Poly-ADP ribose polymerase inhibitor and androgen receptor signaling inhibitor for all comers for first-line treatment of metastatic castration-resistant prostate cancer: is gene sequencing out?

PURPOSE OF REVIEW: The landscape for first-line therapy (1L) of metastatic castration-resistant prostate cancer (mCRPC) is rapidly shifting. In the past 2 years, three phase 3 trials have examined the addition of a poly-ADP ribose polymerase inhibitor (PARPi) to an androgen receptor-signaling inhibitor (ARSI) in 1L. The FDA and the EMA recently considered whether one of these combinations should be approved for "all comers." Here, we review the trial designs, assays for homologous recombination repair mutations (HRRm) and BRCA mutations ( BRCA m), and predictive capacity of mutational status on treatment efficacy to understand the basis for the FDA decision. RECENT FINDINGS: The phase 3 trials, PROpel, MAGNITUDE, and TALAPRO-2, each compared PARPi and ARSI to placebo (PBO) plus ARSI. PROpel and TALAPRO-2 (cohort 1) included all comers (i.e., no prospective biomarker selection), while MAGNITUDE prospectively assigned patients to HRRm and HRR nonmutated cohorts and TALAPRO-2 (cohort 2) included only those with HRRm. Radiographic progression-free survival (rPFS) was the primary endpoint, and overall survival (OS) was a key secondary endpoint in all trials. Although rPFS with a PARPi and ARSI was improved versus PBO with ARSI, major conclusions differed. SUMMARY: The nuances and interpretation of these trials provide an understanding of the rationale for the FDA's decision to restrict the approval of olaparib and abiraterone and prednisone (AAP) as 1L therapy to those with biomarker evidence of BRCA m.

[Chinese expert consensus on drug interaction management of poly ADP-ribose polymerase inhibitors].

Poly ADP-ribose polymerase inhibitors (PARPi), which approved in recent years, are recommended for ovarian cancer, breast cancer, pancreatic cancer, prostate cancer and other cancers by The National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines. Because most of PARPi are metabolized by cytochrome P450 enzyme system, there are extensive interactions with other drugs commonly used in cancer patients. By setting up a consensus working group including pharmaceutical experts, clinical experts and methodology experts, this paper forms a consensus according to the following steps: determine clinical problems, data retrieval and evaluation, Delphi method to form recommendations, finally formation expert opinion on PARPi interaction management. This paper will provide practical reference for clinical medical staff.

BRCA1/2 Pathogenic Variants Are Not Common in Merkel Cell Carcinoma: Comprehensive Molecular Study of 30 Cases and Meta-Analysis of the Literature.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine cancer. Management of advanced MCC is mainly based on immune-checkpoint inhibitors. The high failure rate warrants an investigation of new therapeutic targets. The recent identification of BRCA1 or BRCA2 (BRCA1/2) mutations in some MCC raises the issue of the use of poly-(ADP-Ribose)-polymerase inhibitors in selected advanced cases. The main objective of our study is to determine the accurate frequency of BRCA1/2 pathogenic variants. We studied a series of 30 MCC and performed a meta-analysis of BRCA1/2 variants of published cases in the literature. In our series, we detected only one BRCA2 pathogenic variant. The low frequency of BRCA1/2 pathogenic variants in our series of MCC (3%) was confirmed by the meta-analysis of BRCA1/2 variants in the literature. Among the 915 MCC from 13 published series studied for molecular alterations of BRCA1/2, only 12 BRCA1/2 pathogenic mutations were identified (1-2% of MCC), whereas many other BRCA1/2 variants were variants of unknown significance or benign. BRCA1/2 pathogenic variants are uncommon in MCC. However, in BRCA-mutated MCC, poly-(ADP-Ribose)-polymerase inhibitors might be a valuable therapeutic option requiring validation by clinical trials.

Efficacy and Safety of Mirvetuximab Soravtansine in Patients With Platinum-Resistant Ovarian Cancer With High Folate Receptor Alpha Expression: Results From the SORAYA Study.

