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Abstract
Background Platinum-resistant ovarian cancer patients have a poor prognosis and few treatment options are available. Preclinical and clinical data demonstrated that the combination of poly-ADP ribose polymerase inhibitors with immune checkpoint inhibitors could have a synergistic antitumor activity in this setting of patients.
Primary Objective The primary objective is to assess the efficacy of niraparib plus dostarlimab compared with chemotherapy in recurrent ovarian cancer patients not suitable for platinum treatment.
Study Hypothesis This trial will assess the hypothesis that niraparib plus dostarlimab therapy is effective to increase overall survival, progression-free survival, and time to first subsequent therapy respect to chemotherapy alone, with an acceptable toxicity profile.
Trial Design This is a phase III, multicenter trial, where recurrent ovarian cancer patients not eligible for platinum re-treatment will be randomized 1:1 to receive niraparib plus dostarlimab vs physician’s choice chemotherapy until disease progression, intolerable toxicity, or withdrawal of patient consent. The study will be performed according to European Network for Gynaecological Oncological Trial groups (ENGOT) model B and patients will be recruited from 40 sites across MITO, CEEGOG, GINECO, HeCOG, MANGO, and NOGGO groups.
Major Inclusion/Exclusion criteria Eligible patients must have recurrent epithelial ovarian cancer not eligible for platinum retreatment. Patients who received previous treatment with poly-ADP ribose polymerase inhibitors and/or immune checkpoint inhibitors will be eligible. No more than two prior lines of treatment are allowed.
Primary Endpoint The primary endpoint is overall survival defined as the time from the randomization to the date of death by any cause.
Sample Size 427 patients will be randomized.
Estimated Dates for Completing Accrual and Presenting Results June 2024
Trial Registration Number NCT04679064.
- ovarian cancer
Data availability statement
No data are available.
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Introduction
Epithelial ovarian cancer (EOC) still remains the most lethal among gynecological malignancies, with an estimated 21 750 new cases and 13 949 deaths in 2020.1 In the past few years the introduction of a new class of drugs, the poly-ADP ribose polymerase (PARP) inhibitors, has completely reshaped the ovarian cancer medical treatment landscape, increasing progression-free survival (PFS) and overall survival (OS) in several settings of disease. In 2016, the SOLO 2 trial reported positive results of olaparib as a monotherapy for the maintenance treatment of platinum-sensitive relapsed, BRCA-mutated ovarian cancer.2 Additional trials have evaluated the role of poly-ADP ribose polymerase inhibitors in patients with BRCA wild-type ovarian cancer patients and as first-line maintenance therapy and have demonstrated the efficacy of this treatment .3–7 The PRIMA trial demonstrated that among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer PFS than those who received placebo, regardless of the homologous recombination deficiency status (13.8 months in the niraparib arm vs 8.2 months in the placebo arm, HR 0.62; 95% CI, 0.50 to 0.76; P<0.001).7
Immunotherapy is also emerging as a treatment in multiple cancers, and its safety and tolerability are under investigation in advanced gynecological malignancies. Accumulating evidence show a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in several malignancies, including ovarian cancer. Moreover, a strong interplay exists among the host immune system, DNA damage, and inflammation in the tumor microenvironment. Poly-ADP ribose polymerase inhibition leads to DNA damage resulting in epigenetic changes in tumor cells, making them more vulnerable to T-cells and natural killer-cells, and finally resulting in increased intrinsic cells immunogenicity.8 It has been reported that poly-ADP ribose polymerase inhibitors may enhance the immune response in tumors treated with anti-Programmed Death-1 (PD-1) therapy via generation of cytosolic DNA that activates T-cells through the stimulation of the interferon gene (STING) pathway, rendering tumors immunologically “hot” and increasing infiltrating lymphocytes. When evaluated in preclinical models, niraparib and anti-Programmed Death-Ligand 1 (PD-L1) combination demonstrated a benefit both in BRCA-proficient and BRCA-deficient tumor models.9
In this trial we expect to evaluate the efficacy of niraparib–dostarlimab with respect to physician’s choice chemotherapy in recurrent ovarian cancer patients not suitable for platinum retreatment, regardless of BRCA mutational status.
Methods
Study Hypothesis
The MITO 33 trial will assess the hypothesis that the combination niraparib/dostarlimab therapy is effective in increasing OS, PFS, and time to first subsequent therapy with respect to chemotherapy alone. Moreover the combination of niraparib/dostarlimab is expected to produce a response rate of equal or higher value with respect to chemotherapy, to have an acceptable toxicity profile, and is not expected to worsen patients’ quality of life with respect to chemotherapy alone.
