Efficacy and safety of PARPis combined with an ICIs for advanced or metastatic triple-negative breast cancer: a single-arm meta-analysis.

Although the intervention for triple-negative breast cancer (TNBC) patients has improved and survival time has increased, the combination of immune checkpoint inhibitors(ICIs) and PARP inhibitors (Poly ADP-Ribose Polymerase inhibitors, PARPis) is still controversial. Previous studies revealed that the combined use of ICIs and PARPis led to increased antitumor activity. However, most of these combined regimens are nonrandomized controlled trials with small sample sizes. The purpose of this meta-analysis was to evaluate the efficacy and safety of ICIs combined with PARPis in patients with advanced or metastatic TNBC. The PubMed, Embase, Cochrane Library and Web of Science databases were systematically searched. The results including the objective remission rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse events (AEs), were subjected to further analysis. Four studies involving 110 subjects were included in this meta-analysis. The combined ORR and DCR were 23.6% and 53.6%, respectively; while the ORR and DCR of BRCAmut patients were 38.1% and 71.4%, respectively. The median PFS of the patients was 4.29 months. As for safety, the most common AEs were nausea (49.0%), anemia (44.3%) and fatigue (40.6%). Most of them were grade 1 or 2, and the incidence of adverse events ≥ III was obviously low. Except for anemia, the incidence of AEs ≥ III was < 10%. This meta-analysis revealed that the combination of ICIs and PARPis has good efficacy and safety for advanced or metastatic TNBC patients.

Neurological toxicities with poly (ADP-ribose) polymerase inhibitors in cancer patients: a systematic review and meta-analysis.

We conducted this meta-analysis to investigate neurological toxicities with poly (ADP-ribose) polymerase inhibitors (PARPis) in cancer patients. Databases were searched for randomized controlled trials (RCTs) from 1 January 2000 to 1 November 2023. Forty-six RCTs and 9529 patients were included. PARPis could increase the risk of all-grade headache [risk ratio (RR), 1.22; 95% confidence intervals (CI), 1.14-1.30; P < 0.00001], dizziness (RR, 1.40; 95% CI, 1.28-1.53; P < 0.00001), dysgeusia (RR, 1.93; 95% CI, 1.44-2.60; P < 0.0001) and insomnia (RR, 1.32; 95% CI, 1.09-1.60; P < 0.0001) in cancer patients. Headache was the most common neurological toxicity. Niraparib was associated with a higher risk of headache and insomnia, talazoparib with a higher risk of dizziness and rucaparib with a higher risk of dysgeusia. Breast cancer patients receiving PARPis have a higher risk of dysgeusia, while ovarian cancer patients are at an increased risk of insomnia. PARPis may increase the risk of mild to moderate neurological toxicities, but not severe ones.

Efficacy and safety of niraparib in platinum-sensitive recurrent ovarian cancer: retrospective observational study in a tertiary hospital.

BACKGROUND: Niraparib has been authorized for maintenance treatment of epithelial ovarian cancer after first-line treatment with platinum, in partial or complete response. OBJECTIVES: To evaluate the effectiveness and safety of maintenance niraparib in platinum-sensitive recurrent ovarian cancer (PSROC) patients in a tertiary hospital. MATERIALS AND METHODS: This retrospective observational unicentre study included women diagnosed with ovarian adenocarcinoma who received niraparib. Eligibility criteria encompassed women with PSROC, in response to platinum chemotherapy, and not previously treated with other PARPis. Data on demographics, comorbidities, BRCA mutation status, disease stage, treatment history and adverse events were recorded. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: A total of 33 patients were included, with a median age of 63.5 years. The majority of patients received niraparib at 200 mg/day based on Research on Adverse Drug Events and Report criteria. Median OS was 30 months (95% CI: 16.76-43.23), and median PFS was 8 months (95% CI: 2.48-13.52). Adverse effects were more frequent during the initial months of treatment, with most classified as CTCAE v5 grade 1-2. Dose reductions, interruption of treatment and discontinuations were observed due to haematologic toxicities primarily. CONCLUSION: This real-world study showed that maintenance niraparib in PSROC patients had effectiveness and safety profiles consistent with clinical trials and other observational studies. Median PFS and OS were comparable to previous reports, and most adverse events were manageable with dose modifications. The results support the use of niraparib as a maintenance therapy option in this patient population.

ShallowHRD status acts as an effective prognostic predictor in ovarian cancer patients treated by poly (ADP-ribose) polymerase inhibitors (PARPis).

