 7% of pts; one patient discontinued treatment due to an ocular event. The tolerability profile of MIRV consists of low-grade, reversible ocular and GI events, managed with dose modifications and supportive care. Conclusions: Treatment options for pts with PROC are limited. MIRV is the first biomarker-directed therapy demonstrating anti-tumor activity in pts with FRα high PROC. These results support the clinically meaningful impact MIRV has for pts with FRα high PROC, irrespective of prior therapies or dose modifications. Clinical trial information: NCT04209855.

5574 Background: Available chemotherapies for platinum-resistant ovarian cancer (PROC) have limited clinical activity and considerable toxicity. Mirvetuximab soravtansine (MIRV) is a first-in-class antibody drug conjugate (ADC) comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid payload DM4, a potent tubulin-targeting agent that has demonstrated significant anti-tumor activity in this difficult to treat population. The objective is to characterize the tolerability profile of MIRV in a pooled analysis of experience when administered as monotherapy in patients (pts) with FRα positive recurrent ovarian cancer. Methods: Retrospective pooled analysis included pts enrolled across three studies: phase 1 first-in-human, phase 3 FORWARD I, and phase 3 SORAYA. Analysis included pts with FRα positive recurrent ovarian cancer and those pts with low, medium, and high FRα expression by immunohistochemistry (Roche FOLR1 Assay ≥ 25% of cells with PS2+ staining intensity). All pts received intravenous MIRV at 6 mg/kg, adjusted ideal body weight, on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity. Results: 464 pts were included from 15 countries, with key characteristics: median age 63 yrs, 87% 1-3 prior therapies, 91% platinum free interval ≤6 months, 65% prior bevacizumab, and 25% prior PARPi. The most common treatment-related adverse events (TRAE) (all grade, grade 3+) included blurred vision (42%, 3%), nausea (40%, 2%), diarrhea (33%, 2%), fatigue (31%, 2%), keratopathy (26%, 3%), and dry eye (22%, 1%). TRAEs leading to a dose delay or reduction occurred in 33% and 21% of pts, respectively. Seven % discontinued due to a TRAE. Four pts ( < 1%) discontinued MIRV due to an ocular event. Ninety % of pts with a grade 2+ blurred vision resolved to grade 0 or 1, 93% of pts with grade 2+ keratopathy resolved to grade 0 or 1. No corneal ulcers or perforation have been reported and no patient with a serious ocular event has been reported to have permanent sequelae. Conclusions: In a pooled analysis of 464 patients, MIRV monotherapy has a differentiated and predictable safety profile consisting primarily of low grade and reversible gastrointestinal and ocular events. These events were managed with supportive care and dose modifications if needed, with a low rate of treatment-related discontinuation. The safety profile of MIRV in recurrent ovarian cancer along with the anti-tumor activity in PROC (32.4% ORR Matulonis SGO 2022) support a favorable benefit/risk in this population. Clinical trial information: NCT01609556, NCT04296890, NCT02631876.

5520 Background: The DESKTOP III trial has demonstrated a significant survival benefit in AGO-score positive patients who underwent complete cytoreduction at 1st relapse compared to those treated with chemotherapy alone. The question whether eligible patients who missed the opportunity of potentially life prolonging surgery at 1st relapse would benefit from surgery at the time of their second relapse, remains open. Methods: Patients randomized in the standard, non-surgical arm of the DESKTOP III trial who underwent cytoreductive surgery at a subsequent relapse at investigator’s discretion were separately analyzed. Results: The median progression-free survival (PFS) counted from randomization of 201 patients in the control arm of DESKTOP III was 14.0 months. 171 (85%) had progressive or relapsing disease and 32 of 171 (19%) underwent cytoreductive surgery. Patients’ median age at this subsequent surgery was 63 years (range: 46 – 78). Complete tumor resection was achieved in 19 patients (60%), while 5 (16%) had postoperative residual disease (n = 8 missing data). Sixteen patients (50%) commenced systemic treatment within 90 days from surgery, as documented. Thirty- and 90-day surgical mortality rates were 1 (3%) and 2 (6%), respectively. Within a postoperative median follow-up time of 43.8 months, 12 (38%) deaths were reported. Median overall survival after surgery (OS) was 54.0 months. One- and 2-year OS rates were 91% and 84%, respectively. Conclusions: Cytoreductive surgery for subsequent ovarian cancer relapse appears feasible and with low mortality in selected patients who received non-surgical treatment at 1st relapse despite a positive AGO-score. Surgery should be considered as an option in carefully selected patients also later in their journey within a specialized gynecological cancer setting. Clinical trial information: NCT01166737.

