Therapy Of Advanced Ovarian Cancer Research Articles

A single institutional clinical outcome for stages III and IV ovarian cancer patients treated with dose-dense TC therapy in the frontline or first platinum-sensitive relapse setting.

Dose-dense paclitaxel /carboplatin (ddTC) therapy was shown to be more effective against ovarian cancer than conventional tri-weekly TC in the JGOG3016 study. However, two phase III studies performed after JGOG3016 did not show the same positive results. Because we have been using ddTC in the frontline or first platinum-sensitive relapse of ovarian cancer, we investigated the clinical outcome of the patients treated with ddTC. We retrospectively examined the response rate (RR), progression free survival (PFS) and adverse events of the patients who were treated with ddTC for stage III and IV epithelial ovarian, tubal and peritoneal cancer from January 2012 to December 2018. We analyzed 50 patients for frontline treatment and 11 patients for first platinum-sensitive relapse treatment, excluding those receiving maintenance therapy. Among the patients that received frontline ddTC treatment, RR was 82.9% for those in a neo-adjuvant chemotherapy (NACT) setting and 85.0% for those in an adjuvant setting. The median progression-free survival (PFS) was 20 months after initial therapy. Among 31 cases that achieved remission by frontline surgery and the following ddTC, 22 had a platinum-sensitive relapse. RR of 11 patients treated with ddTC therapy alone for the first platinum-sensitive relapse was 81.8%, and the median PFS of these patients was 22 months after the first recurrence. ddTC therapy for advanced ovarian cancer achieved high response rates in all settings (NACT, adjuvant or platinum-sensitive relapse). ddTC therapy was effective for improving the prognosis of patients with stages III and IV of ovarian cancer.

Real-world TRAE association between niraparib and platinum-based chemotherapy.

Pre-clinical studies showed the anti-tumor mechanisms of PARP inhibitors (PARPi) and platinum have some crossover and overlap in the DNA damage repair pathway, patients who respond to platinum-based chemotherapy are also more likely to be sensitive to PARPi. This real-world study mainly aimed to evaluate whether TRAE (treatment-related adverse event) between platinum based chemotherapy (PBC) and niraparib are also associated. Patients received niraparib as maintenance treatment or salvage therapy for advanced ovarian cancer at the First Affiliated Hospital of Gannan Medical University from January 2020 to August 2023 were included. Survival data of niraparib treatment and adverse events occurred during the last platinum-based chemotherapy cycle before starting niraparib treatment and during niraparib treatment are documented. Fisher's exact test were used for correlation analysis. 1. 40 patients treated with niraparib were included in the analysis, including 31 patients treated with niraparib for 1st-line maintenance therapy, 6 patients for PSR (platinum-sensitive recurrence) maintenance therapy, and 3 patients for salvage therapy. The overall median follow-up time was 15.0 months (ranged from 2.2 months to 32.1 months). 2. Overall grade≥3 TRAE (40% vs 70%, p=0.012) including anemia (20% vs 45%, p=0.041) and neutrophil count decreased (17.5% vs 57.5%, p<0.001) was significantly lower during niraparib treatment compared to during chemotherapy. 3. Any grade TRAE (75% vs 100%, p=0.002) including white blood cell count decreased (47.5% vs 87.5%, p<0.001), red blood cell count decreased (57.5% vs 92.5%, p<0.001), anemia (55% vs 87.5%, p<0.001) and neutrophil count decreased (35% vs 85%, p<0.001) were also significantly lower in niraparib treatment group compared with chemotherapy group. No new safety signals were identified. 1. In this real-world practice, we observed that patients with advanced ovarian cancer who experienced any grade and grade ≥3 TRAE during chemotherapy were well tolerated when treated with niraparib, particularly the incidence of any grade and grade ≥3 anemia, and neutrophil count decreased during niraparib treatment were significantly lower compared with that during chemotherapy. 2. For patients with ovarian cancer who have experienced grade ≥3 hematological adverse reactions during prior platinum-based chemotherapy, greater attention should be paid to the monitoring and management of hematological adverse reactions during subsequent treatment with niraparib.

Phase I and Randomized Phase II Study of Ruxolitinib With Frontline Neoadjuvant Therapy in Advanced Ovarian Cancer: An NRG Oncology Group Study.

