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In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial. Eligible patients for the TH3RESA trial were men and women (aged ≥18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting. Patients had to have an Eastern Cooperative Oncology Group performance status of 0–2, left ventricular ejection fraction of at least 50%, and adequate organ function. Patients were randomly assigned (2:1) by an interactive voice and web response system with permuted block randomisation in blocks of six to receive trastuzumab emtansine (3·6 mg/kg intravenously every 21 days) or treatment of physician's choice administered per local practice. Randomisation was stratified by world region, number of previous regimens for advanced breast cancer, and presence of visceral disease. On Sept 12, 2012, the study protocol was amended to allow patients with disease progression to crossover from treatment of physician's choice to trastuzumab emtansine. The coprimary endpoints for TH3RESA were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. We report results from a preplanned second interim analysis of overall survival, which was planned for when approximately 67% (n=330) of 492 expected deaths had occurred. This study is registered with ClinicalTrials.gov, number NCT01419197. Between Sept 14, 2011, and Nov 19, 2012, 602 patients were enrolled from 146 centres in 22 countries and randomly assigned to trastuzumab emtansine (n=404) or treatment of physician's choice (n=198). At data cutoff (Feb 13, 2015), 93 (47%) of 198 patients in the physician's choice group had crossed over to trastuzumab emtansine. Overall survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice (median 22·7 months [95% CI 19·4–27·5] vs 15·8 months [13·5–18·7]; hazard ratio 0·68 [95% CI 0·54–0·85]; p=0·0007). As the stopping boundary for overall survival was crossed, this overall survival analysis serves as the final and confirmatory analysis of overall survival and the study was terminated according to the protocol. The incidence of grade 3 or worse adverse events was 161 (40%) of 403 patients in the trastuzumab emtansine group and 87 (47%) of 184 patients in the treatment of physician's choice group. Of the most common grade 3 or worse adverse events (affecting ≥2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with trastuzumab emtansine were diarrhoea (three [1%] of 403 patients in the trastuzumab emtansine group vs eight [4%] of 184 patients in the treatment of physician's choice group), neutropenia (ten [3%] vs 29 [16%]), and febrile neutropenia (one [<1%] vs seven [4%]); whereas those that were more frequent with trastuzumab emtansine were thrombocytopenia (24 [6%] of 403 patients vs five [3%] of 184 patients) and haemorrhage of any type (17 [4%] of 403 vs one [<1%] of 184). Serious adverse events were reported in 102 (25%) of 403 patients in the trastuzumab emtansine group and 41 (22%) of 184 in the physician's choice group. Deaths from adverse events were reported in three patients (2%) in the physician's choice group (of which one was judged to be treatment related) and nine (2%) in the trastuzumab emtansine group (of which three were judged to be treatment related). In patients who had progressed on two or more HER2-directed regimens, trastuzumab emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of trastuzumab emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy. F Hoffman-La Roche/Genentech.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

Neuroendocrine carcinomas of the cervix account for less than 2% of all invasive cervical cancers and are classified as low-grade (carcinoid, atypical carcinoid tumor) or high-grade (known as small- and large-cell) neuroendocrine carcinomas. There are increasing data showing that cervical neuroendocrine carcinomas may be associated with the human papillomavirus (HPV), especially HPV18, and most will stain positive for p16. Immunohistochemistry markers such as synaptophysin and CD56 are the most sensitive markers. Although there are no commonly associated mutations, PIK3CA, KRAS, and TP53 are the most frequently found mutations in neuroendocrine tumors. Neuroendocrine cervical carcinomas are exceedingly aggressive tumors with a high tendency for nodal involvement and distant metastases. Age, lymph node metastases, smoking, pure small-cell histology, and tumor size are independent prognostic factors. Overall, the 5-year survival rate is 36% and the median overall survival ranges between 22 and 25 months. Treatment options are often extrapolated from small-cell lung cancer and limited retrospective studies. The preferred treatment is a multimodal approach of surgery, chemoradiation, and systemic chemotherapy. The most common chemotherapy regimen used as initial therapy is a combination of cisplatin and etoposide. In the setting of recurrent disease, a combination of topotecan, paclitaxel, and bevacizumab has demonstrated favorable outcomes. Multicenter tumor registries, such as the Neuroendocrine Cervical Tumor Registry (NeCTuR), are an opportunity to evaluate patterns of disease treatment and oncologic outcomes.

