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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.

The 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup was held in Vancouver, Canada, in June 2010. Representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. Group C, 1 of the 3 discussion groups, examined recurrent ovarian cancer, and we report the consensus reached regarding 4 questions. These included the following: (1) What is the role of cytoreductive surgery for recurrent ovarian cancer? (2) How do we define distinct patient populations in need of specific therapeutic approaches? (3) Should end points for trials with recurrent disease vary from those of first-line trials? (4) Is CA-125 progression alone sufficient for entry/eligibility into clinical trials?

State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin–paclitaxel or carboplatin–gemcitabine) or the most active non-bevacizumab regimen: carboplatin–pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin–pegylated liposomal doxorubicin combined with bevacizumab. This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251. Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin–pegylated liposomal doxorubicin–bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin–gemcitabine–bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3–21·7) in the experimental group and 11·3 months (8·0–18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7–14·2) in the experimental group versus 11·6 months (11·0–12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68–0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage). Carboplatin–pegylated liposomal doxorubicin–bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer. F Hoffmann-La Roche.

Background: Rucaparib is an orally available potent selective small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Rucaparib induces synthetic lethality in cancer cells defective in the homologous recombination repair pathway including BRCA-1/2. We investigated the efficacy and safety of single-agent rucaparib in germline (g) BRCA mutation carriers with advanced breast and ovarian cancers. Methods: Phase II, open-label, multicentre trial of rucaparib in proven BRCA-1/2 mutation carriers with advanced breast and or ovarian cancer, WHO PS 0–1 and normal organ function. Intravenous (i.v.) and subsequently oral rucaparib were assessed, using a range of dosing schedules, to determine the safety, tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and pharmacokinetic (PK) profiles. Results: Rucaparib was well tolerated in patients up to doses of 480 mg per day and is a potent inhibitor of PARP, with sustained inhibition ⩾24 h after single doses. The i.v. rucaparib (intermittent dosing schedule) resulted in an objective response rate (ORR) of only 2% but with 41% (18 out of 44) patients achieved stable disease for ⩾12 weeks and 3 patients maintaining disease stabilisation for >52 weeks. The ORR for oral rucaparib (across all six dose levels) was 15%. In the oral cohorts, 81% (22 out of 27) of the patients had ovarian cancer and 12 out of 13, who were dosed continuously, achieved RECIST complete response/partial response (CR/PR) or stable disease (SD) ⩾12 weeks, with a median duration of response of 179 days (range 84–567 days). Conclusions: Rucaparib is well tolerated and results in high levels of PARP inhibition in surrogate tissues even at the lowest dose levels. Rucaparib is active in gBRCA-mutant ovarian cancer and this activity correlates with platinum-free interval. The key lessons learned from this study is that continuous rucaparib dosing is required for optimal response, the recommended phase 2 dose (RP2D) for continuous oral scheduling has not been established and requires further exploration and, thirdly, the use of a PD biomarker to evaluate dose–response has its limitations.

ObjectivesTo describe the clinical activity of metronomic cyclophosphamide in a population of patients with recurrent ovarian cancer, and to identify predictors of clinical response.MethodsWe retrospectively reviewed all patients treated at our institution with oral metronomic cyclophosphamide for relapsed ovarian cancer between January 2012 and December 2016. These were identified from electronic chemotherapy prescription records. The primary endpoint was response rate by combined Gynecologic Cancer InterGroup (GCIG) criteria. Data on patient demographics, previous therapies, platinum resistance, germline BRCA1/2 (gBRCA1/2) status, disease response by radiological or cancer antigen 125 (CA125) criteria alone, adverse events secondary to metronomic cyclophosphamide treatment, progression-free survival, and overall survival were also evaluated.Results50 out of 68 patients treated with oral metronomic cyclophosphamide were evaluable for disease response. By combination criteria (radiological plus CA125), complete response was 0%, partial response 32%, stable disease 16%, and progressive disease 52%. In the intention-to-treat population (n=68), progression-free survival and overall survival were 2.6 months and 6 months, respectively. Having a gBRCA1/2 mutation reduced the risk of disease progression by radiological criteria (OR 0.07, 95% CI 0.008 to 0.67, p=0.02), and patients with gBRCA1/2 mutations had improved progression-free survival (7.9 vs 2.5 months, HR 0.4, 95% CI 0.23 to 0.74, p=0.003) and overall survival (15.5 vs 6 months, HR 0.49, 95% CI 0.28 to 0.85, p=0.02) with metronomic cyclophosphamide when compared with patients without gBRCA1/2 mutations (or unknown gBRCA1/2 status).ConclusionOral metronomic cyclophosphamide showed a clinical benefit in 48% of patients with recurrent ovarian cancer. gBRCA1/2 status can be an independent predictor of response.

