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Abstract
Background Platinum based chemotherapy is the treatment of choice for ovarian cancer patients with a platinum treatment free interval of >6 months. Niraparib is an oral poly (ADP-ribose) polymerase inhibitor approved as maintenance therapy after a response to platinum rechallenge, regardless of BRCA status. Atezolizumab is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). A combination of poly (ADP-ribose) polymerase inhibitor and anti-PD-L1/programmed cell death protein 1 (PD-1) has shown synergy in preclinical models and promising clinical activity.
Primary objective To determine whether the addition of atezolizumab to carboplatin based chemotherapy and to subsequent maintenance with niraparib improves progression free survival compared with placebo in patients with recurrent disease and a platinum treatment free interval of >6 months.
Trial design The Atezolizumab and NIraparib Treatment Association (ANITA) trial is a GEICO (Grupo Español de Investigación en Cáncer de Ovario) led phase III, randomized, double-blinded, multicenter European Network for Gynecological Oncological Trials (ENGOT) study. Patients will be randomized to arm A (control arm) consisting of platinum based chemotherapy (investigator’s choice) plus a placebo of atezolizumab followed by maintenance niraparib plus a placebo of atezolizumab, or to arm B (experimental arm) consisting of platinum based chemotherapy (investigator’s choice) plus atezolizumab followed by maintenance niraparib plus atezolizumab.
Major inclusion/exclusion criteria Inclusion criteria are women aged over 18 years, diagnosed with relapsed high grade serous, endometrioid, or undifferentiated ovarian, fallopian tube, or primary peritoneal carcinoma. Patients are eligible if they received no more than two previous lines of chemotherapy, relapsed ≥6 months after the last platinum containing regimen, and have at least one measurable lesion according to the response evaluation criteria in solid tumors, version 1.1.
Primary endpoint The primary endpoint for this study is progression free survival.
Sample size Approximately 414 patients will be recruited and randomized in a 1:1 ratio, with the aim of demonstrating a benefit in progression free survival for the experimental arm with a hazard ratio of O.7, using a two sided alpha of 0.05 and a power of 80%.
Estimated dates for completing accrual and presenting results The trial was launched in the fourth quarter of 2018 and is estimated to close in the second quarter of 2021. Mature results for progression free survival are expected to be presented by 2023.
Trial registration Clinicaltrials.gov NCT03598270.
- medical oncology
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Introduction
Up to 70% of patients with high grade epithelial ovarian cancer will relapse during the first 3 years after diagnosis, depending on the initial International Federation of Gynecology and Obstetrics (FIGO) stage, residual tumor after upfront surgery, administration of neoadjuvant chemotherapy, and use of maintenance therapy. With this scenario, the investigation of new therapies is a need for improving patient outcomes after recurrence.
Platinum doublet chemotherapy is the standard treatment for ovarian cancer patients for whom platinum might be the best option and rechallenge appears justified. Two large randomized trials demonstrated that the combination of carboplatin with either paclitaxel (ICON-4)1 or gemcitabine (AGO-OVAR 2.1)2 is superior to carboplatin monotherapy in terms of response rate, progression free survival, and overall survival, in patients with recurrent disease and a platinum treatment free interval of >6 months.
Niraparib is an orally available, potent, highly selective poly (ADP-ribose) polymerase 1 and poly (ADP-ribose) polymerase 2 inhibitor, approved as maintenance therapy in patients with recurrent ovarian cancer following response to their last platinum based chemotherapy. In the European Network for Gynecological Oncological Trials (ENGOT)-OV16/NOVA trial, niraparib significantly improved progression free survival in patients with or without a germline BRCA mutation.3
Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blockade was proposed as a potential strategy for restoring antitumor immunity in ovarian cancer. Several phase II trials developed in a heavily pretreated population have shown a low response rate of 10–15%, but long term responders were observed. Atezolizumab is a humanized monoclonal antibody targeting PD-L1 that showed activity in one of these trials for heavily pretreated ovarian cancer patients. Better knowledge of the tumor microenvironment and its relationship with ovarian cancer cells is key to developing effective immunotherapy strategies.4
Immune desert ovarian cancer is characterized by the absence of immune cells both in the tumor and stroma. This phenotype probably reflects the absence of a prior immune response. Therefore, actions that could increase tumor antigen release may potentially stimulate an immune response and transform this non-inflamed phenotype to an inflamed one. Chemotherapy may be synergistic in combination with anti-PD-L1 through its ability to increase tumor immunogenicity. Emerging evidence indicates that chemotherapy promotes antigen release and may enhance tumor specific T cell activation when combined with immune checkpoint blockade.5
The rational for combining anti-PD-L1 with poly (ADP-ribose) polymerase inhibitors is based on preclinical observations that have shown the upregulation of PD-L1 following exposure to poly (ADP-ribose) polymerase inhibitors as well as evidence of increasing the activity of the stimulator of interferon genes and interferon pathways after niraparib administration, enhancing intratumoral immune cell infiltration and upregulating granzyme B positive T cells.6–8 Encouraging results for the poly (ADP-ribose) polymerase inhibitors and the anti-PD-L1/PD-1 combination are being published. The TOPACIO/KEYNOTE-162 trial evaluated the combination of niraparib and pembrolizumab in 60 pretreated recurrent ovarian, fallopian tube, or peritoneal cancer patients of whom 48% were platinum resistant, 27% platinum refractory, and 24% not eligible for further platinum.9 The majority of the patients were tBRCA wild type (79%). The objective response rate was 18% (5% complete response and 13% partial response) and the median duration of response had not been reached at the time of the data cut-off (range 4.2 to ≥14.5 months).
