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Purpose:PARP inhibitors (PARPi) are standard-of-care therapy for high-grade serous ovarian cancer (HGSOC). We investigated combining cediranib (antiangiogenic) with olaparib (PARPi) at emergence of PARPi resistance.Patients and Methods:The proof-of-concept EVOLVE study (NCT02681237) assessed cediranib–olaparib combination therapy after progression on a PARPi. Women with HGSOC and radiographic evidence of disease progression were enrolled into one of three cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard chemotherapy after progression on PARPi (exploratory cohort). Patients received olaparib tablets 300 mg twice daily with cediranib 20 mg once daily until progression or unacceptable toxicity. The coprimary endpoints were objective response rate (RECIST v1.1) and progression-free survival (PFS) at 16 weeks. Archival tissue (PARPi-naïve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing.Results:Among 34 heavily pretreated patients, objective responses were observed in 0 of 11 (0%) platinum-sensitive patients, 2 of 10 (20%) platinum-resistant patients, and 1 of 13 (8%) in the exploratory cohort. Sixteen-week PFS rates were 55%, 50%, and 39%, respectively. The most common grade 3 toxicities were diarrhea (12%) and anemia (9%). Acquired genomic alterations at PARPi progression were reversion mutations in BRCA1, BRCA2, or RAD51B (19%); CCNE1 amplification (16%); ABCB1 upregulation (15%); and SLFN11 downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or ABCB1 upregulation had poor outcomes.Conclusions:This is currently the largest post-PARPi study identifying genomic mechanisms of resistance to PARPis. In this setting, the activity of cediranib–olaparib varied according to the PARPi resistance mechanism.

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Objective The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with >= 3 lines of chemotherapy (PPS-ROC >= 3). Methods Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated >= 4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of = 10 points above baseline in the QLQ-C30 summary score scale (range 0-100). Results Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC >= 3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC >= 3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p= 3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline. Conclusion Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants. Funding Agencies|NHMRCNational Health and Medical Research Council of Australia [1063012, 570893]; Target Ovarian Cancer [UCL-P001AL]; Cancer Research UKCancer Research UK; UCL Cancer Trials Centre [C444/A15953]; Australian Government through Cancer AustraliaAustralian Government; NHMRC Program grantNational Health and Medical Research Council of Australia; Department of HealthEuropean Commission

Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.

Purpose:PARP inhibitors (PARPi) are standard-of-care therapy for high-grade serous ovarian cancer (HGSOC). We investigated combining cediranib (antiangiogenic) with olaparib (PARPi) at emergence of PARPi resistance.Patients and Methods:The proof-of-concept EVOLVE study (NCT02681237) assessed cediranib–olaparib combination therapy after progression on a PARPi. Women with HGSOC and radiographic evidence of disease progression were enrolled into one of three cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard chemotherapy after progression on PARPi (exploratory cohort). Patients received olaparib tablets 300 mg twice daily with cediranib 20 mg once daily until progression or unacceptable toxicity. The coprimary endpoints were objective response rate (RECIST v1.1) and progression-free survival (PFS) at 16 weeks. Archival tissue (PARPi-naïve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing.Results:Among 34 heavily pretreated patients, objective responses were observed in 0 of 11 (0%) platinum-sensitive patients, 2 of 10 (20%) platinum-resistant patients, and 1 of 13 (8%) in the exploratory cohort. Sixteen-week PFS rates were 55%, 50%, and 39%, respectively. The most common grade 3 toxicities were diarrhea (12%) and anemia (9%). Acquired genomic alterations at PARPi progression were reversion mutations in BRCA1, BRCA2, or RAD51B (19%); CCNE1 amplification (16%); ABCB1 upregulation (15%); and SLFN11 downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or ABCB1 upregulation had poor outcomes.Conclusions:This is currently the largest post-PARPi study identifying genomic mechanisms of resistance to PARPis. In this setting, the activity of cediranib–olaparib varied according to the PARPi resistance mechanism.