e17630 Background: Gynecological sarcomas (GS) are orphan diseases associated with poor prognosis. With the aim to improve our understanding of GS, the German registry for gynecological sarcoma (REGSA) prospectively recorded patients’ data with GS treated in real-life clinical practice at initial diagnosis and the time of relapse. Herein, we present the analysis of demographic and epidemiological data of patients with GS at the time of initial diagnosis. Methods: An exploratory analysis among different histological subtypes of GS was performed and patients’ data were compared to data of the healthy standard population. We analyzed the following variables: age, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status, ethnicity, lifestyle habits, pregnancies, and comorbidities. Results: Data of 389 patients with GS were descriptively evaluated. Leiomyosarcoma (LMS) was the most common histological subtype (47.3%), followed by low-grade endometrial stromal sarcoma (LG-ESS; 17.7%), high-grade ESS (HG-ESS; 10.4%), adenosarcoma (AS; 9.1%) and undifferentiated uterine sarcoma (UUS; 6.2%). Overall, 9.4% of all GS were classified as “other” rarer histological subtypes. The mean age of patients was 57.4 years. The youngest were the patients with LG-ESS (54.3 years), whereas patients with AS were the oldest ones (61.7 years). There were no statistically significant differences in average age nor in BMI among patients with different histological subtypes of GS. In contrast, compared to the standard population, the BMI of patients with GS was significantly higher (27.5 kg/m² vs 25.1 kg/m², p< 0.001). Overall, 70.7% of all patients with LMS had FIGO stage I or II. Therefore, it is not surprising that most of patients had ECOG performance status 0 (68.3%). According to the countries of recruitment (i.e. Germany, Austria, Switzerland), 92.8% of patients were Caucasian. REGSA patients were less likely to be smokers compared to the national average of German women (13.4% vs 18.6%). One or two births per patient were reported in 58.2% of patients. In comparison the current birth ratio in Germany is approximately 1.5 children per woman. Hypertension was the most common comorbidity as observed in 33.2% of all cases, followed by thyroid diseases (18.6%). The prevalence of hypertension in the German female standard population is approximately 30% and approximately every third person will be affected by thyroid diseases in their lifetime. Conclusions: REGSA data showed no statistically significant differences in terms of demographic variables between different histological subtypes of GS, whereas statistically significant difference such as BMI was identified as compared to the standard population. Further research is needed to specify risk factors of GS in order to promote primary prevention of this fatal disease.

5556 Background: Standard treatment for advanced ovarian cancer (aOC) includes primary cytoreductive surgery followed by chemotherapy (PDS > CTX). There is strong evidence that this strategy is accompanied by high risk for early failure in some patients (pts) but prospective multicenter data for this specific question are lacking. Methods: 64 AGO-sites prospectively registered pts with suspected aOC and collected following variables prior to start of therapy: age, Charlson Comorbidity Index (CCI), timed up and go test (TUG), ASA and ECOG performance score, weight, height, estimated ascites, albumin, creatinine, hemoglobin, leucocytes, platelets, CA125, patient reported outcome measures according to EORTC QLQ-C30 and OV28, hospital anxiety and depression score (HADS), physician-assessed suspected FIGO IV stage, abdominal pain requiring treatment, abdominal bloating, dyspnea and required palliative paracentesis (ascites, pleural effusions). Treatment followed according to investigator’s decision. Primary objective was to predict the unfavorable event of death or progression within 10 months after primary diagnosis. We applied univariate and multiple logistic regression with stepwise variable selection after multiple imputation of missing data in order to identify relevant predictors. Results: 223 pts with aOC FIGO IIIB to IVB and PDS were analyzed. Median age was 63 years (range 31-86). 52 (23.3%) pts experienced progression or death within 10 months from time of enrolment. In univariate regression, age (odds ratio (OR) 1.612 per 10 years), ASA (III vs I/II: OR 3.217), TUG (OR 1.087), body height (OR 0.541 per 10cm), ECOG (1 vs 0 OR 2.326, 2-3 vs 0 OR 4.102), estimated ascites ( > 500cc vs. none OR 2.811), paracentesis (OR 1.991), platelets (upper limit of normal (ULN) vs norm or < lower limit of normal (LLN) OR 1.998), albumin ( < LLN vs norm or > ULN OR 2.053), creatinine ( > ULN vs norm OR 3.969) and baseline QoL single-item subscales appetite loss (“very much” vs “not at all” OR 2.611), constipation (“quite a bit” vs “not at all” OR 4.903), and multi-item subscales global health status (OR 0.982 per 1 point) and nausea/vomiting (OR 1.013 per 1 point) were significant (p < 0.05). Multiple logistic regression identified age (OR 1.459 per 10 years), ASA (III vs I/II: OR 2.427), constipation (“quite a bit” vs “not at all” OR 3.786) and global health (OR: 0.985 per 1 point) as independent predictors of progression or death within 10 months after primary diagnosis (p < 0.05). Conclusions: A significant proportion of aOC pts undergoing PDS > CTX are at high-risk for early failure. The finding of independent risk factors including self-ratings of QoL at time of diagnosis should be confirmed and tested against other models to facilitate a more tailored treatment of high-risk pts and design of future trials in aOC. Clinical trial information: NCT02828618.

