Safety Profile of Niraparib as Maintenance Therapy for Ovarian Cancer: A Systematic Review and Meta-Analysis

Background: Patients with epithelial ovarian cancer (EOC), treated with niraparib maintenance, present with haematological and gastrointestinal toxicities. Limited data exist on niraparib safety assessment. Objective: To evaluate niraparib safety profile, as maintenance therapy, in women with platinum-sensitive EOC. Methods: PubMed and Cochrane searches were carried out up to April 2021 for randomised controlled trials (RCTs) evaluating niraparib versus placebo in EOC patients with a response to platinum-based chemotherapy. Regarding the meta-analysis, for dichotomous data, the pooled risk ratio (RR) was calculated. Results: A total of 1539 patients from three RCTs revealed that niraparib-treated patients are associated with a significantly higher risk of any grade of nausea (RR, 2.15; 95% CI, 1.86 to 2.48), fatigue (RR, 1.26; 95% CI, 1.05 to 1.52, p < 0.00001), anemia (RR, 6.86; 95% CI, 2.54 to 18.52, p = 0.0001), thrombocytopenia (RR, 7.02; 95% CI, 1.68 to 29.38, p < 0.00001), vomiting (RR, 2.51; 95% CI, 1.50 to 4.19, p = 0.0005), neutropenia (RR, 2.96; 95% CI, 1.13 to 7.73, p < 0.00001), headache (RR, 2.08; 95% CI, 1.57 to 2.74, p < 0.00001), constipation (RR, 2.10; 95% CI, 1.72 to 2.57, p < 0.00001) and insomnia (RR, 2.48; 95% CI, 1.52 to 2.89, p = 0.0003) when compared with placebo. For grade 3 or 4 adverse effects, significantly higher risk was only noted for fatigue (RR,6.25; 95% CI, 1.70 to 23.05, p = 0.006), anemia (RR, 16.23; 95% CI, 4.86 to 54.17, p < 0.00001), thrombocytopenia (RR, 35.12; 95% CI, 12.23 to 100.82, p < 0.00001) and neutropenia episodes (RR, 6.35; 95% CI, 2.08 to 19.39, p = 0.001) for those taking niraparib. Notably, incidents of adverse effects and discontinuation rates were substantially lower among patients treated with an individualised niraparib dose than those treated with the standard one. Efficacy was not reduced, and no treatment-related deaths occurred during the included trials. Conclusion: Niraparib is considered an effective and well-tolerated choice, with an improved safety profile, for the maintenance treatment of EOC patients.

Assessing frequency and clinical outcomes of BRCA mutated ovarian cancer in Saudi women

Purpose BRCA gene mutations (BRCAm) have an impact on patients’ characteristics and clinical outcomes of ovarian cancer (OC). The frequency and patterns of BRCAm vary among countries and ethnicities. There are limited data from Saudi Arabia (SA); thus, this study aims to determine the frequency, pattern, and impact on patient characteristics and outcomes of BRCAm OC compared to wild-type BRCA (BRCAw) in Saudi women. Methods This retrospective study evaluated women diagnosed with non-mucinous OC, fallopian tube, or peritoneal carcinoma who had BRCA status tested in an accredited lab between January 2016 and December 2017. The associations between various parameters and BRCAm were estimated using logistic regression. Statistical analysis performed with SPSS (Version 27). Result Sixty-one women with a median age of 52 at diagnosis were analyzed. Germline BRCA mutations were found in 41% of cases (25/61). The most common deleterious germline BRCA1 mutation was c.1140dupG (39%). Most women (72%) had no family history of cancers and 82% had advanced stage. Regardless of BRCA mutations, an optimal overall response rate (ORR) to first-line treatment has been achieved although most cases relapsed (84%) and the majority were platinum-sensitive relapse (85%). Higher ORR to subsequent lines and better survival were obtained in women with BRCA-mutation. Conclusion The prevalence of BRCAm of OC was higher in Saudi women compared to regional and most of the international figures. The better clinical outcomes of BRCAm women agreed with the reported evidence. Further studies on BRCA mutations of OC and genetic counseling are highly recommended. Trial registration Trial approved by the Institutional Review Board of King Faisal Specialist Hospital and Research Center (RAC # 2171137) and conducted at King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11,211, Saudi Arabia.