Objective Women with advanced gynecologic cancer and malignant bowel obstruction (MBO) undergo repeated hospitalizations, experience feelings of isolation and abandonment, and often die in acute settings. Innovative outpatient models of care are needed to address the unmet needs of this population at the end-of-life. We implemented a novel supported self-management (SMS) program focused on increasing patients' skill and confidence in managing MBO proactively in the ambulatory setting. Methods We performed a qualitative descriptive study embedded in a prospective single-arm evaluative trial ( Clinicaltrials.gov ID: NCT03260647 ) to understand the impact of this program on patients' sense of support, degree of distress, quality of care, and capacity to self-manage. Semi-structured interviews were completed and analysed using the Chronic Care Model as a theoretical framework. Data saturation was confirmed after 15 interviews. Results Fifteen patients (age range: 47–82) with diagnoses of advanced ovarian, endometrial, and cervical cancer were interviewed; 10 had died by end of follow-up, with a median interval from interview to death of 5 months. Patients were able to self-manage the: (i) medical aspects; (ii) psychological consequences, and (iii) changes in life roles and expectations resulting from their condition. Patients felt greatly supported, less isolated, and secure in their knowledge and ability to access care due to SMS. While patients understood their disease was not curative they did not fully appreciate that MBO signalled a significantly poorer prognosis. Conclusion Outpatient SMS interventions can be successfully implemented even for rapidly fatal conditions at the end-of-life and offer significant benefit to gynecologic cancer patients with MBO. Counselling should focus on the specific trajectory of MBO, and early palliative care referrals should be standard practice.

PURPOSE: Malignant bowel obstruction (MBO) is a common and distressing complication in women with advanced gynecologic cancer. A pilot, interprofessional MBO program was launched in 2016 at a large Canadian tertiary cancer center to integrate these patients’ complex care needs across multiple disciplines and support women with MBO. METHOD: Retrospective analysis to evaluate the outcomes of women with advanced gynecologic cancer who were admitted to hospital because of MBO, before (2014 to 2016: baseline group) and after (2016 to 2018) implementation of the MBO program. RESULTS: Of the 169 women evaluated, 106 and 63 were in the baseline group and MBO program group, respectively. Most had ovarian cancer (n = 124; 73%) and had small-bowel obstruction (n = 131; 78%). There was a significantly shorter cumulative hospital length of stay (LOSsum) within the first 60 days of MBO diagnosis in the MBO program group compared with the baseline group (13 v 22 days, respectively; adjusted P = .006). The median overall survival for women treated in the MBO program was also significantly longer compared with the baseline group (243 v 99 days, respectively; adjusted P = .002). Using the interprofessional MBO care platform, a greater proportion of patients received palliative chemotherapy (83% v 56%) and less surgery (11% v 21%) in the MBO program group than in the baseline group, respectively. A subgroup of women (n = 11) received total parenteral nutrition for longer than 6 months. CONCLUSION: Implementation of a comprehensive, interprofessional MBO program significantly affects patient care and may improve outcomes. Unique to this MBO program is an integrated outpatient model of care and education that empowers patients to recognize MBO symptoms for early intervention.

BackgroundIn this study, we assessed the activity of durvalumab, an antibody to programmed death ligand-1, in two cohorts of women with advanced endometrial cancers (AEC)—mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR).MethodsA multicenter phase two study was performed in women with AEC with pMMR tumor progressing after one to three lines of chemotherapy and women with AEC with dMMR tumor progressing after zero to three lines of chemotherapy. Mismatch repair status was based on immunohistochemistry expression. All women received durvalumab 1500 mg given every 4 weeks until progression or unacceptable toxicity. The primary endpoint was objective tumor response by RECIST V.1.1 modified for immune-based therapeutics.ResultsSeventy-one women were recruited: 35 dMMR and 36 pMMR. Median follow-up was 19 vs 21 months in dMMR versus pMMR, respectively. Median age was 67 years. Histology in dMMR versus pMMR included endometrioid (94% vs 57%) and serous (0% vs 31%) and was high grade in 26% vs 74%. The objective tumor response rate (OTRR) in the dMMR cohort was 47% (17/36, 95% CI 32 to 63), including 6 complete responses and 11 partial responses (PRs)) vs 3% in the pMMR cohort (1/35, 95% CI 1 to 15, PR). In the dMMR cohort, durvalumab was the first-line therapy in 58% (OTRR 57%) and the second-line therapy in 39% (OTRR 38%). Median progression-free survival was 8.3 months in the dMMR cohort vs 1.8 months in the pMMR cohort. The 12-month overall survival (OS) rate was 71% in dMMR vs 51% in pMMR, with median OS not reached for dMMR vs 12 months for pMMR. Immune-related adverse events occurred in 14 women, mostly grades 1–2.ConclusionDurvalumab monotherapy showed promising activity and acceptable safety in AEC with dMMR regardless of prior lines of chemotherapy, but activity was limited in AEC with pMMR.Trial registration numbersANZGOG1601, ACTRN12617000106336, and NCT03015129.