TPS5611 Background: Paclitaxel or pegylated liposomal doxorubicin in combination with bevacizumab constitutes a standard treatment option in patients with relapsed ovarian cancer who are not considered candidate for platinum, but responses are short-lived. Immune checkpoint inhibitors like atezolizumab as single agents have limited activity in ovarian cancer. There is a biologic rationale to combine checkpoint inhibitors with chemotherapy and bevacizumab, however, the role of such combination for the management of ovarian cancer is so far undefined. Because of the intimate relationship between angiogenesis and immunosuppression, it is expected that the inhibition of both pathways could lead to synergism and more durable clinical benefit. The addition of a chemotherapeutic agent is expected to lead to the release of tumor antigens and enhance the efficacy of immunotherapy in turn. Therefore, we aim to test the efficacy of atezolizumab in combination with non-platinum-based chemotherapy and bevacizumab vs the combination of a non-platinum-based chemotherapy and bevacizumab alone. Methods: AGO-OVAR 2.29 is a randomized (1:1), double blinded, phase III trial evaluating the efficacy and safety of atezolizumab plus bevacizumab and chemotherapy (weekly paclitaxel or pegylated liposomal doxorubicin) compared with placebo plus bevacizumab and chemotherapy in patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer with 1st or 2nd relapse within 6 months after completing platinum-based chemotherapy or 3rd relapse. A de novo tumor biopsy to determine the PD-L1 expression status prior to randomization for stratification is mandatory. Patients are treated with chemotherapy plus bevacizumab + atezolizumab/placebo until progression or unacceptable toxicity. Co-primary endpoints are overall survival and progression-free survival. It is planned to randomize approximately 664 patients. Safety interim analyses were performed after inclusion of 24 and an additional 60 and 120 patients who had completed at least one treatment cycle. As of 09th February 2022, 461 patients have been randomized. Clinical trial information: NCT03353831.

ObjectivesPoor survival of high-grade serous pelvic cancer is caused by a lack of effective screening measures. The detection of exfoliated cells from high-grade serous pelvic cancer, or precursor lesions, is a promising concept for earlier diagnosis. However, collecting those cells in the most efficient way while fulfilling all requirements for a screening approach is a challenge. We introduce a new catheter for uterine and tubal lavage (UtL) and the clinical evaluation of its performance.Methods/MaterialsIn study I, the clinical feasibility of the UtL using the new catheter was examined in 93 patients admitted for gynecologic surgery under general anesthesia. In study II, the safety of the UtL procedure was assessed. The pain during and after the UtL performed under local anesthesia was rated on a visual analog scale by 22 healthy women.ResultsIn study I, the UtL was carried out successfully in 92 (98.9%) of 93 cases by 16 different gynecologists. It was rated as easy to perform in 84.8% of patients but as rather difficult in cancer patients (odds ratio, 5.559; 95% confidence interval, 1.434–21.546; P = 0.007). For benign conditions, dilatation before UtL was associated with menopause status (odds ratio, 4.929; 95% confidence interval, 1.439–16.884; P = 0.016). In study II, the pain during UtL was rated with a median visual analog scale score of 1.6. During a period of 4 weeks after UtL, none of the participants had to use medication or developed symptoms requiring medical attention. The UtL took 6.5 minutes on average. The amount of extracted DNA was above the lower limit for a sensitive, deep-sequencing mutation analysis in all cases.ConclusionsOur studies demonstrate that the UtL, using the new catheter, is a safe, reliable, and well-tolerated procedure, which does not require elaborate training. Therefore, UtL fulfils all prerequisites to be used in a potential screening setting.

Objective: The addition of maintenance olaparib to bevacizumab demonstrated a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). We evaluated maintenance olaparib plus bevacizumab in the Japan subset of PAOLA-1. Methods: PAOLA-1 was a randomized, double-blind, phase III trial. Patients received maintenance olaparib tablets 300 mg twice daily or placebo twice daily for up to 24 months, plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total. This prespecified subgroup analysis evaluated investigator-assessed PFS (primary endpoint). Results: Of 24 randomized Japanese patients, 15 were assigned to olaparib and 9 to placebo. After a median follow-up for PFS of 27.7 months for olaparib plus bevacizumab and 24.0 months for placebo plus bevacizumab, median PFS was 27.4 versus 19.4 months, respectively (hazard ratio [HR]=0.34; 95% confidence interval [CI]=0.11-1.00). In patients with tumors positive for homologous recombination deficiency, the HR for PFS was 0.57 (95% CI=0.16-2.09). Adverse events in the Japan subset were generally consistent with those of the PAOLA-1 overall population and with the established safety and tolerability profiles of olaparib and bevacizumab. Conclusion: Results in the Japan subset of PAOLA-1 support the overall conclusion of the PAOLA-1 trial demonstrating that the addition of maintenance olaparib to bevacizumab provides a PFS benefit in patients with newly diagnosed, advanced ovarian cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02477644

Objective Recurrent ovarian cancer is an incurable disease with variable but poor prognosis. Health-related quality of life (HRQoL) is a patient-reported outcome measure generally applied to measure effects of therapies. Our aim was the development and validation of a risk score for the prediction of short-term mortality using the combination of sociodemographic and clinical factors and HRQoL. Methods For exploratory and validation analysis, the North-Eastern German Society of Gynecological Oncology (NOGGO) and Working Group Gynecological Oncology (AGO) study databases were screened for trials. Only trials which obtained defined HRQoL measurements were included in the final analysis. Multivariable logistic regression analyses were used to identify risk factors and their weighting for the risk score. Modulation with cubic regression analyses revealed median survival and short-term mortality defined as 1-year mortality for each value. Results For exploration, 974 patients from three clinical studies of the NOGGO and for validation, 1235 patients from several clinical studies of the AGO were eligible. The risk score included platinum-free interval, performance status, age, global QoL and nausea/vomiting. Receiver operating characteristic analysis showed a good predictive value with an area under the curve of 0.81 for model 1 in the exploration and 0.74 in the validation. Short-term mortality in model 1 was 8.2%, 23.5% and 58.4% in the exploration sample, and 19.7%, 38.1% and 63.4% in the validation sample for patients under low, medium and high risk, respectively. Conclusions This risk score discriminates well between recurrent ovarian cancer patients under low, medium and high risk of short-term mortality. It may help to identify a risk group under high risk for short-term mortality that can be used for randomization in clinical trials and may support decision making for palliative chemotherapy., Highlights • This newly developed NOGGO-AGO QoL prognosis score clearly discriminates recurrent ovarian cancer (rOC) patients under low, medium and high risk for short-term survival (