The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting. Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m2 once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS. Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% v 27%), grade 3 to 4 neutropenia (53% v 37%), and thromboembolic events (12.6% v 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank P = .059). The overall survival HR was 0.785 (P = .24). Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.

Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .

Heterogeneous treatment effect of dose-dense paclitaxel plus carboplatin therapy for advanced ovarian cancer.

A Japanese clinical trial (JGOG3016) showed that dose-dense weekly paclitaxel in combination with carboplatin extensively prolonged overall survival (OS) in patients with advanced ovarian cancer. However, in other clinical trials, dose-dense paclitaxel regimens were not superior to triweekly paclitaxel regimens. In this study, causal tree analysis was applied to explore subpopulations with different treatment effects of dose-dense paclitaxel in a data-driven approach. The 587 participants with stage II-IV ovarian cancer in the JGOG3016 trial were used for model development. The primary endpoint was treatment effect in terms of 3-year OS in patients receiving dose-dense vs. conventional paclitaxel therapies. In patients <50 years, the 3-year OS was similar in both groups; however, it was higher in the dose-dense group in patients ≥50 years. Dose-dense paclitaxel showed strong positive treatment effects in patients ≥50 years with stage II/III disease, BMI <23 kg/m2, non-CC/MC, and residual tumor ≥1 cm. In contrast, although there was no significant difference in OS; the 3-year OS rate was 23% lower in dose-dense paclitaxel than conventional paclitaxel in patients ≥60 years with stage IV cancer. Patients in this group had a particularly lower performance status than other groups. Our causal tree analysis suggested that poor prognosis groups represented by residual tumor tissue ≥1 cm benefit from dose-dense paclitaxel, whereas elderly patients with advanced disease and low-performance status are negatively impacted by dose-dense paclitaxel. These subpopulations will be of interest to future validation studies. Personalized treatments based on clinical features are expected to improve advanced ovarian cancer prognosis.

Abstract B084: Triple checkpoint blockade, but not anti-PD1 alone, enhances the efficacy of engineered adoptive T cell therapy in advanced ovarian cancer

Abstract Background: Over 20,000 women are diagnosed with ovarian cancer annually, and more than half will die within 5 years. This rate has changed little in the last 30 years, highlighting the need for therapy innovation. Although immunotherapy has revolutionized cancer treatment, efforts to harness endogenous patient immune responses have yielded limited therapeutic activity in ovarian cancer patients. T cells engineered to express a T cell receptor (TCR) targeting proteins uniquely overexpressed in tumors have the potential to control tumor growth without toxicity. Mesothelin (Msln) is over-expressed in ovarian cancer, contributes to the malignant and invasive phenotype, and has limited expression in healthy cells, making it a candidate immunotherapy target in these tumors. Methods: The ID8VEGF mouse cell line was used to evaluate if T cells engineered to express a mouse Msln-specific high-affinity T cell receptor (TCRMsln) can kill ovarian cancer. Tumor-bearing mice were treated with TCRMsln T cells plus anti-PD-1, anti-Tim-3 or anti-Lag-3 checkpoint-blocking antibodies alone or in combination, ultimately targeting up to three inhibitory receptors simultaneously. Single-cell RNA-sequencing (scRNAseq) was used to profile the impact of combination checkpoint blockade on engineered T cells and the tumor microenvironment (TME). Results: In a disseminated ID8 tumor model, adoptively transferred TCRMsln T cells preferentially accumulated in established tumors, delayed ovarian tumor growth, and prolonged mouse survival. However, elements in the TME limited engineered T cell persistence and cytolytic function. Triple checkpoint blockade, but not single- or double-agent treatment, dramatically increased antitumor function by intratumoral TCRMsln T cells. scRNAseq of tumor-infiltrating cells revealed distinct transcriptome changes in engineered and endogenous T cells and myeloid-derived cells. Engineered T cells, when combined with triple checkpoint blockade, increased expression of genes associated with effector and memory gene signatures, including proliferation and metabolic function, and reduced expression of genes associated with exhaustion. Moreover, combining adoptive immunotherapy with triple checkpoint blockade significantly prolonged survival in the cohort of treated tumor-bearing mice, relative to mice that received TCRMsln T cells alone or with anti-PD1 or double-agent treatments. Conclusions: Inhibitory receptor/ligand interactions within the TME can dramatically reduce T cell function, suggesting tumor cells may upregulate the ligands for PD-1, Tim-3 and Lag-3 for protection from tumor-infiltrating lymphocytes. In an advanced ovarian cancer model, triple checkpoint blockade significantly improved engineered T cell function and outcomes in mice in a setting where single checkpoint blockade had no significant activity. These results suggest that disrupting multiple inhibitory pathways simultaneously, which can be more safely pursed in a cell intrinsic form through genetic engineering, may be necessary for improved efficacy in patients. Citation Format: Kristin G. Anderson, Yapeng Su, Madison G. Burnett, Breanna M. Bates, Magdalia L. Rodgers Suarez, Susan L. Ruskin, Valentin Voillet, Raphael Gottardo, Philip D. Greenberg. Triple checkpoint blockade, but not anti-PD1 alone, enhances the efficacy of engineered adoptive T cell therapy in advanced ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B084.