PURPOSE: Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor α (FRα). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC. METHODS: SORAYA enrolled FRα-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point. RESULTS: One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively. CONCLUSION: MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRα-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population.

Cost-effectiveness of poly-(ADP-ribose) polymerase (PARP)-inhibitors for the maintenance treatment after responding to first- and second-line chemotherapy in advanced ovarian cancer.

The introduction of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of women with epithelial ovarian cancers (EOC) has radically changed the treatment in maintenance setting after responding to first- and second-line chemotherapy. The aim of this paper was to assess the pharmacological costs of PARP inhibitors (olaparib, niraparib, rucaparib and veliparib) in maintenance treatment after responding to first-line chemotherapy in EOC. Incremental cost-effectiveness ratio (ICER) was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (progression-free survival (PFS)). We have considered the pivotal phase III randomized controlled trials (RCTs). Three different populations were considered: the overall population, patients with germline BRCA mutation (gBRCA) and homologous recombination deficiency (HRD) patients non-gBRCA mutation. Three thousand four hundred and twenty patients and 1209 patients were considered in maintenance treatment after responding to first- and second-line chemotherapy in EOC, respectively. At the actual price, the treatment with PARP inhibitors is not cost-effective in maintenance treatment after responding to first-line and second-line chemotherapy in EOC. A reduction in pharmacological costs is mandatory.

Poly-ADP-ribose polymerase (PARP) inhibitors and ovarian function.

Poly-ADP-ribose polymerase (PARP) plays an important role in DNA damage detection and repair. PARP inhibitors (PARPi) are a novel class of targeted agents used widely in the treatment of female cancer patients with BRCA mutations, including younger patients. However, the impact of PARPi on ovarian function remains a considerable problem in clinical practice. In this review article, we summarize the current understanding of PARPi's effects on the function of ovary and discuss their potential underlying mechanisms, highlighting the significance of further investigation on the criterion for ovarian failure and its preventive approaches during PARPi treatment.

A Randomized, Double-Blind, Biomarker-Selected, Phase II Clinical Trial of Maintenance Poly ADP-Ribose Polymerase Inhibition With Rucaparib Following Chemotherapy for Metastatic Urothelial Carcinoma.

PURPOSE: A DNA repair deficiency (DRD) phenotype exists within a subset of metastatic urothelial carcinomas (mUC) predicting benefit from platinum-based chemotherapy. We tested switch maintenance therapy with the poly ADP-ribose polymerase inhibitor rucaparib, following chemotherapy, for DRD biomarker-positive mUC. METHODS: DRD biomarker-positive mUC patients, within 10 weeks of chemotherapy, and without cancer progression, were randomly assigned (1:1) to maintenance rucaparib 600 mg twice a day orally, or placebo, until disease progression. The primary end point was progression-free survival (PFS). Statistical analysis targeted a hazard ratio of 0.5 with a 20% one-sided α for this signal-seeking trial. PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model. RESULTS: Out of 248 patients, 74 (29.8%) were DRD biomarker-positive and 40 were randomly assigned. A total of 12 (60%) and 20 (100%) PFS events occurred in the rucaparib and placebo arms, respectively (median follow-up was 94.6 weeks in those still alive). Median PFS was 35.3 weeks (80% CI, 11.7 to 35.6) with rucaparib and 15.1 weeks (80% CI, 11.9 to 22.6) with placebo (hazard ratio, 0.53; 80% CI, 0.30 to 0.92; one-sided P = .07). In the safety population (n = 39) treatment-related adverse events were mostly low grade. Patients received a median duration of 10 rucaparib or six placebo cycles on treatment. Treatment-related adverse events (all grades) of fatigue (63.2% v 30.0%), nausea (36.8% v 5.0%), rash (21.1% v 0%), and raised alanine aminotransferase (57.9% v 10%) were more common with rucaparib. CONCLUSION: Maintenance rucaparib, following platinum-based chemotherapy, extended PFS in DRD biomarker-selected patients with mUC and was tolerable. Further investigation of poly ADP-ribose polymerase inhibition in selected patients with mUC is warranted.