The ENGOT-ov41/GEICO (Grupo Español de Investigación en Cáncer de Ovario) 69-O/Atezolizumab and NIraparib Treatment Association (ANITA) trial evaluates the addition of atezolizumab to carboplatin based chemotherapy followed by maintenance niraparib in ovarian cancer patients when platinum is an option, defined as a platinum treatment free interval of ≥6 months.
Methods
The study was approved by the appropriate institutional review board. Written informed consent must be obtained from all subjects.
Trial Design
ANITA is a phase III, randomized, double blinded, multicenter study to assess the efficacy of the addition of atezolizumab versus placebo to platinum based doublet chemotherapy followed by maintenance niraparib in patients with recurrent high grade serous endometrioid or undifferentiated epithelial ovarian, peritoneal, or tubal cancers, who have remained progression free for at least 6 months since completion of their last treatment with platinum based chemotherapy (platinum treatment free interval of ≥6 months) (Figure 1). Approximately 414 patients will be randomized in a 1:1 ratio to the treatments, as specified below.
Study schema. CR, complete response; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death-ligand 1; PFI, platinum-free interval; PFS, progression free survival; PR, partial response; PRO, patient-reported outcome; QoL, quality of life; SD, stable disease; TFlp, treatment free interval; TFST, time from randomization to first subsequent therapy or death; TSST, time to second subsequent therapy.
Placebo of atezolizumab (arm A, control arm) or atezolizumab (arm B, experimental arm) in combination with one of the platinum based regimens below (investigator’s choice) followed by maintenance niraparib with placebo of atezolizumab (arm A, control arm) or atezolizumab (arm B, experimental arm):
Carboplatin (area under the curve (AUC)=5) combined with paclitaxel (175 mg/m²) and placebo/atezolizumab (1200 mg) intravenous every 3 weeks; 3–12 weeks after completing six chemotherapy cycles, non-progressing patients will be switched to maintenance niraparib (oral, once daily, 200 mg or 300 mg) in combination with placebo/atezolizumab (intravenous 1200 mg) every 3 weeks.
Carboplatin (AUC=4) combined with gemcitabine (1000 mg/m2, day 1 and day 8) and placebo/atezolizumab (1200 mg) intravenous every 3 weeks; 3–12 weeks after completing six chemotherapy cycles, non-progressing patients will be switched to maintenance niraparib (oral, once daily, 200 mg or 300 mg) in combination with placebo/atezolizumab (intravenous 1200 mg) every 3 weeks.
Carboplatin (AUC=5) combined with pegylated liposomal doxorubicin (30 mg/m²) and placebo/atezolizumab (840 mg, day 1 and day 15) intravenous every 4 weeks; 3–12 weeks after completing six chemotherapy cycles, non-progressing patients will be switched to maintenance niraparib (oral, once daily, 200 mg or 300 mg) in combination with placebo/atezolizumab (intravenous 1200 mg) every 3 weeks; 2 weeks after the last dose of placebo/atezolizumab 840 mg given on day 15, placebo/atezolizumab will start at 1200 mg every 3 weeks.