Epithelial ovarian cancer (EOC) is among the top ten causes of cancer deaths worldwide, and is one of the most lethal gynecological malignancies in high income countries, with incidence and death rates expected to rise particularly in Asian countries where ovarian cancer is among the 5 most common cancers. Despite the plethora of randomised clinical trials investigating various systemic treatment options in EOC over the last few decades, both progression-free and overall survival have remained at approximately 16 and 40 months respectively. To date the greatest impact on treatment has been made by the use of poly (ADP-ribose) polymerase (PARP) inhibitors in women with advanced EOC and a BRCA1/2 mutation. Inhibition of PARP, the key enzyme in base excision repair, is based on synthetic lethality whereby alternative DNA repair pathways in tumor cells that are deficient in homologous recombination is blocked, rendering them unviable and leading to cell death. The Australia New Zealand Gynaecological Oncology Group (ANZGOG) is the national gynecological cancer clinical trials organization for Australia and New Zealand. ANZGOG's purpose is to improve outcomes and quality of life for women with gynecological cancer through cooperative clinical trials and undertaking multidisciplinary research into the causes, prevention and treatments of gynecological cancer. This review summarizes current ovarian cancer research and treatment approaches presented by Australian and New Zealand experts in the field at the 2020 ANZGOG webinar series entitled “Ovarian Cancer systems of Care”.

Background Completion of continuing professional development (CPD) is mandatory for Medical Oncologists and Trainees (MO&T). Pharmaceutical companies may fund some CPD activities, but there is increasing debate about the potential for conflicts of interest (COI). Aim We aimed to assess current practices around funding to attend CPD activities. Methods An electronic survey was distributed to Australian MO&T. The survey asked questions about current practices, institutional policies and perceptions about attending CPD funded by pharmaceutical companies. The design looked at comparing responses between MO&T, as well as their understanding of and training around institutional and ethical process. Results 157/653 (24%) responses were received, majority from MO (76%). Most CPD activities attended by MO&T were self-funded (53%), followed by funding from institutions (19%), pharmaceutical companies (16%), and salary award (16%). Most institutions allowed MO&T to receive CPD funding from professional organisations (104/157, 66%) or pharmaceutical companies (90/157, 57%). A minority of respondents (13/157, 8%) reported that the process to use pharmaceutical funds had been considered by an ethics committee. Although 103/157 (66%) had received pharmaceutical funding for CPD, most (109/157, 69%) reported never receiving training about potential COI. The lack of education was more noticeable amongst trainees (OR 8.61, p = 0.02). MO&T acknowledged the potential bias towards a pharmaceutical product (p = 0.05), but believed there was adequate separation between themselves and pharmaceutical companies (p

BACKGROUND Women with gynecologic cancer may be at increased risk for adverse events (AEs) due to peritoneal disease burden and prior treatment (surgery, chemotherapy, and pelvic radiotherapy). This study compared the toxicity profiles of patients with and without gynecologic cancer enrolled in phase 1 trials. METHODS This was a retrospective analysis of the National Cancer Institute phase 1 database for all trials enrolling 1 or more patients with gynecologic cancer over 2 decades (1995-2015). Clinical parameters collected included demographics, cancer history, trial information, AEs, and responses. AEs (according to the Common Terminology Criteria for Adverse Events) were documented for each patient during treatment, and they were counted once and analyzed on the basis of the highest grade and drug attribution. Multiple regression models were used to compare AEs at the baseline and during treatment. RESULTS A total of 4269 patients enrolled in 150 trials were divided into 3 groups: 1) women with gynecologic cancer (n = 685), 2) women with nongynecologic cancer (n = 1698), and 3) men with cancer (n = 1886). The median age was 58 years. The mean number of total AEs reported during treatment was highest for women with gynecologic cancer (17.1 vs 14.7 vs 13.5; P