Introduction/BackgroundThe PARP inhibitor (PARPi), niraparib, is EMA approved for maintenance treatment in platinum-sensitive recurrent ovarian cancer. The eligibility criteria set out in niraparib licence are less stringent than those in the NOVA trial, therefore outcomes may be different in the real-world to those observed in trial patients.1 The optimal management of patients after progression on PARPi is unknown and the relationship between platinum free interval and probability of response to platinum may be modified after PARPi therapy. To investigate this, we performed a retrospective analysis of real-world niraparib use and compared it to the NOVA trial.MethodologyData was collected retrospectively for all women receiving maintenance niraparib for BRCA wild-type, platinum sensitive relapsed ovarian cancer between June 2017 and September 2019. Response to prior platinum, median progression-free survival (mPFS) after 1st and subsequent platinum, number of cycles of PARPi, dose, haematological toxicities, and PFS2I (start of subsequent therapy to physician assessed progression or death) were obtained through electronic records.Results37 patients received Niraparib in this timeframe. Median follow up was 16 months (range 5.7–37 months). Demographics were similar to previously published cohorts, however, only 11% (n=4) had a complete response (CR) to prior platinum therapy and 59% (n=22) had a partial response in comparison to 50% CR and 50% PR in the NOVA trial1. 35 (95%) of patients had progressed on niraparib at the time of data collection. The mPFS on niraparib was 4.4 months (95% CI 3.7 – 6.7 months) in comparison to 9.3 months in the NOVA study. Patients who met the NOVA trial radiological and serological response criteria, had a mPFS at 5.1 months (n = 19) compared to 3.9 months (n = 18). Dosing and toxicity data will be reported in full at the meeting. 31 patients received subsequent therapy, 19 (61%) were treated with paclitaxel, 9 (29%) were treated with platinum-based chemotherapy. Median PFS2I was 5.8 months for platinum sensitive disease and 3.5 months for platinum resistant disease.ConclusionThe real-world outcomes for niraparib treatment are worse than observed in the NOVA trial. Patients who meet NOVA trial eligibility criteria have better outcomes, however, these results are still inferior to those reported in the trial. Post PARP outcomes are poorer than expected in both platinum sensitive and platinum resistant settings. Strategies to effectively treat PARPi resistant disease are urgently needed.DisclosuresDr R Glasspool: Grant funding for clinical trials from Boehringer Ingelheim, Lilly/Ignyta and Clovis. Consultancy fees, travel support and/or speaker fees for AstraZeneca, GSK/Tesaro, Clovis, Immunogen and Sotio. Site PI for studies sponsored by AstraZeneca, GSK/Tesaro, Clovis, Immunogen, Lilly and Pfizer.ReferenceMirza MR, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med 2016;375:2154–64.