HSP90 Inhibition Synergizes with Cisplatin to Eliminate Basal-like Pancreatic Ductal Adenocarcinoma Cells

To improve the treatment of pancreatic ductal adenocarcinoma (PDAC), a promising strategy consists of personalized chemotherapy based on gene expression profiles. Investigating a panel of PDAC-derived human cell lines, we found that their sensitivities towards cisplatin fall in two distinct classes. The platinum-sensitive class is characterized by the expression of GATA6, miRNA-200a, and miRNA-200b, which might be developable as predictive biomarkers. In the case of resistant PDAC cells, we identified a synergism of cisplatin with HSP90 inhibitors. Mechanistic explanations of this synergy include the degradation of Fanconi anemia pathway factors upon HSP90 inhibition. Treatment with the drug combination resulted in increased DNA damage and chromosome fragmentation, as we have reported previously for ovarian cancer cells. On top of this, HSP90 inhibition also enhanced the accumulation of DNA-bound platinum. We next investigated an orthotopic syngeneic animal model consisting of tumors arising from KPC cells (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre, C57/BL6 genetic background). Here again, when treating established tumors, the combination of cisplatin with the HSP90 inhibitor onalespib was highly effective and almost completely prevented further tumor growth. We propose that the combination of platinum drugs and HSP90 inhibitors might be worth testing in the clinics for the treatment of cisplatin-resistant PDACs.

Comparison of the Efficacy and Safety of PARP Inhibitors as a Monotherapy for Platinum-Sensitive Recurrent Ovarian Cancer: A Network Meta-Analysis

BackgroundThe present COVID-19 pandemic has tended toward normality. To provide convenient, safe, and effective home treatment programs for patients with recurrent ovarian cancer (ROC), the clinical efficacy and safety of poly (ADP-ribose) polymerase inhibitor (PARPi) (including olaparib, niraparib, and rucaparib) monotherapy as a maintenance treatment for platinum-sensitive ROC were systematically evaluated.MethodsNumerous electronic databases were systematically searched for randomized controlled trials (RCTs) of PARPi maintenance treatment for ROC that were published before June 2021. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoint was grade 3-4 adverse effects (AEs). After data extraction and the quality evaluation of the included studies, Bayesian network meta-analysis (NMA) was performed using R software. The ability of each treatment was ranked using the surface under the cumulative ranking (SUCRA) curve.ResultsThe analysis included five studies and 1390 patients. The NMA results demonstrated that compared with the placebo, olaparib and niraparib exhibited significant benefits in the gBRCA-mutated population, and respectively reduced the risk of death by 31% (HR = 0.69, 95% CI: 0.53-0.90) and 34% (HR = 0.66, 95% CI: 0.44-0.99). Olaparib, niraparib, and rucaparib were all found to be very effective in prolonging PFS in patients with ROC. All three PARPi treatments increased the number of grade 3-4 AEs in patients with ROC as compared with the placebo.ConclusionsOverall, olaparib and niraparib maintenance treatment can significantly prolong the OS of patients with gBRCA mutations. Furthermore, the three investigated PARPi monotherapy maintenance treatments can prolong PFS regardless of BRCA mutation status. Although the incidence of AEs in the treatment groups was found to be significantly higher than that in the placebo group, the patients in the treatment group tolerated the treatment. Home oral PARPi treatment can balance tumor treatment and pandemic prevention and control, and is the most convenient, safe, and effective home treatment method available against the background of the current COVID-19 pandemic. Systematic Review Registrationhttps://inplasy.com/inplasy-2021-6-0033/.