Randomization will be stratified based on: the platinum based regimen selected (paclitaxel–carboplatin vs gemcitabine–carboplatin vs pegylated liposomal doxorubicin–carboplatin); the platinum free interval (6–12 months vs >12 months); BRCA mutation status (mutated vs non-mutated); and PD-L1 expression status (positive vs negative vs non-informative). PD-L1 positivity will be defined as ≥1% of immune cells expressing PD-L1, which will be referred to IC1/2/3, according to the PD-L1 scoring algorithm.
The trial is financially supported by Roche and GSK-TESARO companies, manufacturers of atezolizumab and niraparib, respectively. The study is an ENGOT model B,10 led by GEICO as sponsor and will be run in approximately 81 sites from the national cooperative groups AGO, BGOG, GEICO, GINECO, ISGO, and MANGO in ENGOT.
Participants
Eligible patients are women aged ≥18 years with a histologically confirmed diagnosis (cytology alone excluded) of high grade serous or endometrioid ovarian, primary peritoneal, or tubal carcinoma. In addition, mixed histologies with predominant high grade serous or endometrioid or undifferentiated adenocarcinoma of the ovary are allowed. Disease free interval must be >6 months after the last platinum dose. No more than two previous lines of chemotherapy are allowed, and the last one must contain a platinum based regimen. Major exclusion criteria include patients who have received prior treatment with a poly (ADP-ribose) polymerase inhibitor in the recurrent setting but poly (ADP-ribose) polymerase inhibitors as frontline therapy is permitted.
Outcomes
The primary objective of the study is to determine whether the addition of atezolizumab to carboplatin based chemotherapy followed by maintenance niraparib improves progression free survival compared with placebo combined with carboplatin based chemotherapy followed by maintenance niraparib, in patients with relapsed epithelial ovarian, fallopian tube, or peritoneal cancer after a platinum treatment free interval of at least 6 months.
Secondary objectives include evaluation of overall survival, objective response rate, duration of response, and time from randomization to first subsequent therapy or death, time from randomization to second subsequent therapy or death, and time from randomization to second progression or death. In addition, we will assess the safety and tolerability of atezolizumab treatment compared with placebo treatment and will determine the impact of atezolizumab versus placebo on patient reported abdominal symptoms of ovarian cancer, as measured by two items from the abdominal/gastrointestinal symptom scale of EORTC QLQ-OV28. We will also evaluate patient reported outcomes of function and health related quality of life associated with atezolizumab versus placebo, as measured by the functional and health related quality of life scales of EORTC QLQ-C30.
The primary endpoint is progression free survival from randomization until progression based on investigator assessment determined by RECIST (V.1.1). Major secondary endpoints include overall survival time from randomization to first subsequent therapy or death, frequency and severity of adverse events, objective response rate, duration of response, and quality of life.
Sample Size
With the addition of atezolizumab compared with placebo, it is expected to increase the median progression free survival from 16 months to 22.9 months, corresponding to a 30% reduction of the risk of progression (average hazard ratio of 0.70) and a clinical meaningful difference of 6.9 months in median progression free survival. Using stata V.15.0 built-in sample size functions with a two sided alpha of 0.05 and a power of 80%, it is estimated that a total of 254 events are needed (based on Freedman residuals). Using the average event rate, 30 months of accrual and 30 months of follow-up, this corresponds to 329 patients. Given the even randomization, the aim is to have 330 completers, 165 in each arm. Accounting for 20% dropouts, 412.5 or rather 414 patients need to be randomized.
A preplanned interim safety analysis to assess the tolerability profile of atezolizumab–niraparib will be performed after 60 patients have completed two cycles of maintenance treatment. However, no interim efficacy analysis is planned. The primary progression free survival analysis will be performed when a total of 254 events have occurred, which is expected after 30 months of follow-up. The analysis will be by a two sided log rank test, stratified for platinum free interval, carboplatin based regimen, BRCA status, and PD-L1 expression status. In addition, a stratified Cox proportional hazards model will be used to estimate the treatment hazard ratio and its two sided 95% confidence interval.
Randomization and Blinding
Patients satisfying the eligibility criteria will be randomized using an interactive voice response system/interactive web system in a 1:1 ratio to arm A (control arm) or arm B (experimental arm).
Patient eligibility will be established before treatment randomization. Once the eligibility of a patient has been confirmed, the investigator (or nominated assistant) should contact the interactive voice response system/interactive web system centralized randomization center for allocation of randomized study treatment. The treatment given to individual patients will be determined by a randomization scheme that has been loaded into the (interactive voice response system/interactive web system) database. The randomization scheme will be produced by a computer software program that incorporates a standard procedure for generating random numbers. A blocked randomization will be generated, and all centers will use the same list in order to minimize any imbalance in the number of patients assigned to each treatment group.