Safety of bevacizumab and olaparib as frontline maintenance therapy in advanced ovarian cancer: expert review for clinical practice.

Olaparib, a poly(ADP-ribose) polymerase inhibitor, in combination with the antiangiogenic agent bevacizumab, is approved as maintenance therapy for patients with newly diagnosed stage III or IV epithelial ovarian cancer who have homologous recombination deficient tumors with a deleterious or suspected deleterious BRCA mutation and/or genomic instability based on the long-lasting survival benefit observed in the PAOLA-1 trial. Despite treatment with olaparib and bevacizumab showing an acceptable safety profile, the rate of discontinuations due to adverse events was relatively high, and toxicity related to this regimen may restrict its clinical use. Proper management of olaparib/bevacizumab-related adverse events is important for the improvement of quality of life and maximization of the efficacy of maintenance therapy. Here, we summarize the safety results of the PAOLA-1 study, focusing on treatment discontinuation reasons and adverse event profiles. We sought to shed light on toxicity monitoring and prevention, providing concise recommendations for the clinical management of the most relevant side effects.

Clinical safety and efficacy observation of ex vivo-expanded peripheral blood-derived allogeneic NK cells in the treatment of refractory or recurrent ovarian cancer.

e17553 Background: Ovarian cancer is the most lethal gynecologic malignancy. Nearly 75% of patients were diagnosed at advanced stages. Despite 60%-80% of patients achieve complete remission after treatment with surgery combined with chemotherapy, about 60% of patients relapse within two years, more than 50% of patients develop chemotherapy tolerance with only 30% five-year survival rate. Platinum resistance-induced recurrence and platinum intolerance result in poor prognosis. Thus, there is an unmet need for innovative therapy of advanced ovarian cancer. We have developed a novel non-genetically modified ex vivo-expanded allogeneic NK cells from peripheral blood (PB). The expanded PB-NK cells have highly cytolytic activity and have the capacity to preferentially reside in ovary. We conducted a phase I clinical trial for evaluation of safety and efficacy of allogeneic NK cells in treatment of patients with refractory or recurrent ovarian cancers. Methods: Patients with advanced ovarian cancer who failed after multiline treatment were enrolled and received the treatment with allogeneic NK cells. The treatment was divided into low, medium and high dose groups with a 28-day cycle. safety and efficacy were evaluated after receiving two cycles of allogeneic NK cell infusion. Results: A total of 4 patients with advanced ovarian cancer who failed multiline therapy completed two courses of cell infusion therapy and evaluation. The median age of patients was 58 years (range 50 to 71 years). The median number of lines of treatment was 6 (range 3-7). One recurrent patient with platinum intolerance received low dose of NK cells and three relapse or refractory patients with platinum resistance received medium dose of allogeneic NK cell therapy. The patient in low-dose group and one patient in medium-dose group were evaluated for stable disease (SD), the other two patients in medium-dose group were disease progression after two courses of treatment. Notable, the patient in low-dose group continued to receive treatment with the same dose and achieved partial response (PR) after three courses of treatment. Upon receiving continuous NK cell therapy, the tumor lesions continued to shrink, with the best result was 60% reduction. It was re-evaluated as progressive disease (PD) 6 months after treatment was discontinued. Adverse events during the follow-up period included grade I fever in 4 (100%), grade I drowsiness in 1 (25%), grade I chills in 1 (25%), and grade I malaise in 1 (25%). No CRS or GVHD occurred. Conclusions: We report the safety and efficacy of allogeneic PB-NK cells in treatment of relapse or refractory ovarian cancer. The results showed that the allogeneic PB-NK cells are safe and feasible for the treatment of ovarian cancer, indicating a promising curative effect. There is no host versus graft reaction upon receiving continuous allogeneic NK cell therapy. Clinical trial information: NCT03619954 .

