J. Alejandro Pérez-Fidalgo

Atezolizumab With Bevacizumab and Nonplatinum Chemotherapy for Recurrent Ovarian Cancer: Final Results From the Placebo-Controlled AGO-OVAR 2.29/ENGOT-ov34 Phase III Trial

PURPOSE To evaluate atezolizumab combined with bevacizumab and non–platinum-based chemotherapy for recurrent ovarian cancer. METHODS The double-blind randomized phase III AGO-OVAR 2.29/ENGOT-ov34 trial (ClinicalTrials.gov identifier: NCT03353831 ) enrolled patients with first or second relapse of ovarian cancer ≤6 months after completing platinum-based chemotherapy (or third relapse regardless of treatment-free interval). PD-L1 status was tested centrally (VENTANA SP142 assay) in recent (<3 months) biopsies before random assignment. All patients received bevacizumab and investigator-selected chemotherapy (once weekly paclitaxel or pegylated liposomal doxorubicin) until disease progression or toxicity, plus either atezolizumab 840 mg or placebo once every 2 weeks until progression (maximum 2 years), randomly assigned 1:1, and stratified by number of previous lines, planned chemotherapy, previous bevacizumab, and PD-L1 status. Primary end points were overall survival (OS) and progression-free survival (PFS) in the intention-to-treat population. RESULTS Among 574 patients randomly assigned between September 2018 and July 2022, 72% were bevacizumab-pretreated, 36% had received three previous treatment lines, 26% had PD-L1–positive tumors, and 54% received paclitaxel with study therapy. After 418 patients had died, the hazard ratio for OS was 0.83 (95% CI, 0.68 to 1.01; P = .06; median 14.2 months with atezolizumab and 13.0 months with placebo) and the hazard ratio for PFS was 0.87 (95% CI, 0.73 to 1.04; P = .12; median 6.4 v 6.7 months, respectively). OS hazard ratios were similar regardless of PD-L1 status. Grade ≥3 adverse events occurred in 72% of atezolizumab-treated and 69% of placebo patients. CONCLUSION Combining atezolizumab with bevacizumab and chemotherapy did not significantly improve OS or PFS in patients with recurrent ovarian cancer ineligible for platinum. The safety profile was as expected from previous experience with these drugs.

SEOM–GEICO clinical guideline on epithelial ovarian cancer (2023)

AbstractIn recent years, the incorporation of new strategies to the therapeutic armamentarium has completely changed the outcomes of epithelial ovarian cancer (EOC). The identification of new predictive and prognostic biomarkers has also enabled the selection of those patients more likely to respond to targeted agents. Nevertheless, EOC is still a highly lethal disease and resistance to many of these new agents is common. The objective of this guideline is to summarize the most relevant strategies to manage EOC, to help the clinician throughout the challenging diagnostic and therapeutic processes and to provide evidence-based recommendations.

Consensus on drivers of maintenance treatment choice and patterns of care in advanced ovarian cancer

Maintenance therapies, including poly (ADP-ribose) polymerase (PARP) inhibitors and/or bevacizumab, have substantially improved the prognosis of patients with advanced ovarian cancer. Owing to the variability in treatment strategies across Europe, a Delphi study was conducted among European experts to understand the heterogeneity of clinical practice and identify key factors driving maintenance treatment decisions for advanced ovarian cancer. A pragmatic literature review was conducted to identify key questions regarding maintenance treatment strategies in patients with advanced ovarian cancer. Utilizing a Delphi methodology, consensus was assessed among a panel of 16 experts using a questionnaire based on results of the pragmatic literature review. Panelists agreed that BRCA mutation and homologous recombination status should be assessed in parallel at diagnosis, and that first-line platinum chemotherapy may be initiated concurrently. There was a consensus that alternative homologous recombination deficiency tests are acceptable provided they are clinically validated. Panelists agreed that Response Evaluation Criteria in Solid Tumors (RECIST) and CA-125 elimination rate constant K (KELIM) scores can help assess tumor chemosensitivity and guide treatment-related decisions. Panelists defined high-risk disease as International Federation of Gynecology and Obstetrics (FIGO) stage IV disease or stage III with residual disease after initial/ interval cytoreduction. Risk of disease progression was a key determinant of choice between PARP inhibitor, bevacizumab, or both in combination, as maintenance therapy in advanced ovarian cancer. Key drivers for selecting advanced ovarian cancer maintenance treatments include tumor mutational status as a key biomarker and clinician perception of the risk for early disease progression.

