Data are limited regarding the use of poly(adenosine diphosphate ADP-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in ...patients with high-grade serous ovarian carcinoma.
In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the
-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the
-mutation cohort), and the intention-to-treat population.
A total of 1140 patients underwent randomization. In the
-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval CI, 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall.
Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).
Tumour cells with BRCA1/2 gene mutations demonstrate increased sensitivity to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. 6-mercaptopurine (6MP) was found to selectively kill ...BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AG014699, even after these cells acquired resistance to a PARP inhibitor or cisplatin.
This phase II single-arm trial investigated the activity of 6MP 55-75 mg/m
per day, and methotrexate 15-20 mg/m
per week in advanced breast or platinum-resistant ovarian cancer patients with a BRCA1/2 germline mutation, who had progressed after ≥1 previous line of chemotherapy. The primary outcome was objective response including stable disease (SD) as an assessment of clinical benefit rate (CBR), at 8 weeks, by RECIST v1.1. Secondary outcomes included overall survival (OS) and progression-free survival (PFS).
In total, 67 evaluable patients were recruited; 55 ovarian and 11 breast cancer patients. In total, 21 patients had SD (31%), one had a partial response (1.5%); CBR was 33% at 8 weeks. In total, 12/67 patients (18%) had SD at 16 weeks. In total, five ovarian cancer patients had SD for over 200 days. Median OS was 10.3 months (95% CI 6.9-14.5), median PFS 1.9 months (1.7-2.8).
The overall activity of 6MP and methotrexate in these patients was low; however, there was a small group of patients who appeared to derive longer-term clinical benefit.
NCT01432145 http://www.ClinicalTrials.gov.
Bevacizumab improves survival outcomes in women diagnosed with epithelial ovarian cancer (EOC). Pre-clinical data showed that the c-MET/VEGFR-2 heterocomplex negates VEGF inhibition through ...activation of c-MET signalling, leading to a more invasive and metastatic phenotype. We evaluated the clinical significance of c-MET and VEGFR-2 co-localisation and its association with VEGF pathway-related single nucleotide polymorphisms (SNPs) in women participating in the phase 3 trial, ICON7 (ClinicalTrials.gov identifier: NCT00262847).
Patients had FIGO stage I-IIA grade 3/poorly differentiated or clear cell carcinoma or stage IIB-IV epithelial ovarian, primary peritoneal or fallopian tube cancer. Immunofluorescence staining for co-localised c-MET and VEGFR-2 on tissue microarrays and genotyping of germline DNA from peripheral blood leukocytes for VEGFA and VEGFR-2 SNPs was performed. The significance of these biomarkers was assessed against survival.
Tissue microarrays from 178 women underwent immunofluorescence staining. Multivariable analysis showed that greater c-MET/VEGFR-2 co-localisation predicted worse OS in patients treated with bevacizumab after adjusting for FIGO stage and debulking surgery outcome (hazard ratio HR 1.034, 95% confidence interval 95%CI 1.010-1.059). Women in the c-MET/VEGFR-2
group treated with bevacizumab demonstrated significantly reduced OS (39.3 versus > 60 months; HR 2.00, 95%CI 1.08-3.72). Germline DNA from 449 women underwent genotyping. In the bevacizumab group, those women with the VEGFR-2 rs2305945 G/G variant had a trend towards shorter PFS compared with G/T or T/T variants (18.3 versus 23.0 months; HR 0.74, 95%CI 0.53-1.03).
In bevacizumab-treated women diagnosed with EOC, high c-MET/VEGFR-2 co-localisation on tumour tissue and the VEGFR-2 rs2305945 G/G variant, which may be biologically related, were associated with worse survival outcomes.
This study aimed to assess the impact of multiple COVID-19 waves on UK gynaecological-oncology services.
An online survey was distributed to all UK-British-Gynaecological-Cancer-Society members ...during three COVID-19 waves from 2020 to2022.
In total, 51 hospitals (including 32 cancer centres) responded to Survey 1, 42 hospitals (29 centres) to Survey 2, and 39 hospitals (30 centres) to Survey 3. During the first wave, urgent referrals reportedly fell by a median of 50% (IQR = 25-70%). In total, 49% hospitals reported reduced staffing, and the greatest was noted for trainee doctors, by a median of 40%. Theatre capacity was reduced by a median of 40%. A median of 30% of planned operations was postponed. Multidisciplinary meetings were completely virtual in 39% and mixed in 65% of the total. A median of 75% of outpatient consultations were remote. By the second wave, fewer hospitals reported staffing reductions, and there was a return to pre-pandemic urgent referrals and multidisciplinary workloads. Theatre capacity was reduced by a median of 10%, with 5% of operations postponed. The third wave demonstrated worsening staff reductions similar to Wave 1, primarily from sickness. Pre-pandemic levels of urgent referrals/workload continued, with little reduction in surgical capacity.
COVID-19 led to a significant disruption of gynaecological-cancer care across the UK, including reduced staffing, urgent referrals, theatre capacity, and working practice changes. Whilst disruption eased and referrals/workloads returned to normal, significant staff shortages remained in 2022, highlighting persistent capacity constraints.
Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. ...Improving outcomes in women with platinum-resistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoid receptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol's antiapoptotic effects, enhancing chemotherapy's efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population.BACKGROUNDOvarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinum-resistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoid receptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol's antiapoptotic effects, enhancing chemotherapy's efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population.ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy. The study's primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes.METHODSROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy. The study's primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes.ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18.TRIAL REGISTRATIONClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18.
Ovarian cancer survival in the UK lags behind comparable countries. Results from the ongoing National Ovarian Cancer Audit feasibility pilot (OCAFP) show that approximately 1 in 4 women with advanced ...ovarian cancer (Stage 2, 3, 4 and unstaged cancer) do not receive any anticancer treatment and only 51% in England receive international standard of care treatment, i.e., the combination of surgery and chemotherapy. The audit has also demonstrated wide variation in the percentage of women receiving anticancer treatment for advanced ovarian cancer, be it surgery or chemotherapy across the 19 geographical regions for organisation of cancer delivery (Cancer Alliances). Receipt of treatment also correlates with survival: 5 year Cancer survival varies from 28.6% to 49.6% across England. Here, we take a systems wide approach encompassing both diagnostic pathways and cancer treatment, derived from the whole cohort of women with ovarian cancer to set out recommendations and quality performance indicators (QPI). A multidisciplinary panel established by the British Gynaecological Cancer Society carefully identified QPI against criteria: metrics selected were those easily evaluable nationally using routinely available data and where there was a clear evidence base to support interventions. These QPI will be valuable to other taxpayer funded systems with national data collection mechanisms and are to our knowledge the only population level data derived standards in ovarian cancer. We also identify interventions for Best practice and Research recommendations.
Ovarian cancer is the seventh most common cause of cancer death in women world-wide. Treatment consists of a combination of surgical debulking and platinum-based chemotherapy, alone or in combination ...with paclitaxel. Between 55% and 75% of women who respond to first-line therapy relapse within two years of completing treatment. Second-line chemotherapy is palliative and aims to reduce symptoms and prolong survival. Increased understanding about the molecular basis of ovarian cancer has led to the development of novel agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, and their effectiveness and toxicities in women with advanced ovarian cancer needs to be assessed.
To compare the effectiveness and toxicities of epidermal growth factor receptor (EGFR) inhibitors alone or in combination with standard chemotherapy in the treatment of ovarian cancer.
We searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) Issue 4, 2010, MEDLINE and EMBASE up to October 2010. We also searched registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies, and contacted experts in the field.
Randomised controlled trials (RCTs) comparing anti-EGFR agents with or without conventional chemotherapy versus conventional chemotherapy alone or no treatment in women with histologically proven ovarian cancer.
Two review authors independently abstracted data and assessed risk of bias. We reported adjusted hazard ratios (HRs) for overall and progression-free survival and risk ratios (RRs) comparing adverse events in women who received gemcitabine plus pertuzumab and gemcitabine plus placebo.
We found only one completed and three ongoing RCTs that met our inclusion criteria. The completed trial randomised 131 women with relapsed ovarian cancer to receive gemcitabine and pertuzumab or placebo and gemcitabine (control). There was no statistically significant difference in overall survival (OS), progression-free survival (PFS) and response between women who received gemcitabine and pertuzumab and those who received control, although PFS approached borderline significance (adjusted HR = 0.66, 95% CI 0.43 to 1.03; P = 0.06). The trial reported a higher rate of adverse events in the gemcitabine and pertuzumab arm for most outcomes, but most were not statistically significant (although many approached borderline significance) because the trial lacked statistical power due to its relatively small size and the low number of observed events. The trial was at moderate risk of bias.
EGFR inhibitors, including pertuzumab, may add activity to conventional chemotherapy for treatment of platinum-resistant ovarian cancer. Certain subsets of women with particularly aggressive tumours resistant to conventional chemotherapy may benefit from EGFR inhibitor treatment. Further RCTs are necessary before EGFR inhibitors are introduced as first- or second-line treatment of ovarian cancer.
Similar to tumor-initiating cells (TICs), minimal residual disease (MRD) is capable of reinitiating tumors and causing recurrence. However, the molecular characteristics of solid tumor MRD cells and ...drivers of their survival have remained elusive. Here we performed dense multiregion transcriptomics analysis of paired biopsies from 17 ovarian cancer patients before and after chemotherapy. We reveal that while MRD cells share important molecular signatures with TICs, they are also characterized by an adipocyte-like gene expression signature and a portion of them had undergone epithelial-mesenchymal transition (EMT). In a cell culture MRD model, MRD-mimic cells showed the same phenotype and were dependent on fatty acid oxidation (FAO) for survival and resistance to cytotoxic agents. These findings identify EMT and FAO as attractive targets to eradicate MRD in ovarian cancer and make a compelling case for the further testing of FAO inhibitors in treating MRD.
PARP inhibitors have revolutionized the management of ovarian cancer and are being licensed for other cancer indications. The clinical trials prompting licensing decisions in ovarian cancer were ...dominated by White participants, or participant ethnicity was not documented. To compensate for this, replicative studies like L-MOCA can be run in specific ethnic groups. In the future, strategies such as mandatory collection and publication of race and ethnicity data are essential alongside concerted efforts to widen the inclusivity of trial recruitment. See related article by Gao et al., p. 2278.
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