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Abstract
Background Phase III trial data have shown a significant benefit by the addition of a maintenance treatment with niraparib, irrespective of BRCA or HRD status, in patients with advanced high-grade ovarian cancers; and, a significant benefit of the combination of olaparib and bevacizumab compared with bevacizumab monotherapy in HRD positive patients. However, it is unclear whether a PARP inhibitor monotherapy is sufficient, or if the addition of bevacizumab is needed.
Primary Objectives This trial will investigate if the treatment strategy of carboplatin/paclitaxel/bevacizumab/niraparib is superior to the treatment of carboplatin/paclitaxel/niraparib in an all-comer population.
Study Hypothesis Adding bevacizumab to chemotherapy followed by niraparib maintenance improves progression-free survival in patients with newly diagnosed advanced ovarian cancer.
Trial Design AGO-OVAR 28/ENGOT-ov57 is an international, multicenter, randomized, prospective phase III trial within the the European Network for Gynecological Oncological Trial (ENGOT), led by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) study group. All patients should have completed the first cycle of chemotherapy (carboplatin and paclitaxel) as part of the Study Run-In-Period. Prior to day 1 of cycle 2, patients with a valid central tumor BRCA (tBRCA) test result were randomized in a 1:1 ratio into either: Arm 1, to receive five additional cycles of carboplatin and paclitaxel q21d, followed by niraparib for up to 3 years; or Arm 2, to receive five additional cycles of carboplatin and paclitaxel plus bevacizumab q21d, followed by bevacizumab q21d (for up to 1 year), and niraparib for up to 3 years.
Major Inclusion/Exclusion Criteria The trial population is composed of adult patients with newly diagnosed, advanced high-grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer FIGO III/IV (except FIGO IIIA2 without nodal involvement). Patients who are scheduled for neoadjuvant chemotherapy and interval debulking surgery are also eligible for the trial.
Primary Endpoint The primary endpoint is progression-free survival.
Sample Size The study plans to recruit 970 patients (485 patients in each arm).
Estimated Dates For Completing Accrual And Presenting Results The Last-Patient-In is expected to be enrolled in September 2024, with presentation of the primary endpoint in 2028.
Trial Registration NCT05009082; EudraCT Number: 2021-001271-16
- Ovarian Cancer
Data availability statement
All data relevant to the study are included in the article.
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Introduction
Epithelial ovarian cancer and related malignancies (primary peritoneal carcinoma and fallopian tube carcinoma) represent the fifth most common cause of cancer-related death among women in Europe and the United States.1 Ovarian cancer alone is the fourth most common cause of cancer-related death in women, with an estimated 200 000 cases and 125 000 deaths annually worldwide. Currently, the primary treatment for ovarian cancer consists of surgical debulking of the macroscopic disease, followed by a systemic platinum-based chemotherapy.2 For patients with advanced stage disease, national and international guidelines recommend combination therapy with an intravenous taxane plus carboplatin for six cycles, with the preferred regimen specified as paclitaxel (175 mg/m2) plus carboplatin (AUC5) every 3 weeks for six cycles.3 The vascular endothelial growth factor inhibitor bevacizumab is approved in the first-line maintenance ovarian cancer setting, in combination with carboplatin and paclitaxel, followed by bevacizumab maintenance. The EU approval of bevacizumab for the first-line treatment of advanced ovarian cancer patients was based on the primary analysis of the GOG-218 trial (hazard ratio (HR) 0.71; 95% confidence interval (CI) 0.61 to 0.83; p<0.0001)4 and the ICON7 trial (HR 0.81; 95% CI 0.70 to 0.94; p=0.0041),5 which demonstrated a 3.7 month and 1.7 month improvement in median progression-free survival, respectively. Neither the final mature analysis of the GOG-218 trial nor the ICON7 trial showed a difference in overall survival.6 In both the GOG-218 and ICON7 trials, bevacizumab treatment was shown to be associated with significant toxicity, including but not limited to hypertension, neutropenia, venous thromboembolic events, febrile neutropenia, wound healing complications, and gastrointestinal perforation/fistula/abscess.7 Data from the PRIMA trial have shown a significant benefit in patients at high risk for relapse, by the addition of maintenance treatment with niraparib irrespective of tumor biology (HRD status) in high-grade ovarian cancers after chemotherapy treatment.8 The benefit of the addition of niraparib was significant compared with placebo, with a HR of 0.62; and, depending on tumor biology, was also consistently significant in subsequent subgroup analysis (HR 0.43–0.68). The PAOLA-1 trial evaluated the maintenance treatment in patients with advanced ovarian cancer by the combination of olaparib and bevacizumab, and also showed a significant benefit in the overall population (HR 0.59); and, depending on tumor biology, subgroup analysis compared with bevacizumab (HR 0.31–0.92).9 In conclusion, it is unclear whether the standard option for PARP inhibitor maintenance treatment alone is sufficient, or if the addition of bevacizumab is needed.