Objectives The quality of risk-reducing salpingo-oophorectomy (RRSO) performed in Australasian women was previously reported to be suboptimal. Here we describe the quality of RRSO performed since 2008 in women enrolled in the same cohort and determine whether it has improved. Design Prospective cohort study of women at high risk of pelvic serous cancer (PSC) in kConFab. Eligible women had RRSO between 2008 and 2014 and their RRSO surgical and pathology reports were reviewed. “Adequate” surgery and pathology were defined as complete removal and paraffin embedding of all ovarian and extra-uterine fallopian tube tissue, respectively. Associations between clinical factors and “adequate” pathology were assessed using logistic regression. Data were compared with published cohort data on RRSO performed prior to 2008 using Chi square test. Results Of 164 contemporary RRSOs performed in 78 centres, 158/159 (99%) had “adequate” surgery and 108/164 (66%) had “adequate” pathology. Surgery performed by a gynaecologic oncologist rather than a general gynaecologist [OR 8.2, 95%CI (3.6–20.4), p

Background. A resurgence of Haemophilus influenzae type b (Hib) disease occurred in the United Kingdom between 1999 and 2003 and was partially attributed to lower immunogenicity of combination vaccines. The reservoir for Hib that led to transmission in this period is unknown. Methods. We estimated the point prevalence of Hib carriage in school-aged children and adults, using oropharyngeal swabbing and selective media. We characterized the Hib isolates by multilocus sequence typing (MLST) and measured Hib antibody concentrations in adults by enzyme-linked immunosorbent assay. Results. Point prevalence for Hib carriage in 855 children aged 6 –16 years was 4.2% (95% confidence interval [CI], 2.5%–5.9%). Five clonal groups of Hib were identified by MLST, 86% from the lineage of sequence type 6. No Hib was isolated in 385 adults (upper limit of 95% CI, 0.95%). The geometric mean concentration of serum antibody to polyribosylribitol phosphate was 0.47 g/mL (95% CI, 0.37– 0.59 g/mL) in adults. Conclusions. Hib carriage is common in school-aged children, who are a significant reservoir for ongoing transmission of Hib to susceptible individuals in the United Kingdom. Surveillance of transmission and immunity across all ages of the population is essential to monitor the evolution of Hib epidemiology. Haemophilus influenzae type b (Hib) conjugate vaccines have been widely used around the world since the late 1980s to protect against invasive Hib disease in early childhood. Conjugation of the Hib surface polysaccha

Background: Despite the excellent immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccines, breakthrough cases of Hib disease still affect a small proportion of vaccinated children in the United Kingdom. We performed a retrospective study to compare the avidity of antibody directed against the Hib polysaccharide capsule (PRP) in children who experienced Hib vaccine failure in the United Kingdom among 3 historical cohorts and with age-matched healthy control subjects. Methods: Serum samples from vaccinated children with invasive Hib disease were collected beginning in 1992 as part of enhanced surveillance for Hib disease following vaccine introduction. A total of 251 children who experienced Hib vaccine failure were identified from 3 historical cohorts (1992-1995, 1996-1999, and 2000-2003). The anti-PRP antibody concentration and avidity from healthy age-matched control subjects was obtained for the 3 contemporary time points (1995, 1999, and 2002). Serum anti-PRP antibody concentration was measured in each of the samples using a standard Hib ELISA, and antibody avidity was determined using thiocyanate elution. Results. Within the first 60 days after disease onset, there was no change in the anti-PRP antibody avidity, and there was no statistically significant difference in the geometric mean Hib antibody avidity over the 3 study periods. However, the children who experienced Hib vaccine failure had significantly lower Hib antibody avidity than did healthy control subjects, despite a marked antibody response following infection. Conclusions. Children who experience Hib disease despite vaccination appear to have a defect in immunological priming, leading to a qualitative difference in Hib-specific memory B cells. Low anti-PRP antibody avidity decreases the functional activity of anti-PRP antibody in the sera of these children experiencing vaccine failure, leading to disease susceptibility.