Triple checkpoint blockade, but not anti-PD1 alone, enhances the efficacy of engineered adoptive T cell therapy in advanced ovarian cancer

Abstract Less than 50% of ovarian cancer patients survive five years after diagnosis. This rate has changed little in the last 30 years, highlighting the need for novel therapies. A promising strategy employs T cells engineered to target tumor-expressed proteins. Mesothelin (Msln) is overexpressed in ovarian cancers, contributes to the malignant and invasive phenotype and has limited expression in healthy cells, making it a candidate immunotherapy target. We used the immune-competent ID8 VEGFmouse model of advanced ovarian cancer to show that T cells engineered to express a Msln-specific T cell receptor (TCR Msln) can preferentially accumulate within established tumors, delay tumor growth and significantly prolong mouse survival. However, elements in the tumor microenvironment limited engineered T cell function. Tumor-bearing mice were therefore treated with TCR MslnT cells plus PD1, Tim-3 and/or Lag-3 checkpoint-blocking antibodies, alone or in combination. Triple checkpoint blockade, but not single- or double-agent treatments, dramatically increased effector cytokine production by intratumoral TCR MslnT cells. Single cell RNA-sequencing revealed gene expression changes in intratumoral TCR MslnT cells and myeloid cells consistent with immune activation and inflammation. Moreover, combining adoptive immunotherapy with triple checkpoint blockade prolonged survival in treated mice, relative to TCR Mslnwith or without single- or double-agent checkpoint blockade. These results suggest that disrupting multiple immune-inhibitory pathways simultaneously, which can be more safely pursued in a cell intrinsic form through genetic engineering, may be necessary to improve outcomes for ovarian cancer patients.

Comparative Survival Outcomes of Hyperthermic Intraperitoneal Chemotherapy, Intraperitoneal Chemotherapy and Intravenous Chemotherapy for Primary Advanced Ovarian Cancer: A Network Meta-Analysis.

We aimed to compare the survival outcomes and adverse events of hyperthermic intraperitoneal chemotherapy (HIPEC), intraperitoneal chemotherapy (IP)and intravenous chemotherapy (IP)for primary advanced ovarian cancer. PubMed, CENTRAL (Cochrane Central Registry of Controlled Trials), Embase, Web of Science and Scopus were searched using multiple terms for primary advanced ovarian cancer, including randomized controlled trials and comparative studies in both Chinese and English (up to date 15 August 2022). Outcomes include overall survival, progression-free survival and adverse events. The data were pooled and reported as hazard ratio (HRs) with 95% confidence intervals. The Newcastle-Ottawa Scales were used to assess the risk of bias in the included comparative study. The Cochrane Collaboration's Risk of Bias Tool was used for randomized controlled trials. In total, 32 studies, including 6347 patients and 8 different platinum-based chemotherapy regimens, were included in this network meta-analysis. Our analysis results showed that HIPEC2 (carboplatin with area under the curve 10) exhibited a statistically significant OS benefit compared to IV, weekly dose-dense chemotherapy and HIPEC1 (cisplatin with 75/100 mg/m2). Intraperitoneal plus intravenous chemotherapy was associated with a statistically significantly better likelihood of overall survival compared to IV. For progression-free survival, our statistical results only suggest a better progression-free survival in ovarian cancer patients treated with HIPEC1 compared with weekly dose-dense chemotherapy. No evidence of difference was observed between the other comparison groups. Compared with the non-HIPEC group, HIPEC may had a higher incidence of electrolyte disturbances (≥grade 3). Our statistical analysis suggests that the groups receiving HIPEC2 had a better OS than the groups receiving IV, weekly dose-dense chemotherapy and HIPEC1. For PFS, our analysis only showed HIPEC1 is better than IV. Moreover, HIPEC may lead to a higher incidence of electrolyte disturbances (≥grade 3). HIPEC therapy for advanced ovarian cancer is currently controversial.