Therefore,the AGO-OVAR 28 trial will investigate if the treatment strategy of carboplatin/paclitaxel/bevacizumab/niraparib is superior to the treatment of carboplatin/paclitaxel/niraparib in an all-comer population.
Methods
Trial Design
This is a phase III, randomized, open, multicenter trial to evaluate the efficacy and safety of niraparib in combination with bevacizumab, compared with niraparib alone, in patients with carboplatin-taxane-based chemotherapy in advanced ovarian cancer. Patients will be assessed for eligibility during the 28-day screening period. If a patient has completed screening and meets all eligibility criteria, she will be enrolled in the Study-Run-In-Period, and then receive the first cycle of chemotherapy (carboplatin AUC5 and paclitaxel 175 mg/m²) while determination of central tumor BRCA (tBRCA) status is ongoing.
Patients who have had primary debulking surgery must receive cycle 1 of chemotherapy within a maximum of 8 weeks after upfront primary surgery. It is recommended that cycle 1 begins a minimum of 3 weeks after the primary debulking surgery; however, it can be delayed until the surgical wound is fully healed. Once a patient’s tBRCAm status (based on central tBRCA testing) is known, prior to day 1 of cycle 2, patients will be randomized. Should the central tBRCA assay (TruRisk Panel by the Center for Hereditary Breast and Ovarian Cancer) fail to determine the presence or absence of a deleterious/suspected deleterious mutation prior to the start of cycle 2 (eg, owing to technical failure or a delay in testing), the patient will not be randomized and will be excluded from the study, even if she fulfills all other eligibility criteria. Prior to day 1 of cycle 2 of chemotherapy, patients with a valid central tBRCA test result will be randomized in a 1:1 ratio in the following treatment arms:
Arm 1: patients will receive an additional five cycles of carboplatin AUC5 and paclitaxel 175 mg/m² q21d, followed by niraparib 200 or 300 mg once daily for up to a total of 3 years.
Arm 2: patients will receive a further five cycles of carboplatin AUC5 and paclitaxel 175 mg/m² plus bevacizumab q21d, followed by bevacizumab q21d (for up to 1 year) and niraparib 200 or 300 mg once daily for up to a total of 3 years (figure 1).
The dosage of niraparib will be dependent on baseline criteria: 200 mg niraparib for body weight <77 kg OR platelets <150 x 109/L; or 300 mg niraparib for body weight ≥77 kg AND platelets ≥150 x 109/L.
Study design.
Study treatment will continue until disease progression per RECIST guideline 1.1,10 unacceptable toxicity, a patient or investigator decision to discontinue treatment, or the end of planned treatment (bevacizumab maintenance for 12 months, niraparib maintenance for 36 months). Once patients have been discontinued from all study treatments, other treatment options will be at the discretion of the investigator. The Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) study group is the sponsor of the trial. Financial support and drug supply is covered by GSK. The trial is to be run under the umbrella of the European Network for Gynecological Oncological Trial (ENGOT), with the AGO study group as the leading group. Further participating groups are AGO Austria, the Belgian Gynecologic Oncology Group (BGOG), the Central and Eastern European Gynecologic Oncology Group (CEEGOG), the Spanish Ovarian Cancer Research Group (GEICO), the Mario Negri Gynecologic Oncology group (MaNGO), and Nord-Ostdeutsche Gesellschaft für gynäkologische Onkologie (NOGGO). It is planned to recruit the patients in approximately 200 sites. The study obtained ethics approval by the Landesärztekammer Nordrhein, Germany, under the approval file ID 2 022 116. Patients must give informed consent before taking part in the trial.