There is a high unmet need for treatment regimens that increase the chance of long-term remission and possibly cure for women with newly diagnosed advanced ovarian cancer. In the primary analysis of SOLO1/GOG 3004, the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib significantly improved progression-free survival versus placebo in patients with a BRCA mutation; median progression-free survival was not reached. Here, we report an updated, post-hoc analysis of progression-free survival from SOLO1, after 5 years of follow-up. SOLO1 was a randomised, double-blind, placebo-controlled, phase 3 trial, done across 118 centres in 15 countries, that enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–1 and with BRCA-mutated, newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer with a complete or partial clinical response after platinum-based chemotherapy. Patients were randomly assigned (2:1) via a web-based or interactive voice-response system to receive olaparib (300 mg twice daily) or placebo tablets orally as maintenance monotherapy for up to 2 years; randomisation was by blocks and was stratified according to clinical response after platinum-based chemotherapy. Patients, treatment providers, and data assessors were masked to group assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy is reported in the intention-to-treat population and safety in patients who received at least one dose of treatment. The data cutoff for this updated, post-hoc analysis was March 5, 2020. This trial is registered with ClinicalTrials.gov (NCT01844986) and is ongoing but closed to new participants. Between Sept 3, 2013, and March 6, 2015, 260 patients were randomly assigned to olaparib and 131 to placebo. The median treatment duration was 24·6 months (IQR 11·2–24·9) in the olaparib group and 13·9 months (8·0–24·8) in the placebo group; median follow-up was 4·8 years (2·8–5·3) in the olaparib group and 5·0 years (2·6–5·3) in the placebo group. In this post-hoc analysis, median progression-free survival was 56·0 months (95% CI 41·9–not reached) with olaparib versus 13·8 months (11·1–18·2) with placebo (hazard ratio 0·33 [95% CI 0·25–0·43]). The most common grade 3–4 adverse events were anaemia (57 [22%] of 260 patients receiving olaparib vs two [2%] of 130 receiving placebo) and neutropenia (22 [8%] vs six [5%]), and serious adverse events occurred in 55 (21%) of 260 patients in the olaparib group and 17 (13%) of 130 in the placebo group. No treatment-related adverse events that occurred during study treatment or up to 30 days after discontinuation were reported as leading to death. No additional cases of myelodysplastic syndrome or acute myeloid leukaemia were reported since the primary data cutoff, including after the 30-day safety follow-up period. For patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, after, to our knowledge, the longest follow-up for any randomised controlled trial of a PARP inhibitor in this setting, the benefit derived from 2 years' maintenance therapy with olaparib was sustained beyond the end of treatment, extending median progression-free survival past 4·5 years. These results support the use of maintenance olaparib as a standard of care in this setting. AstraZeneca; Merck Sharpe & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options. We aimed to compare trastuzumab emtansine, an antibody–drug conjugate comprising the cytotoxic agent DM1 linked to trastuzumab, with treatment of physician's choice in this population of patients. This randomised, open-label, phase 3 trial took place in medical centres in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients (≥18 years, left ventricular ejection fraction ≥50%, Eastern Cooperative Oncology Group performance status 0–2) with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting, were randomly assigned (in a 2:1 ratio) to trastuzumab emtansine (3·6 mg/kg intravenously every 21 days) or physician's choice using a permuted block randomisation scheme by an interactive voice and web response system. Patients were stratified according to world region (USA vs western Europe vs other), number of previous regimens (excluding single-agent hormonal therapy) for the treatment of advanced disease (two to three vs more than three), and presence of visceral disease (any vs none). Coprimary endpoints were investigator-assessed progression-free survival (PFS) and overall survival in the intention-to-treat population. We report the final PFS analysis and the first interim overall survival analysis. This