Trial Design
This is a multicenter, prospective, randomized phase 3 trial to evaluate the efficacy and the safety of niraparib in combination with dostarlimab in recurrent ovarian, fallopian tube, or primary peritoneal cancer patients for whom platinum is not an option (Figure 1). Patients will be randomized to receive (Arm A) physician’s choice chemotherapy or (Arm B) niraparib plus dostarlimab until disease progression, intolerable toxicity, or withdrawal of patient consent. Patients randomized to physician’s choice chemotherapy will receive systemic cytotoxic chemotherapy, including gemcitabine, weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan. The use of antiangiogenic therapy in combination with chemotherapy is permitted. Patients randomized in the experimental arm will receive niraparib 300 mg or 200 mg if platelets count <1 50 000/ uL and/or body weight <77 kg QD PO q28 and dostarlimab 500 mg every 3 weeks for four cycles, then 1000 mg every 6 weeks. Patients will receive dostarlimab for up 2 years in the absence of disease relapse. This trial will be performed according to European Network for Gynaecological Oncological Trial groups (ENGOT) model B and patients will be recruited globally from approximately 40 sites across Multicenter Italian Trials in Ovarian Cancer Group (MITO), Central and Eastern European Gynaecologic Oncology Group (CEEGOG), Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), Hellenic Cooperative Oncology Group (HeCOG), Mario Negri Gynaecologic Oncology Group (MANGO), and North-Eastern German Society of Gynaecologic Oncology (NOGGO).
NItCHe (MITO 33) trial schema. Patients with recurrent ovarian, fallopian tube, and primitive peritoneal cancer, platinum-resistant, or unfit to receive platinum retreatment will be enrolled and randomized 1:1 to receive niraparib /dostarlimab combination or physician’s choice chemotherapy. The primary endpoint of the study is the overall survival of patients receiving niraparib/dostarlimab combination therapy compared with chemotherapy. A total of 427 patients will be recruited globally from approximately 40 sites across Multicenter Italian Trials in Ovarian Cancer Group (MITO), Central and Eastern European Gynaecologic Oncology Group (CEEGOG), Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), Hellenic Cooperative Oncology Group (HeCOG), Mario Negri Gynaecologic Oncology Group (MANGO), and North-Eastern German Society of Gynaecologic Oncology (NOGGO).
Participants
Eligible patients must have recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer and not be a candidate for platinum retreatment, including patients for which platinum is not an option because of previous allergic reactions or residual toxicity, patients not able (in physician’s opinion) to receive further platinum, or not willing to receive further platinum and platinum-resistant patients. Patients who had received previous treatment with poly-ADP ribose polymerase inhibitors and/or immune checkpoint inhibitors can be included if at least 6 months from last treatment have occurred. Patients must have adequate hematological and organ function, and ECOG performance status 0 to 1. No more than two prior lines of treatment will be allowed.
Outcomes
Primary Endpoint
The primary endpoint of MITO 33 will be OS defined as the time from the randomization to the date of death by any cause.
Secondary Endpoints
The secondary endpoints will include PFS, time to first subsequent therapy, and objective response rate. PFS is defined as the time from randomization to the earlier date of assessment of progression or death by any cause in the absence of progression. Time to first subsequent therapy is defined as the time interval from the date of randomization to earliest date of first subsequent therapy or death. Objective response rate is defined as the percentage of patients with complete or partial response, as assessed by RECIST v.1.1 criteria evaluated by investigator. In addition, this trial will assess the safety and tolerability of patients receiving chemotherapy or dostarlimab plus niraparib. Finally, patient-reported outcomes (PRO) using EORTC QLQC30, EORTCOV28, and EQ-5DL will be assessed.
Exploratory Objective
The exploratory objective of this study will evaluate the relationship between PD-L1 expression and combined positive score (number of PD-L1 staining cells-tumor cells, lymphocyte, macrophages divided by the total number of viable tumor cells, multiplied by 100) with the efficacy of niraparib/dostarlimab treatment; to investigate the efficacy of niraparib/dostarlimab treatment according to the previous use of poly-ADP ribose polymerase inhibitors and/or immunotherapy treatment; to investigate the relationship between lymphoid or myeloid-derived suppression cells or T-regulatory cells (T-regs) and response to niraparib/dostarlimab treatment using archival formalin-fixed, paraffin-embedded tumor tissue and blood samples; and to assess the association between anti-tumor activity and genetic alterations (homologous recombination deficiency and BRCA among others) that may indicate a specific genotype reflective of greater dependency on PD-1/PD-L1 checkpoint function or poly-ADP ribose polymerase inhibition.
Randomization and Blinding
Patients will be randomized 1:1 to receive:
Arm A (physician’s choice chemotherapy): pegylated liposomal doxorubicin 40 mg/mq d1q28, weekly paclitaxel 80 mg/mq d1,8,15q28, gemcitabine 1000 mg/mq d1,8,15q28, or topotecan 1.25 mg/mq d1-5q21;
Arm B (dostarlimab + niraparib): dostarlimab 500 mg every 3 weeks for four cycles, then 1000 mg every 6 weeks + niraparib 300 mg or 200 mg daily.