Olaparib After Initial Therapy for Advanced Ovarian Cancer

Olaparib After Initial Therapy for Advanced Ovarian Cancer

The contemporary management of peritoneal metastasis: A journey from the cold past of treatment futility to a warm present and a bright future.

Peritoneal metastasis (PM) is often regarded as a less frequent pattern of spread; however, collectively across all spectra of primary tumors, the consequences of PM impact a large population of patients annually. Unlike other modes of metastasis, symptoms at presentation or during the treatment course are common, representing an additional challenge in the management of PM. Early efforts with chemotherapy and incomplete surgical interventions transiently improved symptoms, but durable symptom control and survival extension were rare, which established a perspective of treatment futility for PM through most of the 20th century. Notably, the continued development of better systemic therapy combinations, optimization of cytoreductive surgery (CRS), and rigorous investigation of combining regional therapy-specifically hyperthermic intraperitoneal chemotherapy-with CRS, have resulted in more effective multimodal treatment options for patients with PM. In this article, the authors provide a comprehensive review of the data establishing the contemporary approach for tumors with a high frequency of PM, including appendix, colorectal, mesothelioma, and gastric cancers. The authors also explore the emerging role of adding hyperthermic intraperitoneal chemotherapy to the well established paradigm of CRS and systemic therapy for advanced ovarian cancer, as well as the recent clinical trials identifying the efficacy of poly(adenosine diphosphate ribose) polymerase maintenance therapy. Finally, recent data are included that explore the role of precision medicine technology in PM management that, in the future, may help further improve patient selection, identify the best systemic therapy regimens, detect actionable mutations, and identify new targets for drug development.

Effectiveness and safety of niraparib as neoadjuvant therapy in advanced ovarian cancer with homologous recombination deficiency: NANT study protocol for a prospective, multicenter, exploratory, phase 2, single-arm study (041)