High Serpin Family A Member 10 Expression Confers Platinum Sensitivity and Is Associated With Survival Benefit in High-Grade Serous Ovarian Cancer: Based on Quantitative Proteomic Analysis

This study aims to identify differentially expressed proteins related with platinum sensitivity and to find biomarkers for predicting platinum response and survival outcomes in patients with high-grade serous ovarian cancer (HGSOC). Eligible HGSOC patients were divided into platinum-sensitive and platinum-resistant groups according to platinum-free interval (PFI). Tissue protein lysates from tumor tissues were subjected to an in-solution tryptic digest followed by tandem mass tag (TMT) labeling of the resulting peptides and mass spectrometric analysis. Candidate proteins were identified using differentially expressed protein and gene set enrichment analysis (GSEA) and confirmed by immunohistochemistry (IHC), and their survival relevance was evaluated in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. The results showed that there was a significant difference in the protein expression profiling between the two patient groups. In the GSEA model, a gene set of 239 extracellular matrix (ECM)-related proteins was significantly enriched in the platinum-sensitive group [normalized enrichment score (NES) = 3.82, q &lt; 10−5], and this finding was confirmed in TCGA ovarian cancer cohort. Interestingly, an ECM-related gene expression, serpin family A member 10 (SERPINA10), was identified to be significantly positively correlated with overall survival (OS) and progression-free survival (PFS) in TCGA ovarian cancer cohort (all p &lt; 0.05). IHC results demonstrated that HGSOC patients with high SERPINA10 expression had longer PFI than the patients with low SERPINA10 expression (9 vs. 5 months, p = 0.038), and the SERPINA10 expression had an area under the receiver operating characteristic curve (AUC) value of 0.758 (95% CI = 0.612–0.905; p = 0.005) to discriminate the platinum-sensitive group from the platinum-resistant group. In conclusion, the results suggested that SERPINA10 could be a promising biomarker for predicting the response and survival in platinum-based chemotherapy of HGSOC.

Discovery of metabolomic biomarkers for discriminating platinum-sensitive and platinum-resistant ovarian cancer by using GC-MS

This study aims to determine ovarian cancer (OC) patients with platinum resistance for alternative treatment protocols by using metabolomic methodologies. Urine and serum samples of platinum-resistant and platinum-sensitive OC were analyzed using GC-MS. After data processing of GC-MS raw data, multivariate analyses were performed to interpret complex data for biologically meaningful information and to identify the biomarkers that cause differences between two groups. The biomarkers were verified after univariate, multivariate, and ROC analysis. Finally, metabolomic pathways related to group separations were specified. The results of biomarker analysis showed that 3,4-dihydroxyphenylacetic acid, 4-hydroxybutyric acid, L-threonine, D- mannose, and sorbitol metabolites were potential biomarkers in urine samples. In serum samples, L-arginine, linoleic acid, L-glutamine, and hypoxanthine were identified as important biomarkers. R2Y, Q2, AUC, sensitivity and specificity values of platinum-resistant and sensitive OC patients’ urine and serum samples were 0.85, 0.545, 0.844, 91.30%, 81.08 and 0.570, 0.206, 0.743, 77.78%, 74.28%, respectively. In metabolic pathway analysis of urine samples, tyrosine metabolism and fructose and mannose metabolism were found to be statistically significant (p < 0.05) for the discrimination of the two groups. While 3,4-dihydroxyphenylacetic acid, L-tyrosine, and fumaric acid metabolites were effective in tyrosine metabolism. D-sorbitol and D-mannose metabolites were significantly important in fructose and mannose metabolism. However, seven metabolomic pathways were significant (p < 0.05) in serum samples. In terms of p-value, L-glutamine in the nitrogen metabolic pathway from the first three pathways; L-glutamine and pyroglutamic acid metabolites in D-glutamine and D-glutamate metabolism. In the arginine and proline metabolic pathway, L-arginine, L-proline, and L-ornithine metabolites differed significantly between the two groups.