ENGOT-EN20/GOG-3083/XPORT-EC-042 – A phase III, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with p53 wild-type, advanced, or recurrent endometrial carcinoma: rationale, methods, and trial design

Patients with advanced/recurrent endometrial cancer have a poor prognosis and limited treatment options. Biomarkers such as tumor protein 53 ( To evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent Selinexor administered at 60 mg weekly as maintenance therapy will show manageable safety and maintain efficacy in patients with This is a prospective, multicenter, double-blind, placebo-controlled, randomized phase III study designed to evaluate the efficacy and safety of selinexor as a maintenance therapy in patients with advanced or recurrent Eligible patients must have histologically confirmed endometrial cancer, The primary endpoint is investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the intent-to-treat population. A total of 220 patients will be enrolled. Accrual is expected to be completed in 2024 with presentation of results in 2025. NCT05611931.

Clinical and molecular signature of survival and resistance to olaparib plus pegylated liposomal doxorubicin in platinum-resistant ovarian cancer: a stratified analysis from the phase II clinical trial ROLANDO, GEICO-1601

To determine the potential prognostic value of clinical and molecular biomarkers in the survival of patients with platinum-resistant ovarian cancer treated with olaparib and pegylated liposomal doxorubicin. ROLANDO was a single-arm phase II trial that included patients with high-grade serous or endometrioid tumors and at least one previous platinum-resistant recurrence regardless of Thirty-one patients were included. Median age was 57 years (range 43-75), Eastern Cooperative Oncolgy Group performance status 0/1: 32.3%/67.7% and High neutrophil/lymphocyte ratio at platinum-resistant relapse indicated poor prognosis in patients treated with olaparib plus pegylated liposomal doxorubicin. A multifactorial clinical signature was more precise than single variables for implying the prognosis and may help in therapeutic assignment after further validation in large prospective cohorts.

Controversies in the treatment of advanced ovarian cancer in the PARP inhibitors era: a Delphi consensus

Our aim was to reach a consensus on the management of the most controversial issues of advanced ovarian cancer. Nominal group and Delphi techniques were used. A steering committee of 5 experts analyzed current management of advanced ovarian cancer, identified controversies, critically analyzed the evidence, and formulated guiding statements for clinicians. Subsequently, a panel of 15 experts was selected to test agreement with the statements through two Delphi rounds. Items were scored on a 4-point Likert scale from 1 (totally disagree) to 4 (totally agree). In the first and second rounds, consensus was considered if ≥70% of answers pertained to category 1 or category 4. Overall, 112 statements were incorporated in the following areas: 1) biomarkers and hereditary ovarian cancer; 2) first-line treatment; 3) recurrent disease when platinum might be the best option; and 4) post-poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors setting. In the first Delphi round, 37 statements reached consensus and did thus not pass to the second round. After the second round, another 18 statements reached consensus. Forty-six of the consensus were with the agreement and 9 with the disagreement. Through the methodology used, a consensus was reached in approximately half of the statements. The results of this work may be useful in addressing the most controversial issues on the management of advanced ovarian cancer.

Aurora kinases in ovarian cancer

Aurora kinases (AURK) are key regulators of the mitotic spindle formation. AURK is frequently overexpressed in ovarian cancer and this overexpression has been frequently associated with prognosis in these tumours. Interestingly, AURK have been shown to interact with DNA repair mechanisms and other cell cycle regulators. These functions have brought light to Aurora family as a potential target for anticancer therapy. In the last years, two clinical trials with different AURK inhibitors have shown activity in epithelial and clear-cell ovarian cancer. Although there is a lack of predictive factors of AURK inhibition activity, recent trials have identified some candidates. This review will focus in the functions of the AURK family, its role as prognostic factor in epithelial ovarian cancer and potential clinical implications.