Simple Summary Most ovarian cancer patients initially show a response to primary treatments, but the development of refractory disease is a major problem. Currently, there are no blood-based prognostic biomarkers, and the prognosis of a patient is determined by the International Federation of Gynecology and Obstetrics (FIGO) stage and residual disease after cytoreductive surgery. In this study, we developed and validated a novel test based on the ratio of two circulatory lipids that enables the prognostic stratification of ovarian cancer patients at the time of diagnosis, prior to any oncological treatments. The translational relevance of this test is to find those patients with poor prognosis early on, and to identify patients that are at high risk of recurrence despite complete cytoreduction. Thus, the test enables the early direction of novel targeted therapies to those ovarian cancer patients at greatest risk of recurrence and death. Epithelial ovarian cancer (EOC) generally responds well to oncological treatments, but the eventual development of a refractory disease is a major clinical problem. Presently, there are no prognostic blood-based biomarkers for the stratification of EOC patients at the time of diagnosis. We set out to assess and validate the prognostic utility of a novel two-lipid signature, as the lipidome is known to be markedly aberrant in EOC patients. The study consisted of 499 women with histologically confirmed EOC that were prospectively recruited at the university hospitals in Turku (Finland) and Charite (Berlin, Germany). Lipidomic screening by tandem liquid chromatography-mass spectrometry (LC-MS/MS) was performed for all baseline serum samples of these patients, and additionally for 20 patients of the Turku cohort at various timepoints. A two-lipid signature, based on the ratio of the ceramide Cer(d18:1/18:0) and phosphatidylcholine PC(O-38:4), showed consistent prognostic performance in all investigated study cohorts. In the Turku cohort, the unadjusted hazard ratios (HRs) per standard deviation (SD) (95% confidence interval) were 1.79 (1.40, 2.29) for overall and 1.40 (1.14, 1.71) for progression-free survival. In a Charite cohort incorporating only stage III completely resected patients, the corresponding HRs were 1.59 (1.08, 2.35) and 1.53 (1.02, 2.30). In linear-mixed models predicting progression of the disease, the two-lipid signature showed higher performance (beta per SD increase 1.99 (1.38, 2.97)) than cancer antigen 125 (CA-125, 1.78 (1.13, 2.87)). The two-lipid signature was able to identify EOC patients with an especially poor prognosis at the time of diagnosis, and also showed promise for the detection of disease relapse.

The collection of a peritoneal cytologic sample at the time of surgery for endometrial cancer has traditionally been an important part of surgical staging. In 2009, the International Federation of Gynecology and Obstetrics revised the cancer staging schema for endometrial cancer and removed peritoneal cytology from the staging criteria. The current National Comprehensive Cancer Network guidelines and the International Federation of Gynecology and Obstetrics organization, however, recommend evaluation of peritoneal cytology at the time of hysterectomy. This study examined population-based trends, characteristics, and outcomes of peritoneal cytologic sampling for endometrial cancer surgery following the 2009 staging revision in the United States.This is a retrospective observational study querying the Surveillance, Epidemiology, and End Results Program to examine women with stage I-III endometrial cancer who underwent hysterectomy from 2010 to 2017. Trends, characteristics, and survival associated with peritoneal cytologic evaluation at the time of hysterectomy were assessed in multivariable analysis and with propensity score weighting.Among 62,809 women who underwent hysterectomy, 43,873 (69.9%) had peritoneal cytologic evaluation at surgery and 18,936 (30.1%) did not. Utilization of peritoneal cytologic evaluation decreased from 75.5% to 64.9% during the study period (P 0.001). In multivariable analysis, more recent year of surgery was independently associated with a decreased likelihood of performance of peritoneal cytology (adjusted-odds ratio of peritoneal cytology evaluation in 2017 versus 2010 0.56, 95% confidence interval [CI] 0.52-0.60). Peritoneal cytologic evaluation at the time of hysterectomy was associated with improved all-cause mortality (hazard ratio in the whole cohort 0.94, 95%CI 0.89-0.99; and hazard ratio in endometrioid histology 0.90, 95%CI 0.84-0.97).Performance of peritoneal cytologic sampling has gradually decreased following the 2009 staging revision in the United States. Our study suggests that peritoneal cytology evaluation at hysterectomy may be associated with improved survival in certain tumor groups.