The randomization scheme will be stratified based on: platinum treatment free interval (6–12 months vs >12 months), carboplatin based regimen (paclitaxel vs gemcitabine vs pegylated liposomal doxorubicin), BRCA status (mutated vs not mutated), and PD-L1 expression status (PD-L1 positive vs negative vs non-informative). PD-L1 positivity will be defined as ≥1% of immune cells expressing PD-L1 which will be referred to as immune cells 1/2/3 according to the PD-L1 scoring algorithm.
Atezolizumab and placebo treatment will be double blinded and hence the treatment will be not be known to the subject or study staff, including the treating physician. In order to maintain blinding, atezolizumab and placebo will be identical in appearance and packaging.
The study medication will be labeled using a unique kit identity number, which is linked to the randomization scheme. The active and placebo kits will be presented in the same packaging to ensure blinding of the study medication. Individual treatment codes, indicating the treatment randomization for each randomized patient, will be available to the investigator(s) or pharmacists from the interactive voice response system/interactive web system. Routines for this will be described in the interactive voice response system/interactive web system user manual that will be provided to each center.
The investigator or treating physician may request unblinding of a subject’s treatment assignment, mainly in the case of an emergency, when knowledge of the study treatment is essential for the appropriate clinical management or welfare of the subject. If it becomes necessary to unblind treatment information during the study, the investigator will contact the medical monitor of the study and then the scientific coordinator from GEICO to discuss the reason for unblinding (eg, unblinding because of a serious adverse event), and document the reason in the electronic case report form. Situations other than medical emergencies that request unblinding of a subject’s treatment assignment should be discussed with the scientific coordinator or relevant GEICO team before the patient is unblinded. Specific procedures for emergency unblinding of a subject’s treatment are provided in the interactive voice response system/interactive web system manual.
Statistical Methods
The primary progression free survival analysis will be performed when a total of 254 events have occurred; this is expected to be reached after 30 months of follow-up. The analysis will be by a two sided log rank test, stratified for platinum free interval 6–12 versus >12 months, carboplatin based regimen (paclitaxel vs gemcitabine vs pegylated liposomal doxorubicin), BRCA status, and PD-L1 expression status (PD-L1 positive vs negative vs non-informative). In addition, a stratified Cox proportional hazards model will be used to estimate the treatment hazard ratio and its two sided 95% confidence interval. Progression free survival will also be descriptively summarized using Kaplan–Meier methodology, including medians and two sided 95% confidence interval. For all time-to-event endpoints, the proportional hazard assumption will be checked. Severe deviation from the proportional hazards assumption will be handled on an ad hoc basis.
The secondary efficacy endpoints, time from randomization to first subsequent therapy or death, time to second subsequent therapy, progression free survival 2, progression free survival for maintenance, and overall survival, will be analyzed using a stratified two sided log rank test. Overall survival is a key secondary endpoint, and it is estimated that at least 50% of the subjects will have reached the overall survival endpoint after 36 months of follow-up. The decision to analyze overall survival at this point will be dependent on a positive finding for the primary progression free survival endpoint analysis. The stratified Cox proportional hazards model will be used to estimate the treatment hazard ratio and its two sided 95% confidence interval. In addition, Kaplan–Meier methodology will be used to descriptively summarize the data. Progression free survival for maintenance will additionally be analyzed in the subgroups defined by best response during the treatment phase in the group of patients with complete response or partial response, and in the group of patients with stable disease. Unconditional multiple logistic regression, including the stratification variables, will be used to estimate the treatment odds ratio with two sided 95% confidence interval. Waterfall plots will be used to describe the variation of the sum of target lesions during the treatment.