PURPOSE: Homologous recombination deficiency (HRD) plays a crucial role in ovarian cancer patients who are treated with Poly (ADP-ribose) polymerase inhibitors (PARPis). It could be defined as a prognosis biomarker. However, many high throughput sequencing methods for evaluating HRD, including HRDetect (WGS 10X), SigMA (WGS 40X or panel 1000X), and scarHRD (WGS 30X), are technically complex, time and data-storage consuming, and costly. Herein, we aimed to develop a low-cost method by low sequencing coverage to identify HRD status for precision medication. METHODS: We utilized ShallowHRD, a software tool to evaluate tumor HRD based on whole genome sequencing (WGS) at low coverage (1X), and established a novel scoring system, ShallowHRD score system. RESULTS: Compared with negative ShallowHRD status (ShallowHRD score < 15 or BRCAwild), positive ShallowHRD status (ShallowHRD score ≥ 15 or BRCAmut) presented favorable survival after being treated with PARPis. CONCLUSION: The ShallowHRD status is a good biomarker for predicting prognosis, which could help guide the clinical application of PARPis in ovarian cancer patients by a cost-effective, time and data-storage saving method.

ATR Inhibitors in Platinum-Resistant Ovarian Cancer.

Platinum-resistant ovarian cancer (PROC) is one of the deadliest types of epithelial ovarian cancer, and it is associated with a poor prognosis as the median overall survival (OS) is less than 12 months. Targeted therapy is a popular emerging treatment method. Several targeted therapies, including those using bevacizumab and poly (ADP-ribose) polymerase inhibitor (PARPi), have been used to treat PROC. Ataxia telangiectasia and RAD3-Related Protein Kinase inhibitors (ATRi) have attracted attention as a promising class of targeted drugs that can regulate the cell cycle and influence homologous recombination (HR) repair. In recent years, many preclinical and clinical studies have demonstrated the efficacy of ATRis in PROC. This review focuses on the anticancer mechanism of ATRis and the progress of research on ATRis for PROC.

Pleiotropic role of PARP1: an overview.

Poly (ADP-ribose) polymerase 1 (PARP1) protein is encoded by the PARP1 gene located on chromosome 1 (1q42.12) in human cells. It plays a crucial role in post-translational modification by adding poly (ADP-ribose) (PAR) groups to various proteins and PARP1 itself by utilizing nicotinamide adenine dinucleotide (NAD +) as a substrate. Since the discovery of PARP1, its role in DNA repair and cell death has been its identity. This is evident from an overwhelmingly high number of scientific reports in this regard. However, PARP1 also plays critical roles in inflammation, metabolism, tumor development and progression, chromatin modification and transcription, mRNA stability, and alternative splicing. In the present study, we attempted to compile all the scattered scientific information about this molecule, including the structure and multifunctional role of PARP1 in cancer and non-cancer diseases, along with PARP1 inhibitors (PARPis). Furthermore, for the first time, we have classified PARP1-mediated cell death for ease of understanding its role in cell death pathways.

Sensitivity of Mesothelioma Cells to PARP Inhibitors Is Not Dependent on BAP1 but Is Enhanced by Temozolomide in Cells With High-Schlafen 11 and Low-O6-methylguanine-DNA Methyltransferase Expression.

INTRODUCTION: BRCA1-associated protein-1 (BAP1), a nuclear deubiquitinase thought to be involved in DNA double-strand break repair, is frequently mutated in mesothelioma. Because poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we evaluated whether BAP1 inactivating mutations confer sensitivity to PARPIs in mesothelioma and if combination therapy with temozolomide (TMZ) would be beneficial. METHODS: A total of 10 patient-derived mesothelioma cell lines were generated and characterized for BAP1 mutation status, protein expression, nuclear localization, and sensitivity to the PARPIs, olaparib, and talazoparib, alone or in combination with TMZ. BAP1 deubiquitinase (DUB) activity was evaluated by ubiquitin with 7-amido-4-methylcoumarin assay. BAP1 knockout mesothelioma cell lines were generated by CRISPR-Cas9. Because Schlafen 11 (SLFN11) and O6-methylguanine-DNA methyltransferase also drive response to TMZ and PARPIs, we tested their expression and relationship with drug response. RESULTS: BAP1 mutations or copy-number alterations, or both were present in all 10 cell lines. Nonetheless, four cell lines exhibited intact DUB activity and two had nuclear BAP1 localization. Half maximal-inhibitory concentrations of olaparib and talazoparib ranged from 4.8 µM to greater than 50 µM and 0.039 µM to greater than 5 µM, respectively, classifying them into sensitive (two) or resistant (seven) cells, independent of their BAP1 status. Cell lines with BAP1 knockout resulted in the loss of BAP1 DUB activity but did not increase sensitivity to talazoparib. Response to PARPI tended to be associated with high SLFN11 expression, and combination with temozolomide increased sensitivity of cells with low or no MGMT expression. CONCLUSIONS: BAP1 status does not determine sensitivity to PARPIs in patient-derived mesothelioma cell lines. Combination of PARPI with TMZ may be beneficial for patients whose tumors have high SLFN11 and low or no MGMT expression.

Niraparib in ovarian cancer: results to date and clinical potential.

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.