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Background: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status. Patients and methods: Patients were randomized 2: 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis. Results: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms. Conclusions: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure. in press

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer. ispartof: ANNALS OF ONCOLOGY vol:33 issue:3 pages:276-287 ispartof: location:England status: published

BACKGROUND: Treatment for patients with recurrent ovarian cancer has been mainly based on systemic therapy. The role of secondary cytoreductive surgery is unclear. METHODS: We randomly assigned patients with recurrent ovarian cancer who had a first relapse after a platinum-free interval (an interval during which no platinum-based chemotherapy was used) of 6 months or more to undergo secondary cytoreductive surgery and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Patients were eligible if they presented with a positive Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score, defined as an Eastern Cooperative Oncology Group performance-status score of 0 (on a 5-point scale, with higher scores indicating greater disability), ascites of less than 500 ml, and complete resection at initial surgery. A positive AGO score is used to identify patients in whom a complete resection might be achieved. The primary end point was overall survival. We also assessed quality of life and prognostic factors for survival. RESULTS: A total of 407 patients underwent randomization: 206 were assigned to cytoreductive surgery and chemotherapy, and 201 to chemotherapy alone. A complete resection was achieved in 75.5% of the patients in the surgery group who underwent the procedure. The median overall survival was 53.7 months in the surgery group and 46.0 months in the no-surgery group (hazard ratio for death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.02). Patients with a complete resection had the most favorable outcome, with a median overall survival of 61.9 months. A benefit from surgery was seen in all analyses in subgroups according to prognostic factors. Quality-of-life measures through 1 year of follow-up did not differ between the two groups, and we observed no perioperative mortality within 30 days after surgery. CONCLUSIONS: In women with recurrent ovarian cancer, cytoreductive surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone. (Funded by the AGO Study Group and others; DESKTOP III ClinicalTrials.gov number, NCT01166737.).

Introduction/Background* This study determined whether online continuing medical education (CME) could improve the knowledge of obstetricians/gynaecologists (obs/gyns) and oncologists (oncs) regarding the relevance of Microsatellite Instability (MSI) and deficient Mismatch Repair (dMMR) for immunotherapy paradigms in advanced endometrial cancer, and increase competence in terms of the application of appropriate diagnostic testing. Methodology A 15-minute online video discussion between two expert faculty was launched for physicians outside the USA October 2020 with data collected to March 2021. Educational effect assessed with repeated-pairs pre-/post-activity- individual participants serving as their own control. 3 multiple-choice, knowledge questions and 1 self-efficacy, 5-point Likert scale confidence question were analysed. McNemar’s test assessed pre- to post-activity change (5% significance level, P .80=Large. Result(s)* 393 obs/gyns and 73 oncs completed pre- and post-activity questions. Positive educational effect was observed for obs/gyns (moderate effect, Cohen’s d=.78, P Conclusion* This on-demand, online video discussion resulted in a positive educational impact. However, education gaps remain evident. Online medical education is valuable in supporting the implementation of new diagnostic strategies into clinical practice as well as identifying areas of continued educational need.

Introduction/Background The receptor activator of nuclear factor-κB (RANK) pathway, activated by RANK ligand (RANKL), critically controls bone metabolism and modulates tumour immune response. Denosumab, a neutralizing RANKL antibody, exerts tumour-suppressive effects in mice and humans. Herein, the relevance of RANK signalling was investigated for the first time in human ovarian cancer (OC). Methodology RANK, RANKL and OPG expression of 192 epithelial OCs and 12 non-malignant fallopian tubes was related to clinico-pathological characteristics. Regulation of RANK constituents was studied in four OC cell lines and the impact of RANK ligation or denosumab treatment on cell viability was determined. Results In OC, RANK constituents (RANK, RANKL and OPG) were expressed in epithelial and stromal cells. RANKL (but not RANK) expression was elevated in OC tissue, particularly in BRCA1/2 mutated tumours and correlated with BRCA2 expression. RANKL expression independently predicted progression free and overall survival. Expression of RANK constituents in OC cells was induced by inflammatory cytokines such as IL-1β and TNFα. However, neither RANK ligation nor denosumab treatment influenced OC cell viability. Conclusion This study links RANKL expression independently to patient‘s outcome in OC and implicates RANK signalling in the pathogenesis and the inflammatory response of OC. Denosumab may prove efficacious in OC. Disclosure Nothing to disclose.

Introduction/Background Mutations in cancer susceptibility genes BRCA1/2 are considered to be associated with better survival in ovarian cancer (OC) patients possibly due to a better response to platinum based chemotherapy and PARP inhibitors. However, the impact of the BRCA1/2 mRNA-expression is not well characterized in OC, but could also influence the platinum response and thus predict the clinical outcome in OC patients. Our previous studies have shown that low BRCA1-expression was associated with favorable overall survival (OS) and low BRCA2-expression with better progression-free survival (PFS) and OS in 201 OC patients. The aim of the present study was to validate the prognostic impact of BRCA expression in OC using the TCGA (The Cancer Genome Atlas) cohort. Methodology Clinical and genomic data were obtained from the OC Dataset of The Cancer Genome Atlas (n=581). Overall and progression free survival was estimated using Kaplan-Meier plots and Cox-Regression. Optimal cut off points were defined using Youden index. Results Univariate survival analysis showed that low BRCA2 expression was associated with favorable PFS (p=0.029) and OS (p=0.011). Multivariable survival analysis confirmed the prognostic value of BRCA2 expression both for PFS and OS. Conclusion Low expression of BRCA2 predicts better survival in patients with OC. Our findings may reflect higher platinum-sensitivity due to reduced capacity of DNA damage repair in tissues with low BRCA2 expression. In this context, especially in BRCA-wildtype cancers BRCA2 expression could also be potential predictor for PARP sensitivity. Disclosure Nothing to disclose.