A Comprehensive Systematic Review and Network Meta-analysis: The Role of anti- angiogenic agents in advanced epithelial ovarian cancer

BackgroundThe efficacy of anti-angiogenic agents (AAAs) in epithelial ovarian cancer (EOC) remains unclear. Therefore, we conducted a systematic review and network meta-analysis (NMA) to synthesize evidence of their comparative effectiveness for improving overall survival (OS) among EOC patients. MethodsWe searched six databases for randomized controlled trials (RCTs) from their inception to February 2021. We performed a NMA with hazard ratios (HRs) and 95% confidence intervals (CIs) to evaluate comparative effectiveness among different AAAs in two disease settings, chemotherapy naïve, and recurrent EOC. P-score was used to provide an effectiveness hierarchy ranking. Sensitivity NMA was carried out by focusing on studies that reported high-risk disease chemotherapy-naïve, platinum-resistant, and platinum-sensitive EOC. The primary outcome was OS.FindingsWe identified 23 RCTs (n=11,560) which assessed effectiveness of eight different AAAs. NMA results showed no significant OS difference among anti-angiogenic agents in chemotherapy-naïve. In recurrent EOC, concurrent use of trebananib (10mg/kg) and chemotherapy was likely to be the best option (P-score: 0.88, NMA estimate versus chemotherapy: HR= 1.67, 95% CI: 0.94; 2.94). The sensitivity NMA indicated that bevacizumab plus chemotherapy with maintenance treatment (P-score: 0.99) and pazopanib plus chemotherapy (P-score: 0.79) had the highest probability of being the best intervention for improving OS in high-risk chemotherapy-naïve and platinum-resistant setting, respectively. InterpretationAAAs may not play a significant clinical role in chemotherapy-naïve and platinum-sensitive EOC. Conversely, the concurrent use of trebananib with chemotherapy was likely to be the best intervention in recurrent EOC.

Highly Expressed Progesterone Receptor B Isoform Increases Platinum Sensitivity and Survival of Ovarian High-Grade Serous Carcinoma

Background: Expression of the progesterone receptor (PR) has been reported to influence survival outcomes in patients with ovarian high-grade serous carcinoma (HGSC). In the present study, we attempted to investigate the association among PR and its isoforms’ expression, platinum sensitivity, and survival in ovarian HGSC. Material and methods: This retrospective study reviewed ovarian HGSC patients who received surgery followed by adjuvant chemotherapy. We analyzed total PR and PR isoform-B (PR-B) expression by immunohistochemical staining and quantified using the H-score. Then, we compared platinum sensitivity and survival outcomes between those patients with weak and strong PR-B expression. Cisplatin viability assays were carried out in ovarian HGSC cell lines (OC-3-VGH and OVCAR-3) with different PR-B expression. Results: Among 90 patients, 49 and 41 patients were considered to have platinum-sensitive and platinum-resistant disease, respectively. Pearson’s correlation model showed that the H-score of total PR correlated positively with PR-B (r = 0.813). The PR-B H-score of tumors was significantly higher in the platinum-sensitive group (p = 0.004). Multivariate analysis revealed that the PR-B H-score and optimal debulking status were independent factors predicting platinum sensitivity. When compared with strong PR-B expression, patients with weak PR-B had significantly poorer progression-free (p = 0.021) and cancer-specific survival (p = 0.046). In a cell model, cisplatin-resistant OC-3-VGH cells expressed a lower level of PR-B than wild-type cells. Overexpression of PR-B or progesterone could increase cisplatin sensitivity in both OC-3-VGH and OVCAR-3 cells via the mechanism of promoting cisplatin-related apoptosis. Conclusions: When compared to weak PR-B, ovarian HGSC patients with a strong PR-B expression had a better chance of platinum sensitivity and survival, and this finding was compatible with our experimental results. Progesterone seemed to be a platinum sensitizer, but the value of adding progesterone in the treatment of ovarian HGSC should be further investigated.