Introduction/BackgroundAGO-OVAR 2.21 is the first phase III trial in recurrent ovarian cancer that compared two bevacizumab-containing combination chemotherapy regimens independent of prior anti-angiogenic therapy. As safety and efficacy data on bevacizumab re-challenge is limited, this present exploratory analysis focuses on patients with prior anti-angiogenic therapy.MethodologyClinical data, medical history or ongoing side effects from prior anti-angiogenic therapy (t0), side effects reported during the trial (t1), and response to therapy, was collected. Clinical characteristics were compared for patients with prior anti-angiogenic therapy versus controls with no prior anti-angiogenic therapy with chi squared testing. Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models, were used for the time to event analyses.ResultsOf 682 enrolled patients 324 (47.5%) had previously been treated with anti-angiogenic therapy. Overall relative risk (RR) at t1 for any bevacizumab-associated side effects, including arterial hypertension, thrombosis, proteinuria, and fistula was 44.3% vs 60.3% (RR=0.73, P<0.0001) in patients following prior anti-angiogenic therapy compared to anti-angiogenic-naïve patients (patients with a prior diagnosis of blood pressure, proteinuria, thrombosis, and fistula at t0 were excluded). Similarly, relative risk was comparable for specific subgroups of side effects with arterial hypertension (30.8% vs 49.3%, RR=0.62; P<0.0001), proteinuria (17.5% vs 23.7%, RR=0.74; P=0.061), thrombosis (2.5% vs 4.9%, RR=0.51; P=0.157), and fistula (0.6% vs 1.1%, RR=0.55; P=0.766). PFS was shorter among patients with prior exposure to anti-angiogenic therapy than controls: medians 11.0 vs 14.2 months, (hazard ratio 1.60, 95%- confidence interval 1.35 to 1.89, P<0.0001).ConclusionIn this explorative analysis of patients with and without previous anti-angiogenic therapy undergoing treatment with a bevacizumab-containing combination chemotherapy, we observed that safety profile was within the expected range. Although prognostic impact appears to be lower in patients with prior anti-angiogenic exposure compared to anti-angiogenic drug-naïve patients, overall efficacy from bevacizumab with chemotherapy in platinum-eligible disease was demonstrated independent from prior treatment.DisclosuresHB: Research Funding: GSK, AstraZeneca, Merck, Sharp & Dohme (MSD). Consulting/Ad Bds: GSK, AstraZeneca, Merck, Sharp & Dohme (MSD) JS: Research Funding: Institution: AZ, Clovis Oncology, Merck, Bayer, PharmaMar, Pfizer, Tesaro, MSD Oncology, Roche. Consulting/Ad Bds: AZ, Clovis Oncology, PharmaMar, Merck, Pfizer, Tesaro, MSD Oncology, Lilly, Novocure, J&J, Roche, Ingress Health, Riemser, Sobi, GSK, Novartis; Honoraria: AZ, Eisai, Clovis Oncology, Olympus Medical Systems, J&J, PharmaMar, Pfizer, Teva, Tesaro, MSD Oncology, GSK, Bayer; Travel, Accommodations, Expenses: AZ, Clovis Oncology, PharmaMar, Roche Pharma AG, Tesaro, MSD Oncology, Olympus; AL: Honoraria: MSD, AZ, Tesaro, Clovis Oncology FT: Research Funding: AstraZeneca, ImmunoGen, SAGA diagnostics; Honoraria: AstraZeneca, Clovis, Eisai, GSK, MSD, Roche PH: Research Funding: Astra Zeneca, Roche, GSK, Genmab, Immunogen, Seagen, Clovis, Novartis (all institutional); Consulting/Ad Bds: Amgen, Astra Zeneca, Clovis, Eisai, Immunogen, GSK, Exscientia, Mersana, Miltenyi, MSD, Novartis, Roche, Stryker, Zai Lab; Travel support: Astra Zeneca. RG: Research Funding: Clovis; Honoraria: GSK, Clovis. PW: Research Funding:: Roche; Honoraria: Roche. JP: Research Funding: Roche, GSK. Honoraria: Medupdate, Decision Resources, Simon-Kucher and Partners, Juniper, Bionest Partner, Vox Bio, Axiom Healthcare Strategies, Prosapient, Lilly, Sai Med Partners. Travel: Roche. SM: Research funding, honorary, or travel expenses from and is a member of the advisory board of AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Hubro, Medac, MSD, Novartis, Nykode, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, and Tesaro. FM reports institutional research funding from Roche, Novartis, AstraZeneca, GSK and Tesaro, MED, Clovis, Vaccibody, Gilead Sciences, and Eisai; consulting fees from AstraZeneca, GSK and Tesaro, Pfizer, Eisai, Gilead Sciences, Vaccibody, and GenomicHealth; honoraria from AstraZeneca, Clovis, GSK and Tesaro, Eli Lilly, Novartis, Pfizer, Roche, Myriad Genetics, PharmaMar, Eisai, MSD, Immunomedics and Gilead Sciences, Pierre-Fabre, Agendia, Genomic Health, and Seattle Genetics; support for meeting attendance and travel from Pfizer, Roche, and AstraZeneca; and participation on a data safety monitoring board. Ahmed.Abstract 803 Figure 1

BackgroundPreclinical data show that belinostat (Bel) is synergistic with carboplatin and paclitaxel in ovarian cancer. To further evaluate the clinical activity of belinostat, carboplatin, and paclitaxel (BelCaP), a phase 1b/2 study was performed, with an exploratory phase 2 expansion planned specifically for women with recurrent epithelial ovarian cancer (EOC).MethodsThirty-five women were treated on the phase 2 expansion cohort. BelCap was given as follows: belinostat, 1000 mg/m2 daily for 5 days with carboplatin, AUC 5; and paclitaxel, 175 mg/m2 given on day 3 of a 21-day cycle. The primary end point was overall response rate (ORR), using a Simon 2 stage design.ResultsThe median age was 60 years (range, 39–80 years), and patients had received a median of 3 prior regimens (range, 1–4). Fifty-four percent had received more than two prior platinum-based combinations, sixteen patients (46%) had primary platinum-resistant disease, whereas 19 patients (54%) recurred within 6 months of their most recent platinum treatment. The median number of cycles of BelCaP administered was 6 (range, 1–23). Three patients had a complete response, and 12 had a partial response, for an ORR of 43% (95% confidence interval, 26%–61%). When stratified by primary platinum status, the ORR was 44% among resistant patients and 63% among sensitive patients. The most common drug-related adverse events related to BelCaP were nausea (83%), fatigue (74%), vomiting (63%), alopecia (57%), and diarrhea (37%). With a median follow-up of 4 months (range, 0–23.3 months), 6-month progression-free survival is 48% (95% confidence interval, 31%–66%). Median overall survival was not reached during study follow-up.ConclusionsBelinostat, carboplatin, and paclitaxel combined was reasonably well tolerated and demonstrated clinical benefit in heavily-pretreated patients with EOC. The addition of belinostat to this platinum-based regimen represents a novel approach to EOC therapy and warrants further exploration.