Participants
The screening of the patients will be performed in the participating study sites. The target population comprises women who are ≥18 years of age with newly diagnosed, histologically confirmed, advanced (FIGO stage III/IV, except FIGO IIIA2 without nodal involvement) invasive high-grade epithelial (serous, endometrioid, mucinous (infiltrative), and clear cell) ovarian cancer, who have either undergone upfront primary surgery or plan to undergo chemotherapy with interval debulking surgery; with the planned interval debulking surgery population including patients who have undergone partial or unsuccessful primary surgery and are also planned to have interval debulking surgery. Key exclusion criteria include non-epithelial tumor origin of the ovary, ovarian tumors of low malignant potential (eg, borderline tumors), low-grade tumors, and planned intraperitoneal cytotoxic chemotherapy.11
Primary Endpoints
The primary endpoint is progression-free survival. Secondary endpoints include progression free survival according to tBRCA status, overall survival, time to first subsequent therapy (TFST), progression-free survival 2, time to second subsequent therapy (TSST), safety and tolerability, and quality of life.
Sample Size
We expect that screening of 1078 patients will result in 970 subjects eligible for trial. The recruitment period will last for 24 months. We assume a median progression-free survival of 23 months in Arm 1, which was the median progression-free survival of the control arm of the VELIA trial.12 A prolongation of 6 months to 29 months for Arm 2 is regarded as the minimal clinically relevant difference, which corresponds to a HR of 0.793 between arms. We calculate that 586 progression-free survival events are needed to achieve a power of 80% for a two-sided log-rank test with significance level 0.05. Assuming exponential progression-free survival, an accrual period of 24 months and a drop-out rate of 10%, 970 patients need to be recruited to observe the targeted event number after 30 additional months of follow-up.
Randomization and Blinding
Randomization is performed centrally through KKS Marburg. Randomization should be done within 3 days before day 1 of cycle 2, provided that valid central tBRCA status is available. Random assignment will be conducted in a 1:1 ratio to the treatment arms with the following stratification factors: surgical outcome, complete resection of all macroscopic tumor at primary debulking surgery, tumor biology (tBRCA status), and planned bevacizumab dosing (7.5 mg/kg vs 15 mg/kg body weight). The randomization sequence will be generated by KKS Marburg using permuted block randomization with random block length stratified for above mentioned factors.
Statistical Methods
Confirmatory testing of H0: “Equal progression-free survival between randomized treatment arms” will be based on a two-sided stratified log-rank test stratified by randomization stratification factors at significance level 0.05. A stratified Cox regression will be employed to estimate the HR together with its 95% CI for the comparison of progression-free survival between randomized treatments. The proportional hazards assumption will be explored, and if strong evidence for its violation is found, we will employ restricted mean survival methods to compare the progression-free survival between randomized treatments. The analysis of progression-free survival will be performed in the intention-to-treat population. The analysis will be repeated in the per protocol population as a sensitivity analysis.
Discussion
PARP inhibitor maintenance treatment of patients with high-grade ovarian cancer has revolutionized first-line therapy, as the SOLO-1, PRIMA, PAOLA-1, PRIMA, and ATHENA trials have shown that progression-free survival was significantly improved in distinctive subgroups if PARP inhibitors were given, in comparison to placebo.8 9 13 14 However, some questions remain, and AGO-OVAR 28/ENGOT-ov57 will address one of the most important questions. Data from the PRIMA trial showed a significant benefit by the addition of a maintenance treatment with niraparib irrespective of tumor biology (HRD status) in high-grade ovarian cancers.2 The PAOLA-1 trial evaluated the maintenance treatment in patients with advanced ovarian cancer by the combination of olaparib and bevacizumab, and also showed a significant benefit in the overall population compared with bevacizumab.3 Thus, it is unclear if the standard option for a PARP inhibitor maintenance treatment alone is sufficient or if the addition of bevacizumab is needed.
The planning of the trial started at a time when HRD testing was not widely available, and therefore, biomarker testing was limited to BRCA testing. However, as this has changed in the meantime, additional HRD testing and an analysis of HRD defined subgroups is planned.15
If AGO-OVAR 28/ENGOT-ov57 reaches its primary endpoint, we believe that bevacizumab should be the preferred partner for PARP-inhibitor-based maintenance therapy in patients with advanced high-grade ovarian cancer. Based on the stratification factors, further insight might be gained as to whether distinct subgroups would benefit from the combination of niraparib and bevacizumab, or whether niraparib monotherapy is a sufficient alternative.
Data availability statement
All data relevant to the study are included in the article.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Ethikkommission der Landesärztekammer Nordrhein. Participants gave informed consent to participate in the study before taking part.