Atezolizumab Combined With Platinum and Maintenance Niraparib for Recurrent Ovarian Cancer With a Platinum-Free Interval >6 Months: ENGOT-OV41/GEICO 69-O/ANITA Phase III Trial

PURPOSE To evaluate atezolizumab combined with platinum-based chemotherapy (CT) followed by maintenance niraparib for late-relapsing recurrent ovarian cancer. METHODS The multicenter placebo-controlled double-blind randomized phase III ENGOT-OV41/GEICO 69-O/ANITA trial (ClinicalTrials.gov identifier: NCT03598270 ) enrolled patients with measurable high-grade serous, endometrioid, or undifferentiated recurrent ovarian cancer who had received one or two previous CT lines (most recent including platinum) and had a treatment-free interval since last platinum (TFIp) of >6 months. Patients were stratified by investigator-selected carboplatin doublet, TFIp, BRCA status, and PD-L1 status in de novo biopsy and randomly assigned 1:1 to receive either atezolizumab or placebo throughout standard therapy comprising six cycles of a carboplatin doublet followed (in patients with response/stable disease) by maintenance niraparib until progression. The primary end point was investigator-assessed progression-free survival (PFS) per RECIST v1.1. RESULTS Between November 2018 and January 2022, 417 patients were randomly assigned (15% BRCA- mutated, 36% PD-L1–positive, 66% TFIp >12 months, 11% previous poly [ADP-ribose] polymerase inhibitor after frontline CT, and 53% previous bevacizumab). Median follow-up was 28.6 months (95% CI, 26.6 to 30.5 months). Atezolizumab did not significantly improve PFS (hazard ratio, 0.89 [95% CI, 0.71 to 1.10]; P = .28). Median PFS was 11.2 months (95% CI, 10.1 to 12.1 months) with atezolizumab versus 10.1 months (95% CI, 9.2 to 11.2 months) with standard therapy. Subgroup analyses generally showed consistent results, including analyses by PD-L1 status. The objective response rate (ORR) was 45% (95% CI, 39 to 52) with atezolizumab and 43% (95% CI, 36 to 49) with standard therapy. The safety profile was as expected from previous experience of these drugs. CONCLUSION Combining atezolizumab with CT and maintenance niraparib for late-relapsing recurrent ovarian cancer did not significantly improve PFS or the ORR.

Cost-effectiveness of olaparib plus bevacizumab versus bevacizumab monotherapy in the maintenance of patients with homologous recombination deficiency-positive advanced ovarian cancer after response to first-line platinum-based chemotherapy

The PAOLA-1 trial confirmed that adding olaparib to bevacizumab significantly increased clinical benefit following response to platinum-based chemotherapy in homologous recombination deficiency-positive ovarian cancer. The objective of this analysis was to determine the cost-effectiveness of olaparib plus bevacizumab compared with bevacizumab alone as maintenance treatment for patients with homologous recombination deficiency-positive advanced ovarian cancer from the Spanish National Health System perspective. A lifetime partitioned survival model with four health states (progression-free, post-progression 1, post-progression 2, and death) and monthly cycles was developed. Long-term survival, defined as 60 months, was included as a landmark to extrapolate progression-free survival from PAOLA-1. Weibull distribution was selected as the most accurate survival model for progression-free survival extrapolation. Time to second progression and overall survival were extrapolated using parametric survival models. Mortality was obtained from the overall survival and adjusted by Spanish women mortality rates. Health state utilities and utility decrements for adverse events were included. An expert panel validated data and assumptions. Direct costs (in 2021 euros (€)) were obtained from local sources and included drug acquisition and administration, subsequent therapies, monitoring costs, adverse events, and palliative care. A 3% annual discount rate was applied to costs and outcomes. The incremental cost-effectiveness ratio was calculated as cost per quality-adjusted life-years (QALYs) gained. Deterministic and probabilistic sensitivity analyses were performed. Compared with bevacizumab alone, olaparib plus bevacizumab increased QALYs and life-years by 2.39 and 2.77, respectively, at an incremental cost of €58 295.31, resulting in an incremental cost-effectiveness ratio of €24 371/QALY. Probabilistic sensitivity analysis demonstrated that olaparib plus bevacizumab had a 49.5% and 90.3% probability of being cost-effective versus bevacizumab alone at a willingness-to-pay threshold of €25 000 and €60 000 per QALY gained, respectively. For patients with homologous recombination deficiency-positive advanced ovarian cancer, olaparib plus bevacizumab is a cost-effective maintenance therapy compared with bevacizumab alone in Spain.