Objectives: In 2009, the International Federation of Gynecology and Obstetrics revised 30 cancer staging schema for endometrial cancer and removed peritoneal cytology from the staging criteria. This study examined population-based trends, characteristics, and outcomes of peritoneal cytologic sampling for endometrial cancer surgery following the 2009 staging revision in the United States. Methods: This is a retrospective observational study querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program to examine women with stage I-III endometrial cancer who underwent hysterectomy from 2010-2017. Trends, characteristics, and survival associated with peritoneal cytologic evaluation at the time of hysterectomy were assessed in multivariable analysis and with propensity score weighting. Results: Among 62,809 women who underwent hysterectomy, 43,873 (69.9%) had peritoneal cytologic evaluation at surgery and 18,936 (30.1%) did not. Utilization of peritoneal cytologic evaluation decreased from 75.5% to 64.9% during the study period (P Download : Download high-res image (94KB) Download : Download full-size image Conclusions: Despite guideline recommendations, performance of peritoneal cytologic sampling has gradually decreased following the 2009 staging revision in the United States. Our study suggested that peritoneal cytology evaluation at hysterectomy may be associated with improved survival in endometrial cancer.

We evaluated the clinical impact of germline (g)BRCA1/2-mutation on initial disease presentation, surgical implications, surgical morbidity and survival in patients with advanced epithelial ovarian cancer (EOC) undergoing debulking surgery (DS).Data of all consecutive EOC patients with stage III/IV, high-grade serous disease and known gBRCA1/2 status (gBRCA; non-gBRCA), who underwent DS at our department between 01/2011 and 06/2019 were analyzed. Associations between gBRCA-status and severe postoperative complications and survival were analyzed.gBRCA-status was determined in 50.1% (612/1221) of all patients. gBRCA was present in 21.9% (134/612). Significant differences were observed in terms of median age (p = 0.001) and histology (high-grade serous histology gBRCA: 98.5%, non-gBRCA 76.2%; p 0.001). gBRCA-status had no impact on intraoperative disease presentation, surgical complexity or complete resection rate (gBRCA: 74.4%, non-gBRCA: 69.0%; p = 0.274). gBRCA-status was not predictive for severe postoperative complication (gBRCA: 12.0%, non-gBRCA: 19.1%; p = 0.082). Median PFS and OS was 31/22 and 71/53 months in patients with/without gBRCA-mutation, respectively. gBRCA was a significant prognostic factor for PFS (HR 0.57 p 0.001) and for OS (HR 0.64, p = 0.048) after adjusting for established prognostic factors.gBRCA-status had no impact on initial disease presentation, surgical results or postoperative complications. gBRCA patients have a significantly longer PFS but the impact on the long term prognosis is unclear. Complete resection remains the most important prognostic factor in patients with EOC independent of gBRCA-status.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

Objective: The therapeutic role of pelvic and para-aortic lymphadenectomy in surgical staging of apparent early-stage epithelial ovarian cancer (eEOC) is still under debate. The aim of this study was to evaluate the potential therapeutic role of systematic lymphadenectomy in patients with eEOC. Methods: Multi-center retrospective cohort study, comparing women with apparent eEOC who underwent comprehensive bilateral pelvic and para-aortic lymphadenectomy (defined as ≥20 lymph nodes) versus patients receiving no lymphadenectomy or lymph node sampling, from 05/1985 to 12/2016. Patients with bulky nodes at CT-scan and those without complete intra-peritoneal surgical staging were excluded. Only patients who received at least 3 cycles of platinum-based adjuvant chemotherapy were included. Results: Out of 2559 patients with FIGO stage IA-IIIA1 ovarian cancer, 639 (25.0%) met inclusion criteria. 360 (56.3%) underwent comprehensive lymphadenectomy, 150 (23.5%) lymph node sampling and 129 (20.2%) no lymphadenectomy. Patients who underwent comprehensive lymphadenectomy were younger (p < 0.001), experienced a higher number of severe post-operative complications (p = 0.008) and had a longer time to start chemotherapy (p = 0.034). There was no difference in intra-operative complications. Median follow-up was 63 months (range, 5–342). The 5-year disease-free survival (DFS) was 79.7% vs. 76.5% vs. 68.3% (p = 0.006), and 5-year overall survival (OS) was 92.3% vs. 94.5% vs. 89.8% (p = 0.165) in women who received comprehensive lymphadenectomy vs. lymph node sampling vs. no lymphadenectomy, respectively. Lymphadenectomy represented an independent factor for DFS improvement, HR 0.52 (95%CI 0.37–0.73) (p < 0.001). Conclusion: Pelvic and para-aortic lymphadenectomy in surgical staging of eEOC improves DFS for the price of increasing post-operative complications and time to chemotherapy but does not affect OS. Better understanding of tumor biology may help to identify those patients in whom lymphadenectomy should still play a role.