Introduction/Background The SWI/SNF complex - a chromatin remodelling complex - is recurrently mutated and inactivated in ∼20% of human cancers. Mutations of the SMARCA4 gene, which encodes the ATPase of the SWI/SNF complex, can be found in the majority of small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT). EZH2 is the catalytic subunit of the PCR2 complex, which is an opponent of the SWI/SNF complex. EZH2 inhibitors could play a potential role in the therapy of SCCOHT. The aim of this study was to explore the role of SMARCA4 mRNA-expression in ovarian cancer. Methodology SMARCA4 mRNA-expression was investigated in 20 non-neoplastic fallopian tubes and 276 ovarian carcinomas (OC) (including 144 high grade serous ovarian carcinomas, HGSOC) in relation to their clinical characteristics, p53- and BRCA1/2- mutational status, BRCA1/2 mRNA-expression and EZH2 mRNA-expression. Results The SMARCA4 mRNA-expression in OCs was significantly higher compared to the control group (P A subgroup-analysis of HGSOC showed higher SMARCA4-expression in patients younger than 65 years (P=0,021), in patients without residual disease after surgical debulking (P=0,008) and in patients with early FIGO stages I-II (P=0,004). High SMARCA4-expression was associated with better progression-free survival (PFS) (P=0,05) and better overall survival (OS) (P=0,002). Patients with p53-mutations showed higher SMARCA4-expression (P=0,004). There was a significant correlation between the expression of SMARCA4 and EZH2 (P=0,000 r=0,377). Multivariate Cox-regression model revealed independency of the prognostic value of SMARCA4-expression for OS in patients under the age of 65 years (P=0,015). Conclusion High SMARCA4-expression in patients with HGSOC is associated with younger age at onset of disease, early FIGO stage and with absence of residual disease after primary debulking. In patients younger than 65 years, high SMARCA4-expression is independently associated with better overall survival. Disclosure Nothing to disclose.

Introduction/Background The tumor suppressor miR-34 family is transcriptionally induced by p53. Clinical significance of the various miR-34 family members has not been studied in ovarian cancer. Methodology In 228 ovarian cancers and in 19 non-neoplastic fallopian tube samples we analysed miR-34a/b/c expression in relation to clinicopathological characteristics and clinical outcome. Results We found significantly lower levels of miR-34a/b/c in ovarian cancers as compared to control-tissues (P=0.002, P Conclusion Our findings suggest that downregulation of miR-34 family is a crucial part in ovarian cancer development. Low miR-34 levels are linked to a worse overall survival and progression free survival and may indicate a more aggressive disease. Disclosure Nothing to disclose.

Objectives Low-grade serous ovarian carcinomas (LGSOC) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30–60% of LGSOC. A phase II study of the MEK inhibitor selumetinib showed promising response rate of 15% in LGSOC and binimetinib, a potent MEK1/2 inhibitor, has demonstrated activity across multiple cancers. Methods MILO (MEK-Inhibitor in Low-grade Serous Ovarian Cancer)/ENGOT-ov11 was an open-label, 2:1-randomized study of binimetinib (45-mg BID) vs PCC in LGSOC. Eligible patients had recurrent or persistent measurable LGSOC following ≥1 prior platinum-based chemotherapy, ≤3 prior chemotherapy lines, and no prior MEK-or BRAF-inhibitor. The primary endpoint was progression-free survival (PFS) by blinded central review; additional assessments: overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety.(NCT01849874). Results 303 patients were randomized (201 binimetinib,102 PCC). Median PFS was 9.1 months (95% CI:7.3,11.3) for binimetinib and 10.6 months (95% CI:9.2,14.5) for PCC (HR:1.21(0.79,1.86);closed early for futility). Secondary efficacy endpoints were similar in the two groups: ORR 16%(complete/partial responses[CR/PRs]=32) vs 13%(CR/PRs=13); median DOR 8.1 (range:0.3–12.0+ months) vs 6.7 (0.3–9.7+ months); and median OS 25.3 vs 20.8 months, for binimetinib and PCC, respectively. Safety results were consistent with known safety profile of binimetinib; most common ≥grade 3 events were blood CK increased(20%) and hypertension(20%). Post-hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Conclusions Although MILO did not meet its primary endpoint, binimetinib showed activity in LGSOC across the efficacy endpoints evaluated. Chemotherapy responses were higher than predicted. Further evaluation is warranted.

Summary Background Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations. Methods We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial ( NCT00003636 ) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic. Findings Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0–9·6; EORTC, 9·2 years [IQR 7·3–10·4]; CHORUS, 5·9 years [IQR 4·3–7·4]). Median age was 63 years (IQR 56–71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8–13·0). 55 (5%) women had FIGO stage II–IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1–51·3] and 26·9 months [12·7–50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86–1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7–53·7) and 23·6 months (10·5–46·9), respectively (HR 1·20, 95% CI 1·06–1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1–47·6] and 21·2 months [10·0–36·4], respectively; HR 0·76, 95% CI 0·58–1·00; p=0·048; median progression-free survival 10·6 months [7·9–15·0] and 9·7 months [5·2–13·2], respectively; HR 0·77, 95% CI 0·59–1·00; p=0·049). Interpretation Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC–IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status. Funding National Cancer Institute and Vlaamse Liga tegen kanker (Flemish League against Cancer).