References
Footnotes
Contributors FH is the guarantor and accepts full responsibility for the work or the conduct of the study, had access to the data, and controlled the decision to publish. FH, CM, SH, AR, DC, LG, NC, BS, NDG, PW, AH, JS, MGM, PCS, EH, JH, SP, and PH provided substantial contributions to the conception or design of the work. As the manuscript describes a trial in progress, we anticipate that all authors will be participating in the acquisition, analysis, or interpretation of data for the work. FH, CM, SH, AR, DC, LG, NC, BS, NDG, PW, AH, JS, MGM, PCS, EH, JH, SP, and PH were included in drafting the work or revising it critically for important intellectual content. FH, CM, SH, AR, DC, LG, NC, BS, NDG, PW, AH, JS, MGM, PCS, EH, JH, SP, and PH gave the final approval of the version to be published. FH, CM, SH, AR, DC, LG, NC, BS, NDG, PW, AH, JS, MGM, PCS, EH, JH, SP, and PH gave the agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding All support for the present manuscript (eg, funding, provision of study materials, article processing charges, etc.) and the grant for the reported trial is from GSK.
Competing interests Grants or contracts from any entity is reported by PH (AstraZeneca, Roche, GSK, Genmab, Immunogen, Seagen, Clovis, and Novartis (all institutional)), by JS (Roche, MSD, GSK, Tesaro, AstraZeneca, MSD, Eisai, Merck, and Novocure), and by NC (Roche, GSK, and AstraZeneca). Consulting fees are reported by FH (NovoCure, PharmaMar, AstraZeneca, Roche, Tesaro, GSK, Clovis, and Amedes), by CM (MSD, Roche, GSK, Seagen, Novartis, and PharmaMar), by LG (GSK, MSD, AstraZeneca, PharmaMar, and Clovis Oncology), by BS (GSK, AstraZeneca, Roche Pharma, MSD, and Eisai), by AH (AstraZeneca, Celgen, GSK, LEO Pharma, MedConcept GmbH, Med update GmbH, Medicultus, Pfizer, Promedicis GmbH, Softconsult, Roche Pharma AG, and Streamedup!GmbH), by PH (AstraZeneca, Roche, GSK, Clovis, Immunogen, MSD, Miltenyi, Novartis, and Eisai), by JS (Immunogen, Incyte, GSK, AstraZeneca, Clovis, Novocure, MSD Eisai, and Merck), and by NC (AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, Pieris, and Roche). Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events are reported by FH (NovoCure, PharmaMar, AstraZeneca, Roche, Tesaro, GSK, Clovis, and Amedes), by CM (GSK, AstraZeneca, and MSD), by BS (GSK, AstraZeneca, Roche, MSD, and Eisai), by PW (AstraZeneca, Roche, MSD, Eisai, Lilly, GSK, and Daiichi Sankyo), by NDG (Roche, AstraZeneca, Clovis Myriad, Novartis, GSK, and MSD), by PH (Amgen, AstraZeneca, GSK, Roche, Sotio, Stryker, Zai Lab, MSD, Clovis, Eisai, Mersana, and Exscientia), by JS (Immunogen, Incyte, GSK, AstraZeneca, Clovis, Novocure, Bristol Myers Squibb, Eisai, and Novartis), and by NC (AstraZeneca, Novartis, Clovis Oncology, GSK, and MSD/Merck). Participation on a Data Safety Monitoring Board or Advisory Board is reported by CM (GSK and Karypharma), by BS (GSK, AstraZeneca, Roche, MSD, and Eisai), by JS (Immunogen, Incyte, GSK, AstraZeneca, Clovis, Novocure, Bristol Myers Squibb, MSD, Merck, Bayer, and PharmaMar), and by NC (AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, Pieris, and Roche). Support for attending meetings and/or travel is reported by LG (GSK, MSD, AstraZeneca, and Clovis Oncology) by BS (GSK, AstraZeneca, and Roche) by NDG (AstraZeneca), by PW (Gilead, Novartis, Roche, MSD, AstraZeneca, Lilly, Eisai, Pfizer, GSK, and Daiichi Sankyo), by PH (AstraZeneca), and by JS (GSK, AstraZeneca, Roche, Novocure, Immunogen, Incyte, MSD, and Eisei). Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid is reported by BS (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe), JS (ENGAGE, ESGO, ASCO, ESGO, GCIG, Deutsche Stiftung Eierstockkrebs). AGOJS reports receipt of equipment, materials, drugs, medical writing, gifts, or other services. Medical writing services by MSD. SH reports none; AR reports none; DC reports none; MGM reports none; PCS reports none; EH reports none; SP reports none.
Provenance and peer review Not commissioned; internally peer reviewed.