SN-38 Sensitizes BRCA-Proficient Ovarian Cancers to PARP Inhibitors through Inhibiting Homologous Recombination Repair.

As a multifunctional protein posttranslational modification enzyme in eukaryotic cells, Poly-ADP-ribose polymerase (PARP) acts as a DNA damage sensor, which helps to repair DNA damage through recruiting repair proteins to the DNA break sites. PARP inhibitors offer a significant clinical benefit for ovarian cancer with BRCA1/2 mutations. However, the majority of ovarian cancer patients harbor wild-type (WT) BRCA1/2 status, which narrows its clinical application. Here, we identified a small compound, SN-38, a CPT analog, which sensitizes BRCA-proficient ovarian cancer cells to PARP inhibitor treatment by inhibiting homologous recombination (HR) repair. SN-38 treatment greatly enhanced PARP inhibitor olaparib induced DNA double-strand breaks (DSBs) and DNA replication stress. Meanwhile, the combination of SN-38 and olaparib synergistically induced apoptosis in ovarian cancer. Furthermore, combination administration of SN-38 and olaparib induced synergistic antitumor efficacy in an ovarian cancer xenograft model in vivo. Therefore, our study provides a novel therapeutic strategy to optimize PARP inhibitor therapy for patients with BRCA-proficient ovarian cancer.

Management of human epidermal growth factor receptor 2-negative metastatic breast cancer: Role of poly adenosine diphosphate (ADP-ribose) polymerase inhibitors.

Human epidermal growth factor receptor 2 (HER2)-negative subset is the most heterogeneous group of metastatic breast cancers (MBCs) as it includes both hormone receptor (HR)-positive and HR-negative breast cancer (or TNBC), which have different therapies and treatment challenges. Though endocrine therapy (ET) remains the treatment backbone in HR-positive HER2-negative cases, about 40% of the patients show intrinsic or acquired resistance to ET due to multiple mechanisms. Combining different therapies such as ET and other targeted therapies with or without chemotherapy fails to give continued benefit, unlike cyclin-dependent kinase (CDK) 4/6 inhibitors that have shown a great benefit. TNBC has conventionally been treated ineffectively with systemic chemotherapy. Recently, poly (ADP-ribose) polymerase inhibitors (PARPi) have emerged for HER2-negative breast cancer (BC) patients, including TNBC. Olaparib and talazoparib have recently been approved in germline BRCA-mutated (gBRCAm) HER2-negative MBC. Additionally, ongoing trials of PARPi in combination with various therapies are expected to provide more and better treatment options for gBRCAm HER2-negative breast cancer.

Treatment patterns after poly-ADP ribose polymerase (PARP) inhibitors in epithelial ovarian cancer patients.

OBJECTIVES: The primary objective of this study was to describe treatment patterns after poly-ADP ribose polymerase (PARP) inhibitor in patients with epithelial ovarian cancer. Secondary objectives were to evaluate duration of response, time to first subsequent therapy, progression-free survival and overall survival. METHODS: This was a retrospective analysis of patients with epithelial ovarian cancer treated with PARP inhibitor therapy at six Australian gynecological oncology centers. Eligible patients were identified via clinics, trial databases and pharmacy dispensing logs between January 2005 and September 2019. Information regarding clinico-pathological characteristics and treatment outcomes were collated from medical records. RESULTS: A total of 85 patients with epithelial ovarian cancer were identified. Of these, 61% had germline BRCA1/2 mutations, 9% had somatic BRCA1/2 mutations, 5% had confirmed homologous recombination deficiency and 25% were BRCA1/2 wildtype mutations. A total of seventy-seven (91%) patients received chemotherapy after PARP inhibitor, with fifty-six (72.7%) of these patients receiving platinum-based chemotherapy. Four patients (5%) had a complete response, 15 (20%) a partial response, 15 (20%) stable disease and 41 (55%) progressive disease. Median duration of response to chemotherapy was 7.0 months (range 0.2-20.4). Median time to first subsequent therapy was 17.6 and 15.1 months in patients who received a PARP inhibitor as maintenance therapy and treatment, respectively. Median progression-free survival of first line treatment after PARP inhibitor was 9.6, 3.5 and 4.6 months for platinum doublet, single agent platinum and non-platinum chemotherapy, respectively. Adjusting for age and FIGO (Federation of Gynecological Oncologists classification) stage progression-free survival did not differ between treatment groups (p=0.14). Median overall survival for the cohort was 69 months, and patients with platinum sensitive ovarian cancer had improved survival compared with those with platinum refractory or resistant disease. CONCLUSION: Platinum doublet chemotherapy resulted in non-significant improved progression-free survival compared with other regimens, suggesting potential independent mechanisms of resistance between PARP inhibitor and platinum compounds.