study is registered with ClinicalTrials.gov, number NCT01419197. From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned (404 to trastuzumab emtansine and 198 to physician's choice). At data cutoff (Feb 11, 2013), 44 patients assigned to physician's choice had crossed over to trastuzumab emtansine. After a median follow-up of 7·2 months (IQR 5·0–10·1 months) in the trastuzumab emtansine group and 6·5 months (IQR 4·1–9·7) in the physician's choice group, 219 (54%) patients in the trastuzumab emtansine group and 129 (65%) of patients in the physician's choice group had PFS events. PFS was significantly improved with trastuzumab emtansine compared with physician's choice (median 6·2 months [95% CI 5·59–6·87] vs 3·3 months [2·89–4·14]; stratified hazard ratio [HR] 0·528 [0·422–0·661]; p<0·0001). Interim overall survival analysis showed a trend favouring trastuzumab emtansine (stratified HR 0·552 [95% CI 0·369–0·826]; p=0·0034), but the stopping boundary was not crossed. A lower incidence of grade 3 or worse adverse events was reported with trastuzumab emtansine than with physician's choice (130 events [32%] in 403 patients vs 80 events [43%] in 184 patients). Neutropenia (ten [2%] vs 29 [16%]), diarrhoea (three [<1%] vs eight [4%]), and febrile neutropenia (one [<1%] vs seven [4%]) were grade 3 or worse adverse events that were more common in the physician's choice group than in the trastuzumab emtansine group. Thrombocytopenia (19 [5%] vs three [2%]) was the grade 3 or worse adverse event that was more common in the trastuzumab emtansine group. 74 (18%) patients in the trastuzumab emtansine group and 38 (21%) in the physician's choice group reported a serious adverse event. Trastuzumab emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received trastuzumab and lapatinib. Genentech.

BackgroundCurrently, a lively debate exists within the scientific community regarding the most suitable procedure for treating stages IIIB–IVB carcinoma of the ovary, fallopian tubes, and peritoneum. The options under most consideration are primary cytoreductive surgery or neoadjuvant chemotherapy followed by interval cytoreductive surgery.Primary ObjectiveTo compare overall survival at 5 years in patients who underwent primary cytoreductive surgery versus neoadjuvant chemotherapy and interval cytoreductive surgery for stage IIIB–IVB ovarian cancerStudy HypothesisThe treatment with primary cytoreductive surgery results in superior patient survival compared with neoadjuvant chemotherapy followed by interval cytoreductive surgery.Trial DesignThis is a multicenter, retrospective cohort observational study. Data will be collected from patients undergoing surgery in hospitals worldwide. Two arms will be compared: primary cytoreductive surgery and neoadjuvant chemotherapy followed by interval cytoreductive surgery.Major Inclusion/Exclusion CriteriaPatients must have suspected or histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stages IIIB–IVB ovarian, peritoneal, or fallopian tube cancers. They must have undergone primary surgery or first course of neoadjuvant chemotherapy between January 1, 2018 and December 31, 2019. Based on all available information before the surgery (primary or interval), the patient must have been considered completely resectable.Primary EndpointOverall survival at 5 years from the first treatment (chemotherapy in the case of neoadjuvant chemotherapy and cytoreduction in the case of primary cytoreductive surgery).Sample SizeAn estimated total of 5000 patients will be enrolled in the study.Estimated Dates for Completing Accrual and Presenting ResultsMarch 2025Trial Registration NCT06223763

BackgroundPlatinum based chemotherapy is the treatment of choice for ovarian cancer patients with a platinum treatment free interval of >6 months. Niraparib is an oral poly (ADP-ribose) polymerase inhibitor approved as maintenance therapy after a response to platinum rechallenge, regardless of BRCA status. Atezolizumab is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). A combination of poly (ADP-ribose) polymerase inhibitor and anti-PD-L1/programmed cell death protein 1 (PD-1) has shown synergy in preclinical models and promising clinical activity.Primary objectiveTo determine whether the addition of atezolizumab to carboplatin based chemotherapy and to subsequent maintenance with niraparib improves progression free survival compared with placebo in patients with recurrent disease and a platinum treatment free interval of >6 months.Trial designThe Atezolizumab and