Background PAOLA1 is a phase III study assessing olaparib maintenance therapy in advanced high-grade ovarian carcinoma patients responding to first-line platinum-taxane–based chemotherapy plus bevacizumab as standard of care. Randomization was stratified by treatment outcome and tumor BRCA1/2 status (tBRCA) at screening. Methods tBRCA was tested on formalin-fixed, paraffin-embedded tumor blocks on 5 French platforms using 2 next-generation sequencing methods based either on hybrid capture or amplicon technology. One of the exploratory objectives was to assess the concordance between germline (gBRCA) and tBRCA testing in French patients. gBRCA testing was performed on blood samples on the same platforms. Results From May 2015 to July 2017, tBRCA tests were performed for 1176 screened patients. Only 52 (4.4%) tumor samples were noncontributive. The median interval between reception of the tumor sample and availability of the tBRCA status result was 37 days (range = 8-260). A pathogenic variant was reported in 27.1% tumor samples (319 of 1176 screened patients). tBRCA and gBRCA testing were performed for 451 French patients with negative results for both tests in 306 patients (67.8%) and positive results for both tests in 85 patients (18.8%). Only 1 large genomic rearrangement of BRCA1 was detected, exclusively in the blood sample. Interestingly, tBRCA testing revealed 6.4% of pathogenic variant (29 of 451) not detected by gBRCA testing. Conclusions tBRCA testing is an appropriate tool with an acceptable turnaround time for clinical practice and a low failure rate, ensuring reliable identification of patients likely to benefit from poly(ADP-ribose) polymerase inhibitor therapy.

Inhibidors de PARP; Càncer d’ovari avançat Inhibidores de PARP; Cáncer de ovario avanzado PARP inhibitors; Advanced ovarian cancer Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with BRCA1/2 mutation, establishing a new standard of care. Subsequently, the results of three phase III trials (PRIMA, PAOLA-1, VELIA) evaluating the use of first-line PARP inhibitors beyond patients with BRCA1/2 mutations and as combination strategies were presented in 2019, leading to the recent approval of maintenance niraparib irrespective of biomarker status and olaparib in combination with bevacizumab in homologous recombination deficiency-positive-associated advanced ovarian cancer. An ESMO Open - Cancer Horizons round-table expert panel discussed the four phase III trials of first-line PARP inhibitor therapy and how they are changing the clinical management of advanced ovarian cancer. The project is supported by an unrestricted educational grant from AstraZeneca. The authors received an honorarium for their participation in the round table from BMJ.

Introduction/Background Malignant ovarian germ cell tumours (OGCT) account for about five percent of all ovarian malignancies in Western countries. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) has established a clinicopathological (Current Ovarian geRm cell and SEx cord stromal Tumour Treatment strategies, CORSETT) database for a better documentation and understanding of this rare disease. Here, we present the first descriptive analysis for patients with confirmed OGCT from the CORSETT database. Methodology 20 German centres entered mixed retro- and prospective data of OGCT patients with histology specimens available treated between 2000 to 2014 into the CORSETT database. An independent CORSETT pathology reference panel checked the primary histological diagnosis. We conducted a descriptive analysis of the treatment strategies and created Kaplan-Meier curves and cox regression analyses for the survival analysis. Results The reference pathology panel diagnosed 36 patients with dysgerminoma (FIGO stage I = 77.8%), 20 patients with mixed OGCT (FIGO stage I = 66.7%) and 21 with malignant teratoma (FIGO stage I = 85%). The median age of patients with dysgerminoma was 30.2 years (mixed OGCT: 35.6 and teratoma 36.4 years). 23 of dysgerminoma (63.8%), six of mixed OGCT (31.6%) and eight of teratoma (38.1%) patients were treated with laparoscopy and the tumour ruptured intraoperatively in 21% (dysgerminoma, mixed OGCT: 50%, teratoma: 22%) of the cases. 29 dysgerminoma (85.6%), 15 mixed OGCT (78.9%) and 17 teratoma (85%) patients received fertility-sparing surgery. 20 of dysgerminoma (57%), 14 of mixed OGCT (70%) and 11 of teratoma (55%) patients received adjuvant chemotherapy which decreased the likelihood of disease recurrence significantly in mixed OGCT patients to the highest degree (hazard ratio = 0.21, 95% confidence interval 0.04 – 0.97). In total, two dysgerminoma (4.6%), nine mixed OGCT (45%) and three teratoma (14.3%) patients experienced disease recurrence. The median progression-free and overall survival was not reached in the total cohort of OGCT patients. Conclusion In this analysis, OGCT patients had an excellent prognosis despite non-negligible rates of intraoperative tumour spillages. Adjuvant chemotherapy appeared to prevent disease recurrence. Disclosures