Objectives: Neoadjuvant chemotherapy followed by interval debulking surgery did not achieve survival benefits compared to primary debulking surgery in advanced ovarian cancer. Niraparib is the only approved poly (ADP-ribose) polymerase inhibitor by the FDA to treat homologous recombination deficiency (HRD)-positive ovarian cancer patients with platinum-sensitive relapse after ≥ 3 lines of chemotherapy hitherto. We aimed to assess the efficacy and safety of neoadjuvant niraparib monotherapy in BRCAmut/HRD-positive patients with advanced unresectable ovarian cancer. Methods: This multi-center phase II single-arm study followed Simon’s two-stage design. We planned to recruit 53 patients (aged 18-75 years) with newly diagnosed BRCAmut/HRD positive, unresectable (Fagotti score ≥ 8 or upper abdominal computed tomography score ≥ 3), FIGO stage III-IV high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Enrolled patients received two cycles (four weeks per cycle) of individualized starting dose of neoadjuvant niraparib (200mg or 300mg per day), interval debulking surgery, and at least four cycles of platinum-based chemotherapy. Maintenance therapy of niraparib was dosed (200mg or 300mg per day) within 12 weeks up to three years or disease progression or patient withdrawal. The dual primary objectives were objective response rate (ORR) and R0 resection rate. Both progression-free survival and overall survival were secondary objectives. The data manager will record adverse events (AEs). If more than five patients achieved OR in the first stage, the study would enter the second stage. Results: Since February 2021, 16 patients have been enrolled. By September 20, 2021, six patients had completed neoadjuvant niraparib monotherapy, and four had completed interval debulking surgery. Their baseline characteristics are shown in Table 1. The ORR was 100% (CR n=0; PR n=6) and R0 reduction rate was 75% (R0, n=3; R1, n=1). CA-125 began to decline since day-14 after the first dose of niraparib, significantly decreased after the first cycle of neoadjuvant niraparib (median decrease, 70.8% [min, 23.8%; max, 97.4%] of baseline concentration), and continued to decline thereafter. Treatment-emergent adverse events (TEAEs) could be analyzed in nine patients, and the most common TEAEs were hematological AEs, including any grade leukopenia (66.7%), anemia (66.7%), and thrombocytopenia (55.6%). No treatment-related death was recorded. The grade ≥3 TEAEs were anemia (n=1) and thrombocytopenia (n=5). Thrombocytopenia mainly occurred after the first cycle of neoadjuvant niraparib, which synchronized with the decline of CA-125. Objectives: Neoadjuvant chemotherapy followed by interval debulking surgery did not achieve survival benefits compared to primary debulking surgery in advanced ovarian cancer. Niraparib is the only approved poly (ADP-ribose) polymerase inhibitor by the FDA to treat homologous recombination deficiency (HRD)-positive ovarian cancer patients with platinum-sensitive relapse after ≥ 3 lines of chemotherapy hitherto. We aimed to assess the efficacy and safety of neoadjuvant niraparib monotherapy in BRCAmut/HRD-positive patients with advanced unresectable ovarian cancer. Methods: This multi-center phase II single-arm study followed Simon’s two-stage design. We planned to recruit 53 patients (aged 18-75 years) with newly diagnosed BRCAmut/HRD positive, unresectable (Fagotti score ≥ 8 or upper abdominal computed tomography score ≥ 3), FIGO stage III-IV high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Enrolled patients received two cycles (four weeks per cycle) of individualized starting dose of neoadjuvant niraparib (200mg or 300mg per day), interval debulking surgery, and at least four cycles of platinum-based chemotherapy. Maintenance therapy of niraparib was dosed (200mg or 300mg per day) within 12 weeks up to three years or disease progression or patient withdrawal. The dual primary objectives were objective response rate (ORR) and R0 resection rate. Both progression-free survival and overall survival were secondary objectives. The data manager will record adverse events (AEs). If more than five patients achieved OR in the first stage, the study would enter the second stage. Results: Since February 2021, 16 patients have been enrolled. By September 20, 2021, six patients had completed neoadjuvant niraparib monotherapy, and four had completed interval debulking surgery. Their baseline characteristics are shown in Table 1. The ORR was 100% (CR n=0; PR n=6) and R0 reduction rate was 75% (R0, n=3; R1, n=1). CA-125 began to decline since day-14 after the first dose of niraparib, significantly decreased after the first cycle of neoadjuvant niraparib (median decrease, 70.8% [min, 23.8%; max, 97.4%] of baseline concentration), and continued to decline thereafter. Treatment-emergent adverse events (TEAEs) could be analyzed in nine patients, and the most common TEAEs were hematological AEs, including any grade leukopenia (66.7%), anemia (66.7%), and thrombocytopenia (55.6%). No treatment-related death was recorded. The grade ≥3 TEAEs were anemia (n=1) and thrombocytopenia (n=5). Thrombocytopenia mainly occurred after the first cycle of neoadjuvant niraparib, which synchronized with the decline of CA-125.

Abstract 3608: Triple checkpoint blockade, but not anti-PD1 alone, enhances the efficacy of engineered adoptive T cell therapy in advanced ovarian cancer

