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Although around 80% of endometrial cancers are diagnosed at early stages and present with a 5-year survival rate exceeding 95%, patients with advanced and recurrent disease show a poor prognosis and low response rates to standard chemotherapy. In the era of targeted therapy, the great advances in the understanding of programmed death-ligand 1 (PD-L1) upregulation in cancer cells, which is responsible for tumor immune escape, have contributed to the increasing interest in immune checkpoint inhibitors as a promising strategy for the treatment of several refractory solid malignancies, including endometrial cancer. Several clinical trials have investigated the efficacy and safety of immune checkpoint inhibitors in endometrial cancer, which already led to the approval of the anti-programmed cell death protein 1 (anti-PD-1) antibody pembrolizumab as a satisfactory alternative for selected patients with unresectable or metastatic disease. As the future of cancer treatment will probably rely on combination therapy strategies, currently, innovative ongoing trials are exploring the potential role of immune checkpoint inhibitors associated with chemotherapy, radiotherapy, and other targeted therapies. Moreover, further research is warranted to discover new specific biomarkers that can accurately predict the response to immunotherapy.

In the era of single and combination maintenance therapies as well as platinum and Poly (ADP-ribose) polymerase inhibitors (PARPi) resistance, the choice of subsequent treatments following first-line platinum-based chemotherapy in recurrent ovarian cancer (ROC) patients has become increasingly complex. Within the ovarian cancer treatment algorithm, particularly in the emerging context of PARPi resistance, the role of trabectedin, in combination with pegylated liposomal doxorubicin (PLD) still preserves its significance. This paper offers valuable insights into the multifaceted role and mechanism of action of trabectedin in ROC. The main results of clinical trials and studies involving trabectedin/PLD, along with hints of Breast Cancer genes (BRCA)-mutated and BRCAness phenotype cases, are critically discussed. Moreover, this review provides and contextualizes potential scenarios of administering trabectedin in combination with PLD in ROC, according to established guidelines and beyond.

Olaparib is currently approved in maintenance treatment of advanced ovarian cancer after response to first-line chemotherapy for breast related cancer antigens (BRCA) mutated patients. The use of this agent is based on data from SOLO1 study that observed a decreased risk of disease progression or death and a median progression-free survival about 36 months longer in case of therapy with olaparib. However, this trial recruited only patients with advanced stage ovarian cancer. The aim of this review is to retrace the available data in order to clarify the potential efficacy and feasibility of olaparib administration in newly diagnosed epithelial ovarian cancer also in early stages. Keywords: newly diagnosed ovarian cancer, early stage ovarian cancer, olaparib, PARPinhibitors, BRCA mutation

Introduction/BackgroundDespite optimal surgery and appropriate first-line chemotherapy, 70%–80% of patients with epithelial ovarian cancer will develop disease relapse. The aim of this study is to evaluate the radiological distribution of disease at the first recurrence in patients with advanced ovarian cancer treated with different maintenance therapies (PARP-inhibitors versus Bevacizumab).MethodologyWe retrospectively collected data on patients with recurrent advanced ovarian cancer from January 2017 to December 2022, who had III-IV FIGO stage at the diagnosis, a complete debulking (primary or interval surgery) followed by adjuvant chemotherapy and maintenance therapy. We included those with an available contrast-enhanced CT at the time of recurrence (clinical, serological or radiological).Recurrence was assessed at radiological imaging as: i) visible vs. non-visible solid tissue; ii) macronodular vs. micronodular pattern; iii) number of localisations (oligometastatic (<4 sites) vs. multi-metastatic; iv) site of relapse (lympnodal only vs. others).ResultsWe evaluated 80 patients; 40 had Bevacizumab and 40 had PARP-i.The incidence of recurrence without any clearly visible soft tissue was significantly higher during Bevacizumab (20% vs 10%; p=0.04). Micronodular diffuse relapse was more frequent in patients treated with Bevacizumab (58% vs 30%; p=0.03). Oligometastatic recurrence was more frequent in PARP-i (45% vs 24%; p=0.03). No difference was found in only nodal relapse between the two groups (18% vs 15%, p>0.05).ConclusionThe recurrence pattern in ovarian cancer significantly differs based on the administered maintenance therapy at first line. This is a valuable information for clinicians to i) plan secondary cytoreduction; ii) avoid delayed diagnosis of recurrence in patients treated with Bevacizumab.DisclosuresNone.