Prospective Real-World Gynaecological Cancer Clinical Registry with Associated Biospecimens: A Collaborative Model to Promote Translational Research between GEICO and the Spanish Biobank Network.

Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated with biobanks for the collection of real-world data and biological samples of gynaecological cancer patients. This collaborative project aims to promote research by providing broad access to high-quality clinical data and biospecimens for future research according to the needs of investigators and to increase diagnostic and therapeutic opportunities for gynaecological cancer patients in Spain. The VCR will include the participation of more than 60 Spanish hospitals entering relevant clinical information in harmonised electronic case report forms (eCRFs) in four different cohorts: ovarian, endometrial, cervical, and rare gynaecological cancers (gestational trophoblastic disease). Initial data for the cases included till December 2021 are presented. The model described herein establishes a real-world win-win collaboration between multicentre structures, promoted and supported by GEICO, that will contribute to the success of translational research in gynaecological cancer.

Selinexor in Maintenance Therapy After Systemic Therapy for Participants With p53 Wild-Type, Advanced or Recurrent Endometrial Carcinoma

The purpose of this study is to evaluate the efficacy and safety of selinexor as a maintenance treatment in patients with p53 wt endometrial carcinoma (EC), who have achieved a partial response (PR) or complete response (CR) (per Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST v 1.1\]) after completing at least 12 weeks of platinum-based therapy. A total of 276 participants will be enrolled in the study and randomized in a 1:1 ratio to maintenance therapy with either selinexor or placebo.

Platinum-based Chemotherapy With Atezolizumab and Niraparib in Patients With Recurrent Ovarian Cancer

Atezolizumab in this study is expected to have a positive benefit-risk profile for the treatment of patients with platinum-sensitive relapse of ovarian cancer. Of interest, atezolizumab is being investigated also in combination with platinum-based doublet chemotherapy in second line (2L)/ third line (3L) platinum-sensitive recurrent ovarian cancer patients in ATALANTE (NCT02891824), which also includes bevacizumab in the combination. The study is proceeding as expected after \>100 patients enrolled and under independent Data Monitoring Committee (IDMC) supervision. Platinum-containing therapy is considered the treatment of choice for patients with platinum-sensitive relapse. However the duration of response and the prolongation of the progression free interval with chemotherapy are usually brief, among other because these chemotherapy regimens cannot be continued until progression as they are associated with neurological, renal and hematological toxicity and cannot generally be tolerated for more than about 6 to 9 cycles. Niraparib received FDA approval in March 2017 as maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. Recently, the European Medicines Agency (EMA) has also approved niraparib as maintenance monotherapy. Despite the progress brought about by niraparib, there is a need for a more effective treatment to extend the progression free interval in this patient population. The combination with immune checkpoint inhibitors such as anti-death protein 1 (anti-PD1) or anti-death protein ligand 1 (anti-PD-L1) has a compelling rationale to this aim, especially under the light of the emerging clinical data of this combination. The use of atezolizumab concurrent to platinum-containing chemotherapy followed by niraparib as maintenance therapy after completion of chemotherapy, as per normal clinical practice, may provide further benefit to patients in terms of prolonging the progression free interval and increasing the interval between lines of chemotherapy, hence delaying further hospitalization and the cumulative toxicities associated with chemotherapy. Additionally, preliminary studies with atezolizumab suggest an acceptable tolerability profile for long term clinical use in recurrent ovarian cancer patients and other indications.

Atezolizumab With Bevacizumab and Chemotherapy vs Bevacizumab and Chemotherapy in Early Relapse Ovarian Cancer

This is a phase III, randomized, partially blinded, multicenter trial to evaluate the efficacy and safety of atezolizumab plus bevacizumab and chemotherapy compared to placebo plus bevacizumab and chemotherapy in patients with recurrent ovarian-, fallopian tube, or primary peritoneal cancer with 1st or 2nd relapse within 6 months after platinum based chemotherapy or 3rd relapse.