Discussion
ENGOT-ov41/GEICO 69-O/ANITA is the largest randomized clinical trial exploring the role of the combination of anti-PD1/PD-L1 therapy with poly (ADP-ribose) polymerase inhibitors for patients with recurrent ovarian cancer for whom platinum might be the best option. There is a solid rational for the combination of atezolizumab and niraparib in patients with recurrent ovarian cancer. From the clinical perspective, patients with recurrent high grade epithelial ovarian cancer with a platinum treatment free interval of >6 months and suitable for platinum therapy should be rechallenged with a platinum doublet as the standard of care. Approximately 60% of patients will respond again to platinum based therapy with a median duration of progression free survival of 5–6 months since the last platinum. The administration of niraparib, a potent oral poly (ADP-ribose) polymerase inhibitor, as maintenance therapy once the patient has obtained a new response helps in prolonging progression free survival significantly, both in patients with germline BRCA non-mutated and especially in those with germline BRCA associated tumors. The same results have been observed with other poly (ADP-ribose) polymerase inhibitors,11 12 making the therapy with a platinum doublet followed by maintenance with poly (ADP-ribose) polymerase inhibitor the treatment of choice for patients for whom platinum is the best option in the relapse and do not need a rapid response.13 Unfortunately, despite the improvement in progression free survival obtained with maintenance, most of the patients will progress again and new therapies that could prolong the progression free survival are still needed.
From the biological perspective, the association of atezolizumab (a humanized monoclonal antibody targeting PD-L1) with niraparib has a well established background. Although the results of phase 1–2 trials with checkpoint inhibitors have been disappointing so far, with an observed response rate of 10–15% and a lack of a clear biomarker identified, the patients included in these trials were usually heavily pretreated, and long term responders were observed. Consequently, strategies for improving the efficacy with checkpoint inhibitors in ovarian cancer and the identification of predictive biomarkers are valuable strategies.
One of the arguments for the low response to checkpoint inhibitors in recurrent ovarian cancer is the potential presence of an immune desert phenotype, characterized by the absence of immune cells both in the tumor and stroma. The concomitant administration of checkpoint inhibitors with chemotherapy may have some advantages due to the increase in tumor immunogenicity induced by chemotherapy by several mechanisms, including the release of neoantigens, the generation of specific changes in cell surface structures that allow dendritic cells to detect the dying cell and, in addition, some chemotherapies have been shown to reduce the number of circulating Treg cells, which are a key component in immunosuppression.
As mentioned in the introduction, preclinical observations that have shown the upregulation of PD-L1 following exposure to poly (ADP-ribose) polymerase inhibitors as well as the evidence of increasing the activity of the stimulator of interferon genes and interferon pathways after niraparib administration, support the combination of atezolizumab and niraparib from the bench perspective. In addition, the encouraging results of the TOPACIO/KEYNOTE-162 with the combination of niraparib and pembrolizumab achieving a response rate of 18% and a median duration of response not reached in 60 pretreated recurrent ovarian cancer patients mainly with refractory or resistant disease, makes the combination of atezolizumab and niraparib very attractive in a population of patients without resistance to platinum.
We hope that the combination of atezolizumab and niraparib will improve the outcome of patients with recurrent ovarian cancer for whom platinum might be the best option, with a reduction in the hazard of progression or death of 30%, and a clinical meaningful improvement in the median progression free survival of around 6 months. However, it is possible that some patients will obtain a remarkable benefit in comparison with others; for this reason, seeking biomarkers that could better predict long term responders and also resistant patients to this new combination is considered a priority for the research of immunotherapy in ovarian cancer and for this sponsored academic trial in particular. For this reason, patients are asked to consent to provide archival tumor tissue and blood samples at each tumor evaluation for biomarker research.
In terms of prospective biomarker evaluation, we decided to include PD-L1 expression as a stratification factor based on data from a randomized clinical trial. In the JAVELIN 200 trial, 566 patients with platinum resistant or refractory ovarian cancer were randomized to avelumab, avelumab + pegylated liposomal doxorubicin, or pegylated liposomal doxorubicin.14 This trial did not show any benefit with the avelumab combination in the intent to treat population. However, in PD-L1 positive patients, an improvement in progression free survival was seen (hazard ratio 0.65, 95% confidence interval 0.457–0.919) and a trend for improvement in overall survival. For the ANITA trial, PD-L1 expression is determined in a recent biopsy due to the expected low correlation of expression of PD-L1 between the archival tissue and the most recent biopsy.
In conclusion, the ENGOT ov-41/GEICO 69-O/ANITA trial has a robust clinical and preclinical background and is a unique randomized clinical trial exploring the combination of atezolizumab with niraparib for improving the outcome of patients with recurrent ovarian cancer for whom platinum might be the best option. The biomarker research for identifying patients with the best chance of long term progression free survival is also a priority in the ANITA trial.
References
Footnotes
Correction notice Since Online First publication, the third affiliation has been updated from 'European Institute of Oncology' to 'European Institute of Oncology IRCCS'.
Contributors All authors have read, reviewed, and approved the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement There are no data in this work.