ObjectivePoly (ADP-ribose) polymerase (PARP) inhibitor resistance is problematic in epithelial ovarian cancer management and sequencing strategies may be performed to overcome this issue. In this context, our study evaluated the role of non-platinum doublet pegylated liposomal doxorubicin/trabectedin in ovarian cancer platinum-sensitive patients who experienced disease progression under PARP inhibitor maintenance.MethodsThis case–control study includes patients with recurrent epithelial ovarian cancer treated between March 2016 and April 2021 who progressed under PARP inhibitor maintenance. Data of patients treated with pegylated liposomal doxorubicin/trabectedin (experimental group) were matched 1:1 with a series of patients who received platinum-based treatment (control group). The study outcomes were overall clinical benefit (including complete, partial, and stable response), progression-free survival, and overall survival. The safety of both treatments was also evaluated.ResultsA total of 26 patients in both groups were analyzed. Clinical benefit was achieved in 15 (57%) patients in the study group and 17 (65%) patients in the control group (p=0.38). Patients receiving pegylated liposomal doxorubicin/trabectedin had 5 months of progression-free survival, compared with 5 months in patients treated with platinum-based treatment (p=0.62). Patients in the experimental group achieved a median overall survival of 16 months compared with 19 months in the control group (p=0.26) There was no difference concerning severe toxicities (G3-G4) between groups, except for hepatic toxicity, which was experienced in 30% of the patients receiving pegylated liposomal doxorubicin/trabectedin and none in the control group (p<0.009).ConclusionsPegylated liposomal doxorubicin/trabectedin might be an alternative option to platinum-based treatment in patients experiencing disease progression during PARP inhibitor maintenance with an acceptable toxicity profile. This might be a therapeutic option in this setting, sparing platinum compounds for subsequent relapse.

ObjectivesDespite the individualized starting dose for maintenance therapy in ovarian cancer, the niraparib dose reduction rate remains high. The aim of this study was to evaluate the impact of niraparib dose reduction on progression-free survival in newly diagnosed primary advanced ovarian cancer and recurrent ovarian cancer patients. We also aimed to compare the reduction rates and the safety of niraparib on primary and relapse groups, and identify which factors may predict dose reduction.MethodsPatients with primary or recurrent ovarian cancer in maintenance who received niraparib between 2019 and 2022 were retrospectively evaluated. Niraparib dosing was based on individualized starting dose of 300 or 200 mg/day. The impact of niraparib dose reductions was focused on patients treated with 200 or 100 mg in both groups. Reduction rates, adverse events and predictive factors of reduction were assessed in each study group. The primary endpoint was progression-free survival in primary and relapse groups; the secondary endpoints were the reduction rates, the safety and tolerability of niraparib in both groups.ResultsOf 215 patients identified, 124 (57.7%) primary and 91 (42.3%) recurrent ovarian cancer patients were included. The majority of patients started niraparib at 200 mg/day (92.7% primary and 80.2% relapse group); dose reductions from 300 or 200 mg/day to 200 or 100 mg/day occurred more frequently within cycles 1–3 (67% primary and 45% relapse group, p=0.001). Grade≥3 adverse events were lower in the relapse group (54.8% primary and 35.1% relapse, p=0.001). In both groups, dose modifications over the treatment did not significantly impair median progression-free survival. Univariate and multivariate analysis demonstrated that weight and platinum-doublets were possible risk factors for dose reduction.ConclusionsNiraparib dose reduction occurs in almost half of patients within cycles 1–3, although it is significantly more common in the first-line setting. Survival outcomes seem not to be impaired by dose reduction.

Introduction/BackgroundPARP inhibitors resistance is a problematic step in epithelial ovarian cancer (EOC) management and sequencing strategies should be carried out to overcome it. In this context, to lack of data, our study evaluated the role of a non-platinum doublet pegylated liposomal doxorubicin(PLD)/trabectedin in ovarian cancer platinum-sensitive patients who experienced disease progression under PARP inhibitors maintenance.MethodologyThis is a case-control study including patients with recurrent EOC treated between 2016–2021 who progressed under PARP inhibitors maintenance. Data of patients, treated with PLD/trabectedin were matched 1:1 with a series of patients who received platinum-based treatment. The study outcomes were: overall clinical benefit (including complete, partial and stable response), progression-free survival(PFS) and overall survival(OS). The safety of both treatments was also evaluated.Abstract 2022-RA-634-ESGO Figure 1Progression free survivalAbstract 2022-RA-634-ESGO Figure 2Overall survivalResults26 patients in both groups were analyzed. Clinical benefit was achieved in 15 (57%) patients in study group and 17 (65%) in control one (p = 0.38). Patients receiving PLD/trabectedin had 5 months of PFS, compared with 5 months of patients treated with platinum-based treatment (p = 0.62). OS of the entire population was 84 months (95% CI = 68–99), with no significant difference between the experimental and control group (75 vs. 87 months, p = 0.30). No clinically relevant differences were found in terms of safety.ConclusionPLD/trabectedin might be as effective as a platinum-based treatment in patients experiencing disease progression while on PARP inhibitors maintenance, with acceptable toxicity profile. Therefore, it could be a good therapeutic option in this setting, sparing platinum compounds for subsequent relapse.

Ovarian cancer (OC) is the second most common cause of death in women with gynecological cancer. Considering the poor prognosis, particularly in the case of platinum-resistant (PtR) disease, a huge effort was made to define new biomarkers able to help physicians in approaching and treating these challenging patients. Currently, most data can be obtained from tumor biopsy samples, but this is not always available and implies a surgical procedure. On the other hand, circulating biomarkers are detected with non-invasive methods, although this might require expensive techniques. Given the fervent hope in their value, here we focused on the most studied circulating biomarkers that could play a role in PtR OC.