Patients will be stratified according to homologous recombination deficiency status (positive vs negative), PD-L1 status, previous immunotherapy, previous poly-ADP ribose polymerase inhibitors treatment, and bevacizumab therapy. Homologous Recombination Deficiency status will be evaluated with Foundation One CDx test and tumor PD-L1 expression will be evaluated on archival pre-therapy lesion.
Sample Size and Statistical Methods
This is a randomized phase 3 trial. Median OS in the standard arm is estimated to be about 13 months. An increase in OS in the experimental arm with an HR of 0.7 is expected (power 80%, alfa 0.05). A sample size of 427 patients will be required (194 patients per arm plus 10% possible drop out) with a total number of 247 events. With an estimated accrual rate of 14 patients/month, the total duration of the trial will be approximately 4 years.
The sample will be described in its clinical and demographic features using descriptive statistics techniques. Quantitative variables will be described using the following measures: minimum, maximum, range, mean, and SD. Qualitative variables will be summarized with absolute and percentage frequency tables. Normality of continuous variables will be checked using the Kolmogorov–Smirnov test.
The primary objective will be achieved assessing survival function with the Kaplan–Meier method. The Mantel–Cox log-rank test will be used to compare different survival functions according to clinical and therapeutic factors. PFS will be investigated as a survival function following the same model used for the primary objective. The response rate (RECIST 1.1 Criteria) will be described applying descriptive statistics techniques, particularly absolute and percentage frequencies. Safety and tolerability will be assessed describing the type and frequencies of adverse events (according to CTCAE version 5.0). Comparisons between the two groups will be performed with a χ2 test. Statistical descriptive analysis will be performed on the EORTC QLQC30, EORTCOV28, and EQ-5DL results.
Discussion
Among drugs available for patients not candidate for platinum retreatment, pegylated liposomal doxorubicin, gemcitabine, weekly paclitaxel, and topotecan are usually given as single agents, since the superiority of any chemotherapy combination has not been proven in platinum-resistant patients. According to published data, however, the response rate with these drugs is poor (10%–15%) and the time to progression short (about 4 months).10 Thus, new strategies are urgently needed and novel systemic acting compounds need to be identified and tested in prospective clinical trials. In the past few years, the allure of the antitumor activity that immunotherapy achieved in different types of tumors has led to the study of immune checkpoint blockade also in epithelial ovarian cancer. However the results of immune checkpoint inhibitors used in monotherapy or in combination with antiangiogenic agents were not encouraging. Data coming from Keynote 100 showed a disappointing objective response rate of 8% in all comers, EOC patients treated with pembrolizumab alone, and a median PFS of 2.1 months.11 Similarly, in the JAVELIN trial, avelumab monotherapy resulted in an objective response rate of 9.6% with a median PFS of 2.6 months.12 Genomic studies demonstrated that approximately 50% of high-grade serous ovarian cancer harbor genetic and epigenetic alterations responsible for causing homologous recombination deficiency and that these tumors exhibit statistically significant higher tumor mutational burden and higher PD-L1 expression with respect to homologous recombination-proficient tumors. Surprisingly, BRCA 1/2 mutational status and homologous recombination deficiency were not predictive of response to immunotherapy in the Keynote 100 and Javelin trials. Preclinical studies demonstrated that poly-ADP ribose polymerase inhibitors elicit an important activation of local and systemic antitumor immune response, activating the STING pathway, increasing the expression of intratumoral CD8 +T cells, the production of interferon (IFN)γ, and tumor necrosis factor (TNF)α. In light of these observations, multiple preclinical results showed that immune checkpoint inhibitors increase their antitumor effect when given in combination with poly-ADP ribose polymerase inhibitors. Several clinical trials have evaluated or are currently investigating the synergistic effects between poly-ADP ribose polymerase inhibitors and immune checkpoint blockade in ovarian cancer. Among others, the MEDIOLA and TOPACIO trials were performed in different settings of disease and patient populations (i.e., in patients enriched for homologous recombination-deficient tumors (MEDIOLA) and in patients enriched for homologous recombination-proficient tumors (TOPACIO)), suggesting the potential beneficial role of this combined approach in both settings.13 14 The phase II MEDIOLA trial evaluated the combination of durvalumab plus olaparib in 34 germline BRCA-mutated platinum-sensitive relapsed ovarian cancer patients demonstrating stable disease in three patients (9%), partial response in 17 patients (53%), and complete response in six patients (19%), with an objective response rate of 71.9% (95% CI: 53.25%, 86.25%) and an 28-weeks disease control rate of 65.6% (90% CI: 49.6%, 79.4%).13 In addition, in the phase I/II TOPACIO trial, 62 patients, mostly platinum-resistant (50%) or refractory (29%) and BRCA1/2 WT (74%), were treated with niraparib and pembrolizumab, with stable disease in 28 patients (47%), partial response in eight patients (13%), and complete response in three patients (5%). The objective response rate was 18% and disease control rate was 65%. Interestingly, homologous recombination deficiency status was not predictive of response to treatment. The combination was well tolerated with most frequent grade 3–4 AEs represented by anemia (9%), increased pancreatic enzymes (6%–9%), and neutropenia (3%).14 Other ongoing trials are evaluating the role of niraparib in combination with dostarlimab. Cohort A of the OPAL trial will evaluate the novel triple combination of the poly-ADP ribose polymerase inhibitors niraparib, angiogenesis inhibitor bevacizumab, and anti-PD-1 dostarlimab in platinum-resistant ovarian cancer patients, who are poly-ADP ribose polymerase inhibitors naïve (NCT03574779). The MOONSTONE is a phase II, single-arm trial evaluating the safety and the efficacy of niraparib + dostarlimab in patients with advanced, relapsed, platinum-resistant ovarian cancer without a known BRCA mutation that received and progressed on prior bevazizumab (NCT03955471). Finally, the FIRST study is a phase III, randomized trial evaluating the role of niraparib and dostarlimab in a first- line maintenance setting (NCT03602859).