Introduction/Background Women with BRCA1 and 2 mutation are at increased risk for developing ovarian and breast cancer. Risk-reducing salpingo-oophorectomy (RRSO) can be offered to these women to minimize their risk. The pathologic sectioning and extensively examining the fimbriated end (SEE-FIM)-protocol is applied by the pathologist to detect premalignant lesions and early stage cancer. The rate of occult serous tubal intraepithelial carcinoma (STIC) lesions and ovarian cancer in this RRSO-population ranges between 0.6–10.0%. The prevalence of pathogenic lesion in RRSO is clinically relevant. Methodology All consecutive patients with a pathogenic mutation (BRCA1/2, RAD51C, Lynch gene mutation, PALB2, BRIP1) who underwent RRSO between 11/2011 and 05/2020 in our Department of Gynecologic Oncology at Kliniken-Essen-Mitte were assessed from our prospectively managed database. All specimens were analysed according to the SEE-FIM-protocol. Results In total, 241 women underwent RRSO of whom 216 were included in the final analysis. Median age was 48 years (range 22–79). 134 (62.0%) women had breast cancer in their past medical history. Family history showed breast and ovarian cancer in 104 (48.1%) and 49 patients (22.7%). BRCA1 mutation was underlying in 121 (56.0%) patients, whereas 64 (29.6%) patients had a BRCA2 mutation, 22 women (10.2%) an unknown mutation status. Nine patients (4.2%) presented with a RAD51C, Lynch gene, PALB2, or BRIP1 mutation. Most patients (99.1%) underwent minimal invasive surgery. Incidental findings of a STIC lesion and/or ovarian cancer was detected in 7 (3.2%) and 5 (2.3%) patients. Median age of those 12 women was 56 years (range 44–79) and all underwent a staging surgery. Final histopathological results showed high grade serous ovarian cancer in 5 patients: FIGO IA (n=1), FIGO IB (n=1), FIGO IC (n=1), FIGO IIA (n=1), FIGO IIIC (n=1). Seven women had STIC lesions. All patients with ovarian cancer had a BRCA1 mutation and one patient even had a BRCA1 and RAD51C mutation. Of all STIC patients five (71.4%) had a BRCA1 and two (28.6%) had a RAD51C mutation. Conclusion Our results of incidental STIC/ovarian cancer findings confirm the results published in the literature. RRSO is highly recommended in mutation carriers. Genetic counselling and testing need to be routinely offered to family members of mutation gene carriers. It is from tremendous importance to raise awareness that in women at high risk, the development of premalignant neoplasms and malignancies can be prevented. Timing of RRSO should be independent of age and promptly after completion of family planning. Disclosures SE received non-financial support from Tesaro, outside the submitted work. JPR has no conflict of interest to declare. AdB reports personal fees from Roche, Astra Zeneca, Tesaro, Clovis, Pfizer, Genmab, Pharmar, and Biocad, outside the submitted work. PH reports grants and personal fees from Astra Zeneca and Roche, personal fees from Sotio, grants and personal fees from Tesaro and GSK, personal fees from Stryker,Zai Lab, and MSD, grants from Public funding (DKH, DFG, EU), personal fees from Clovis, andImmunogen, grants from Boehringer Ingelheim, Medac, and Genmab, outside the submitted work. SS reports personal fees from Roche, Astra Zeneca, personal fees and travel grants from GSK/Tesaro, personal fees from Clovis and travel grants from Pharmamar, outside the submitted work. TB has been an advisor for Tesaro and received research grant from Amgen, non-financial support from Amgen, MSD, Roche, and Tesaro, outside the submitted work. AT, SH, NP have no conflicts of interest do declare. BA reports personal fees and non-financial support from Roche, personal fees from Amgen and Astra Zeneca, personal fees and non-financial support from Tesaro, personal fees from Clovis and Celgene, non-financial support from PharmaMar, outside the submitted work.

Introduction/Background The 3-Tier Chemotherapy Response Score (CRS) was developed to quantify the response after neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer patients undergoing interval debulking surgery. CRS3 (optimal response) identifies patients with a longer progression-free (PFS) and overall survival (OS) compared to patients with a CRS1/2 (no or minimal response/partial response). We critically evaluated the clinical value of CRS and compared its predictive power to standard serological (CA125) and radiological response in patients with advanced epithelial ovarian cancer. Methodology A retrospective analysis of 277 patients, who received primary chemotherapy for advanced epithelial ovarian cancer was performed. CRS, serological, and radiological findings, and pathological complete remission (pCR) were correlated to PFS and OS. Results Only 62.1% (172/277) patients treated with NACT could be assessed by CRS, as the CRS score can only be determined in patients that undergo interval debulking surgery, have a representative biopsy of the omentum, and have tumours with a high-grade serous histology. In patients with CRS3 (n=50) a longer median PFS and OS was observed compared to patients with CRS1/2 (n=122) (31.2 vs. 18.9, P In the total study cohort, serological and radiological complete response was better at predicting PFS (hazard ratio 2.23 and 2.77). Radiological complete response was better at predicting OS (hazard ratio 2.34). Conclusion In this study, evaluation of response to chemotherapy by CRS was not superior to conventional methods (CA125 or radiology). Independent of the used evaluation method, response to NACT was predictive of PFS and OS. Conventional methods should even be considered more clinically relevant, as these can be applied to all ovarian cancer patients receiving upfront chemotherapy, while only 62% of patients in our cohort could be assessed by CRS. Conventional response assessment, based on radiology and/or CA125, is used to evaluate whether a patient should be offered IDS and can, similar to CRS, be used to predict PFS and OS. As CRS has no influence on the treatment of patients undergoing NACT for ovarian cancer, the added value of response assessment using CRS is negligible. Disclosures JPR has no conflict of interest to declare. TB has been an advisor for Tesaro and received research grant from Amgen, non-financial support from Amgen, MSD, Roche, and Tesaro, outside the submitted work. MLM, AT, KUW, SH have no conflict of interest to declare. PH reports grants and personal fees from Astra Zeneca and Roche, personal fees from Sotio, grants and personal fees from Tesaro and GSK, personal fees from Stryker, Zai Lab, and MSD, grants from Public funding (DKH, DFG, EU), personal fees from Clovis, and Immunogen, grants from Boehringer Ingelheim, Medac, and Genmab, outside the submitted work. AdB reports personal fees from Roche, Astra Zeneca, Tesaro, Clovis, Pfizer, Genmab, Pharmar, and Biocad, outside the submitted work.

