•This ESMO Clinical Practice Guideline provides key recommendations for managing endometrial cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, treatment ...and follow-up.•Treatment and management algorithms according to risk groups and for advanced/metastatic or recurrent disease are provided.•Authorship includes a multidisciplinary group of experts from different institutions in Europe, the USA and South America.•Recommendations are based on available scientific data and the authors’ collective expert opinion.
Among patients with platinum-sensitive, recurrent ovarian cancer, the use of niraparib, a PARP inhibitor, was associated with a significantly longer duration of progression-free survival than ...placebo, with moderate bone marrow toxicity.
Ovarian cancer is a leading cause of death from gynecologic cancers worldwide.
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Despite a high initial response rate to platinum and taxane treatment in patients with advanced cancer, the effectiveness of the treatments diminishes over time, and most patients have a relapse.
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Platinum retreatment is used in patients in whom there is an assumed platinum sensitivity, with diminishing effectiveness and a cumulative increase in toxicity.
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Niraparib is a highly selective inhibitor of poly(adenosine diphosphate ADP–ribose) polymerase (PARP) 1/2,
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nuclear proteins that detect DNA damage and promote its repair. Clinical studies have evaluated PARP inhibitors in patients with recurrent ovarian . . .
This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the fifth Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November ...2015. Three important questions were identified: (i) What are the subgroups for clinical trials in ROC? The historical definition of using platinum-free interval (PFI) to categorise patients as having platinum-sensitive/resistant disease was replaced by therapy-free interval (TFI). TFI can be broken down into TFIp (PFI), TFInp (non-PFI) and TFIb (biological agent-free interval). Additional criteria to consider include histology, BRCA mutation status, number/type of previous therapies, outcome of prior surgery and patient reported symptoms. (ii) What are the control arms for clinical trials in ROC? When platinum is considered the best option, the control arm should be a platinum-based therapy with or without an anti-angiogenic agent or a poly (ADP-ribose) polymerase (PARP) inhibitor. If platinum is not considered the best option, the control arm could include a non-platinum drug, either as single agent or in combination. (iii) What are the endpoints for clinical trials in ROC? Overall survival (OS) is the preferred endpoint for patient cohorts with an expected median OS < or = 12 months. Progression-free survival (PFS) is an alternative, and it is the preferred endpoint when the expected median OS is > 12 months. However, PFS alone should not be the only endpoint and must be supported by additional endpoints including pre-defined patient reported outcomes (PROs), time to second subsequent therapy (TSST), or time until definitive deterioration of quality of life (TUDD).
Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. ...The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC).
Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review in the intention-to-treat (ITT) population and in the prespecified FRα high population.
A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT hazard ratio (HR), 0.98, P = 0.897 or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy.
In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.
•In platinum-resistant EOC MIRV did not significantly improve PFS over chemotherapy.•No unexpected toxicities were observed, and tolerability profiles were consistent with those observed in previous studies.•The most promising signals of efficacy were observed with MIRV in patients with high FRα expression.•The findings support ongoing trials designed to select the patients with EOC most likely to derive benefit from this agent.
•This ESMO Clinical Practice Guideline provides key recommendations for managing epithelial ovarian cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, ...treatment and follow-up.•Treatment and management algorithms for early and advanced disease, as well as recurrent disease, are provided.•ESMO-MCBS and ESCAT scores are given to describe the levels of evidence for treatment choices including targeted therapies.•The multidisciplinary expert author group stems from different institutions and countries in Europe, Asia and the USA.
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 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.
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.
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.
•First PARPi trial to show clinically meaningful OS benefit in HRD+ (BRCA/non-BRCA) newly diagnosed advanced ovarian cancer.•5-Year OS rate in HRD+ disease was 66% with olaparib + bevacizumab versus 48% with placebo + bevacizumab.•Forty-six percent of HRD+ patients receiving olaparib + bevacizumab were progression free at 5 years, versus 19% on bevacizumab alone.•No new safety signals were observed, and the incidence of myelodysplastic syndrome/acute myeloid leukemia remained low.•Maintenance olaparib + bevacizumab as a standard of care may enhance potential for cure for HRD+ disease in this setting.
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