The cumulative toxicity of chemotherapy in terms of myelotoxicity, nephrotoxicity, and neurotoxicity is a limiting factor in patients who are expected to receive multiple lines of treatment, and the development of active and well tolerated chemotherapy-free regimens may provide an attractive alternative for these patients. In addition, platinum-resistant disease still remains an important unmet clinical need. As the AURELIA trial represents the only positive published study in platinum-resistant ovarian cancer in the past 20 years, innovative combination therapies are needed to improve the prognosis in these patients.15
To our knowledge, MITO 33 represents the first trial evaluating the efficacy of combined poly-ADP ribose polymerase inhibitor niraparib plus immunecheckpoint inhibitor dostarlimab compared with chemotherapy in ovarian cancer patients not suitable for platinum treatment. Aggregate translational studies will also help to determine the relevant biomarkers of sensitivity and resistance to immune checkpoint inhibitors in combination with poly-ADP ribose polymerase inhibitor in ovarian cancer patients.
Supplemental material
Data availability statement
No data are available.
Ethics statements
Patient consent for publication
Acknowledgments
This study was supported by a research grant from GSK.
Footnotes
LM and VS contributed equally.
Contributors Conceptualization: LM and DL; data curation: SG; writing original draft preparation: LM, VS, and DL; writing, review, and editing: all authors; visualization: all authors; supervision: DL and GS; project administration: DL.
Funding This study is funded by GSK.
Competing interests VS reports personal financial interest with Roche, Pharmamar, Astrazeneca, MSD, Clovis, Tesaro, GSK, and EISAI. SP reports honoraria from GSK, Roche, AstraZeneca, MSD, Clovis, and Pharmamar. EB reports funded research from EU, BMBF, AstraZeneca, Roche Diagnostics, Bayer, and MSD, honoraria/travels from Roche, Amgen, MSD, Clovis, AstraZeneca, Tesaro, GSK, and Roche Diagnostics, consulting/advisory board for Amgen, AstraZeneca, Clovis, Eisai, GSK, MSD, Tesaro, Roche, and Seattle Genetics. DC has been part of the advisory board of Roche, AstraZeneca, Merck, GSK, and Sotio. NC reports personal financial interest with Pharmamar, AstraZeneca, Roche, MSD/Merck, Clovis Oncology, Tesaro/GSK, Novartis, Pfizer, Takeda, Biocad, Immonogen, Mersana, and EISAI, and institutional financial interests (Research Grants) with AstraZeneca, Pharmamar, and Roche. JSF has been part of the advisory board of Novartis, Pfizer, AstraZeneca, Lilly, Roche, Biocad, Daiichi, Tesaro, GSK, and Pierre Fabre. FZ reports honoraria for lectures and advisory role for AstraZeneca, Daiichi, Eli-Lilly, Merck, Novartis, and Pfizer. GS reports Grant/Research Support by MSD and consultant for Tesaro, Johnson & Johnson, and AstraZeneca. DL reports personal financial interests (advisory roles) with AstraZeneca, Clovis Oncology, Merck, Roche, Tesaro-GSK, Amgen, and Pharmamar, and institutional financial interests (Study Grants) with Tesaro/GSK, Merck, Roche, Pharmamar, and Clovis. Board of Directors, and GCIG (Gynecologic Cancer Inter Group).
Provenance and peer review Commissioned; internally peer reviewed.
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