Abstract Background: Less than half of ovarian cancer patients survive five years after diagnosis. This rate has changed little in the last 30 years, highlighting the need for novel therapies. A promising new strategy with the potential to control tumor growth without toxicity to healthy tissues employs immune T cells engineered to target proteins uniquely overexpressed in tumors. Mesothelin (Msln) is overexpressed in high grade serous ovarian cancer, contributes to the malignant and invasive phenotype, and has limited expression in healthy cells, making it a candidate immunotherapy target in these tumors. Methods: The ID8VEGF mouse cell line was used to evaluate if T cells engineered to express a mouse Msln-specific high-affinity T cell receptor (TCRMsln) can kill murine ovarian tumor cells in vitro and in vivo. Tumor-bearing mice were treated with TCRMsln T cells plus anti-PD-1, anti-Tim-3 or anti-Lag-3 checkpoint-blocking antibodies administered alone or in combination, ultimately allowing targeting up to three inhibitory receptors simultaneously. Single cell RNA sequencing was used to profile the impact of combination checkpoint blockade on both the engineered T cells and the tumor microenvironment. Results: In a disseminated ID8 tumor model, adoptively transferred TCRMsln T cells preferentially accumulated within established tumors, delayed ovarian tumor growth, and significantly prolonged mouse survival. However, our data also revealed that elements in the tumor microenvironment (TME) limited engineered T cell persistence and ability to kill cancer cells. Triple checkpoint blockade, but not single- or double-agent treatment, dramatically increased effector cytokine production by intratumoral TCRMsln T cells. Single cell RNA-sequencing revealed gene expression changes in engineered T cells and myeloid cells in the TME consistent with activation and inflammation. Moreover, combining adoptive immunotherapy with triple checkpoint blockade prolonged survival in the cohort of treated tumor-bearing mice, relative to TCRMsln with or without anti-PD1, or double-agent treatments. Conclusions: Inhibitory receptor/ligand interactions within the tumor microenvironment can dramatically reduce T cell function, suggesting tumor cells may increase expression of the ligands for PD-1, Tim-3 and Lag-3 for protection from tumor-infiltrating lymphocytes. In a model of advanced ovarian cancer, triple checkpoint blockade significantly improved the anti-tumor function of transferred engineered T cells and improved outcomes in mice in a setting in which single checkpoint blockade had no significant activity. These results suggest that disrupting multiple inhibitory signaling pathways simultaneously, which can be more safely pursued in a cell intrinsic form through genetic engineering, may be necessary for improved efficacy in patients. Citation Format: Kristin G. Anderson, Yapeng Su, Madison G. Burnett, Breanna M. Bates, Magdalia L. Rodgers Suarez, Susan L. Ruskin, Aesha Vakil, Valentin Voillet, Raphael Gottardo, Philip Greenberg. Triple checkpoint blockade, but not anti-PD1 alone, enhances the efficacy of engineered adoptive T cell therapy in advanced ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3608.

OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab

ObjectiveTo assess safety and efficacy of niraparib + bevacizumab as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer. MethodsThis multicenter, phase II, single-arm, open-label study enrolled adult patients with stage IIIB to IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03326193). Patients were required to have an attempt at debulking surgery and have a complete response, partial response, or no evidence of disease following first-line, platinum-based chemotherapy with ≥3 cycles of bevacizumab. The primary endpoint was the progression-free survival (PFS) rate at 18 months. Secondary endpoints included PFS, overall survival, and safety. ResultsAmong the 105 evaluable patients, the PFS rate at 18 months was 62% (95% CI 52–71%) in the overall population and 76% (95% CI 61–87) in the homologous recombination deficient (HRd), 47% (95% CI 31–64%) in the HR proficient (HRp), and 56% (95% CI 31–79%) in the HR not determined (HRnd) subgroups (December 24, 2020, cutoff). After a median follow-up time of 28.7 months (IQR, 23.9–32.5 months), median PFS was 19.6 months (95% CI 16.5–25.1) in the overall population (N = 105) and 28.3 months (95% CI 19.9–NE), 14.2 months (95% CI 8.6–16.8), and 12.1 months (95% CI 8.0–NE) in the HRd, HRp, and HRnd subgroups, respectively (June 16, 2021, cutoff). The most common any-grade treatment-related adverse events (related to niraparib and/or bevacizumab) were thrombocytopenia (74/105), fatigue (60/105), and anemia (55/105; December 24, 2020, cutoff). ConclusionNiraparib + bevacizumab first-line maintenance therapy displayed promising PFS results. Safety was consistent with the known safety profiles of niraparib and bevacizumab as monotherapy.

Effectiveness and Safety of Niraparib as Neoadjuvant Therapy in Advanced Ovarian Cancer With Homologous Recombination Deficiency (NANT): Study Protocol for a Prospective, Multicenter, Exploratory, Phase 2, Single-Arm Study.