NIraparib Treatment Association (ANITA) trial is a GEICO (Grupo Español de Investigación en Cáncer de Ovario) led phase III, randomized, double-blinded, multicenter European Network for Gynecological Oncological Trials (ENGOT) study. Patients will be randomized to arm A (control arm) consisting of platinum based chemotherapy (investigator’s choice) plus a placebo of atezolizumab followed by maintenance niraparib plus a placebo of atezolizumab, or to arm B (experimental arm) consisting of platinum based chemotherapy (investigator’s choice) plus atezolizumab followed by maintenance niraparib plus atezolizumab.Major inclusion/exclusion criteriaInclusion criteria are women aged over 18 years, diagnosed with relapsed high grade serous, endometrioid, or undifferentiated ovarian, fallopian tube, or primary peritoneal carcinoma. Patients are eligible if they received no more than two previous lines of chemotherapy, relapsed ≥6 months after the last platinum containing regimen, and have at least one measurable lesion according to the response evaluation criteria in solid tumors, version 1.1.Primary endpointThe primary endpoint for this study is progression free survival.Sample sizeApproximately 414 patients will be recruited and randomized in a 1:1 ratio, with the aim of demonstrating a benefit in progression free survival for the experimental arm with a hazard ratio of O.7, using a two sided alpha of 0.05 and a power of 80%.Estimated dates for completing accrual and presenting resultsThe trial was launched in the fourth quarter of 2018 and is estimated to close in the second quarter of 2021. Mature results for progression free survival are expected to be presented by 2023.Trial registrationClinicaltrials.gov NCT03598270.

This is a report from the European Society of Gynaecological Oncology State-of-the-Art Virtual Meeting held December 14–16, 2020. The unique 3-day conference offered comprehensive state-of-the-art summaries on the major advances in the treatment of different types of gynecological cancers. Sessions opened with a case presentation followed by a keynote lecture and interactive debates with opinion leaders in the field. The speakers also presented scientific reviews on the clinical trial landscape in collaboration with the European Network of Gynecological Oncological Trial (ENGOT) groups. In addition, the new ESGO-ESRTO-ESP endometrial cancer guidelines were officially presented in public. This paper describes the key information and latest studies that were presented for the first time at the conference.

ObjectiveThe aim of this study was to assess the safety and efficacy of extending bevacizumab therapy beyond 15 months in nonprogressive ovarian cancer.Patients and MethodsIn this multinational prospective single-arm study (ClinicalTrials.gov NCT01239732), eligible patients had International Federation of Gynecology and Obstetrics stage IIB to IV or grade 3 stage I to IIA ovarian cancer without clinical signs or symptoms of gastrointestinal obstruction or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the preceding 6 months. Prior neoadjuvant chemotherapy was permitted. After debulking surgery, patients received bevacizumab 15 (or 7.5) mg/kg every 3 weeks (q3w) with 4 to 8 cycles of paclitaxel (investigator’s choice of 175 mg/m2 q3w or 80 mg/m2 weekly) plus carboplatin AUC 5 to 6 q3w. Single-agent bevacizumab was continued until progression or for up to 24 months. The primary end point was safety.ResultsBetween December 2010 and May 2012, 1021 patients from 35 countries began study treatment. Bevacizumab was administered at 15 mg/kg in 89% of patients and for more than 15 months in 53%. Median follow-up duration was 32 months (range, 1–50 months). The most common all-grade adverse events were hypertension (55% of patients), neutropenia (49%), and alopecia (43%). The most common grade 3 or higher-grade adverse events were neutropenia (27%) and hypertension (25%). Bevacizumab was discontinued because of proteinuria in 5% of patients and hypertension in 3%. Median progression-free survival (PFS) was 25.5 months (95% confidence interval, 23.7–27.6 months).ConclusionExtended bevacizumab demonstrated increased incidences of proteinuria and hypertension compared with 12 or 15 months of bevacizumab in previous trials, but these rarely led to bevacizumab discontinuation. Median PFS is the longest reported for frontline bevacizumab-containing therapy. The longer bevacizumab duration beyond 15 months in this study may improve PFS without substantially compromising safety.