Despite an increasing incidence with simultaneous decreasing age of onset, vulvar squamous cell carcinoma (VSCC) is still a disease that mainly effects the elderly population. Data on the association of age with prognosis and treatment patterns in VSCC are sparse.This is an analysis of the AGO-CaRE-1 cohort. Patients with VSCC (FIGO stage ≥1B), treated at 29 cancer centers in Germany from 1998 to 2008, were included in a centralized database (n = 1618). In this subgroup analysis patients were analyzed according to age [50 yrs. (n = 220), 50-69 yrs. (n = 506), ≥70 yrs. (n = 521)] with regard to treatment patterns and prognosis. Only patients with documented age, surgical groin staging and known nodal status were included (n = 1247). Median follow-up was 27.5 months.At first diagnosis, women ≥70 yrs. presented with more advanced tumor stages (0.001), larger tumor diameter (0.001), poorer ECOG status (0.001), more frequent HPV negative tumors (p = 0.03) as well as a higher rate of nodal involvement (0.001). Disease recurrence occurred significantly more often in elderly patients (p = 0.001) and age as well as ECOG status, microscopic residual resection, tumor stage, grading, and (chemo)radiation were independent prognostic factors for death or recurrence in multivariate analysis. 2-year disease-free survival rates were 59.3% (≥70 yrs), 65.8% (50-69 yrs) and 81.1% (50 yrs), respectively (p 0.001).Older women with VSCC present with advanced tumor stages at first diagnosis and have an increased risk of recurrence as well as a decreased 2-year DFS in comparison to younger patients. Potential reasons could be self-awareness and/or more aggressive tumor biology due to HPV independent disease.

The aim of this study was to examine the survival effect of adjuvant therapy in stage II-III endometrial cancer based on peritoneal cytology results.The National Cancer Institute's Surveillance, Epidemiology, and End Results Program was retrospectively queried to examine 7467 women with stage II-III endometrial cancer who underwent hysterectomy, and with available peritoneal cytology results, from 2010 to 2016. A Cox proportional hazard regression model was fitted to assess the association between adjuvant therapy and all-cause mortality stratified by peritoneal cytology results.Malignant peritoneal cytology was reported in 1662 (22.3%) women and was associated with non-endometrioid histology, higher tumor stage, and nodal metastasis (p 0.05). In a propensity score-weighted model, malignant peritoneal cytology was associated with increased all-cause mortality compared with negative peritoneal cytology (hazard ratio 1.35, 95% confidence interval 1.23-1.48). Adjuvant therapy types varied based on histology and peritoneal cytology results. In non-endometrioid histology, the combination of chemotherapy and whole pelvic radiotherapy (WPRT) was associated with improved overall survival compared with chemotherapy or WPRT alone irrespective of the peritoneal cytology results (p 0.05). The combination of chemotherapy and WPRT was also associated with improved overall survival in women with endometrioid histology and malignant peritoneal cytology (p = 0.026). Women with endometrioid histology and negative peritoneal cytology represented the most common subpopulation (46.5%), and overall survival was similar regardless of which of the three adjuvant therapy modalities was used (p = 0.319).Malignant peritoneal cytology is prevalent and prognostic in stage II-III endometrial cancer. This study found that the surgeon's choice and benefit of adjuvant therapy for women with stage II-III endometrial cancer differed depending on the status of peritoneal cytology.

Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with BRCA1/2 mutation, establishing a new standard of care. Subsequently, the results of three phase III trials (PRIMA, PAOLA-1, VELIA) evaluating the use of first-line PARP inhibitors beyond patients with BRCA1/2 mutations and as combination strategies were presented in 2019, leading to the recent approval of maintenance niraparib irrespective of biomarker status and olaparib in combination with bevacizumab in homologous recombination deficiency-positive-associated advanced ovarian cancer. An ESMO Open - Cancer Horizons round-table expert panel discussed the four phase III trials of first-line PARP inhibitor therapy and how they are changing the clinical management of advanced ovarian cancer.

6000 Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (ROC) has been under debate for decades. A recent trial in unselected patients (pts) failed to show an OS benefit. Methods: Pts with ROC and 1st relapse after 6+ months (mos) platinum-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were prospectively randomized to second-line chemotherapy alone vs. cytoreductive surgery followed by the same chemotherapy; platinum combination therapy was recommended. OS was primary endpoint in this superiority trial. Results: 407pts were randomized 2010-2014. The TFIp exceeded 12 mos in 75% of pts. 206 pts were allocated to the surgery arm of whom finally 187 (91%) were operated. A complete resection was achieved in 75%; almost 90% in both arms received a platinum-containing second-line chemo. Primary endpoint analysis showed median OS of 53.7 mos with and 46.2 mos without surgery (HR 0.76, 95%CI 0.59-0.97, p=0.03); median PFS was 18.4 and 14 mos (HR: 0.66, 95%CI 0.54-0.82, p

Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 × 10−7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.