BackgroundOvarian cancer (OC) is a heterogeneous gynecological malignancy with a poor prognosis as the majority of patients are diagnosed at an advanced stage. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is recommended for patients who cannot achieve optimal cytoreduction or cannot endure primary debulking surgery (PDS). As there is an increased risk of chemoresistance for platinum-based NACT, it is important to investigate an alternative option. A Poly (ADP-ribose) polymerase inhibitor (PARPi), niraparib, has shown high anti-tumor activity, especially in homologous recombination deficiency (HRD) positive patients with OC. Thus, niraparib as a neoadjuvant treatment agent may help improve surgery accessibility and create survival benefits.MethodsThis multicenter, prospective, single-arm, open-label, phase II study plans to recruit 53 patients (aged 18-75 years) with newly diagnosed HRD positive, unresectable (Fagotti score ≥ 8 or upper abdominal computed tomography [CT] score ≥ 3) International Federation of Gynecology and Obstetrics (FIGO) stage III-IV OC. The HRD status was detected by next-generation sequencing and HRD positive patients will be counseled for study participation. Enrolled patients will receive niraparib capsules QD (200mg or 300mg per day) for two cycles (4 weeks/cycle). After neoadjuvant niraparib treatment, patients exhibiting complete response (CR), partial response (PR), or stable disease (SD) will undergo tumor reduction surgery and subsequent standard carboplatin/paclitaxel-based chemotherapy. The primary objectives include the objective response rate (ORR) and R0 resection rate. The rate of treatment interruption/termination and progression-free survival (PFS) will be secondary objectives. The study uses Simon’s optimal two-stage design (24 and 21 patients for the first and second stage respectively). The data manager will record all adverse events (AEs).DiscussionThis is the first prospective study to evaluate the effectiveness and safety of niraparib in neoadjuvant treatment for advanced OC. The result of this study will provide a solid base for further expanding the clinical applications of the PAPRi and exploring more therapeutic possibilities for patients with HRD positive advanced OC. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04507841.

Inhibition of PKM2 Enhances Sensitivity of Olaparib to Ovarian Cancer Cells and Induces DNA Damage.

Poly (ADP-ribose) polymerase inhibitors (PARPi) have showed clinical benefit as maintenance therapy in advanced ovarian cancer by impairing the homologous recombination (HR) pathway. Pyruvate kinase M2 (PKM2), the significant cancer metabolic biomarker, integrates with DNA damage to directly promote HR. We aimed to investigate the role and molecular mechanism of PKM2 downregulation on sensitization of ovarian cancer cells to PARPi. Inhibitory effects in vitro were assessed by cell viability, clone formation, transwell assay, and flow cytometry. Downregulation of PKM2 by siRNA or small molecular inhibitor shikonin (Sk) enhanced anti-tumour activity of olaparib (Ola) in ovarian cancer cells. Silencing PKM2 or Sk synergized with Ola and reduced cell growth, colony formation and migration, and induced apoptosis. Western blot and immunofluorescence demonstrated that inhibition of PKM2 amplified Ola-induced γH2AX and phospho-ATM (p-ATM) activation and interfered with BRCA1 accumulation in the nucleus. A xenograft animal model demonstrated in vivo antitumor combination effect of Sk and Ola. Furthermore, Western blot and immunofluorenscent analyses of tissue samples revealed that treatment of Sk increased DNA damage, reduced expression of BRCA1 and PKM2. Therefore, this study identified that PKM2 downregulation is a novel therapeutic strategy to enhance Ola effectiveness in treating ovarian cancer.

A review on mechanisms of resistance to PARP inhibitors.

Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA-associated cancers, especially high-grade OC and breast cancers. They lead to synthetic lethality in BRCA-mutated cells by stalling the replication forks in homologous recombination-deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA-associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance.

Correction to: Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer

Correction to: Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer.

Niraparib (Zejula™) is a PARP inhibitor which is approved for maintenance therapy in adults with advanced ovarian cancer in complete or partial response to platinum-based chemotherapy. In a placebo-controlled phase III trial in patients with newly diagnosed advanced ovarian cancer, niraparib significantly extended progression free survival in two predefined populations, namely a patient population with altered homologous-recombination DNA repair pathways [i.e. homologous-recombination deficiency positive (HRd)] and the overall trial population. A prespecified exploratory subgroup analysis indicated that niraparib was also efficacious in patients who were homologous recombination deficiency negative or homologous recombination proficient (HRp). Niraparib has a manageable tolerability profile with myelosuppression as the main safety concern. Haematological reactions were managed with monitoring and dose reduction or interruption. A weight- and platelet count-based individualised dosage regimen introduced during the trial (and subsequently approved) appeared to improve haematological tolerability. Niraparib is a useful option for first-line maintenance therapy for advanced ovarian cancer in adults who responded to platinum-based chemotherapy, regardless of homologous-recombination deficiency status and is a promising option for HRp patients, for whom maintenance treatment options are limited.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-021-00841-2.