Correlation of poly (adenosine diphosphate[ADP]-ribose) polymerase expression and prognosis in ovarian cancer: A systematic review and meta-analysis.

PURPOSE: This meta-analysis evaluated the correlation between poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) expression and prognosis in patients with ovarian cancer. METHODS: Eligible studies were extracted from the electronic databases of PubMed, Web of Science, and EMBASE until 1 August 2019. The included studies investigated the correlation between PARP expression and clinical outcomes in patients with ovarian cancer. Clinical outcomes are overall survival (OS) and progression free survival (PFS). The clinical data of patients, such as clinicopathologic characteristics and survival, were analyzed. The language was limited to English, and studies conducted at the cellular level, animal studies, and non-original research were excluded. The odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used for this meta-analysis. RESULTS: A total of 9 eligible studies involving 1230 patients were included in our meta-analysis. Based on the analysis, higher PARP expression was correlated with worse overall survival [OS] (HR,1.64; 95% CI, 1.08-2.49; P = 0.020) in the univariate analysis, whereas results from multivariate analysis indicated that PARP overexpression wasn't statistically associated with worse OS (HR, 1.36; 95% CI, 0.98-1.90; P = 0.069). Moreover, the pooled results revealed that patients with PARP overexpression were not associated with worse histologic grade (OR,2.22; 95% CI, 0.98-5.02; P = 0.06). CONCLUSION: PARP overexpression maybe associated with poor prognosis and survival in patients with ovarian cancer. The patients with PARP over expression were not tended to have a worse histologic grade. Findings require further validation.

BLM helicase inhibition synergizes with PARP inhibition to improve the radiosensitivity of olaparib resistant non-small cell lung cancer cells by inhibiting homologous recombination repair.

OBJECTIVE: We aimed to investigate the radiosensitizing efficacy of the poly-ADP-ribose polymerase (PARP) inhibitor, olaparib, and the Bloom syndrome protein (BLM) helicase inhibitor, ML216, in non-small cell lung cancer (NSCLC) cells. METHODS: Radiosensitization of NSCLC cells was assessed by colony formation and tumor growth assays. Mechanistically, the effects of ML216, olaparib, and radiation on cell and tumor proliferation, DNA damage, cell cycle, apoptosis, homologous recombination (HR) repair, and non-homologous end joining (NHEJ) repair activity were determined. RESULTS: Both olaparib and ML216 enhanced the radiosensitivities of olaparib-sensitive H460 and H1299 cells, which was seen as decreased surviving fractions and Rad51 foci, increased total DNA damage, and γH2AX and 53BP1 foci (P < 0.05). The expressions of HR repair proteins were remarkably decreased in olaparib-treated H460 and H1299 cells after irradiation (P < 0.05), while olaparib combined with ML216 exerted a synergistic radiosensitization effect on olaparib-resistant A549 cells. In addition to increases of double strand break (DSB) damage and decreases of Rad51 foci, olaparib combined with ML216 also increased pDNA-PKcs (S2056) foci, abrogated G2 cell cycle arrest, and induced apoptosis in A549 lung cancer after irradiation in vitro and in vivo (P < 0.05). Moreover, Western blot showed that olaparib combined with ML216 and irradiation inhibited HR repair, promoted NHEJ repair, and inactivated cell cycle checkpoint signals both in vitro and in vivo (P < 0.05). CONCLUSIONS: Taken together, these results showed the efficacy of PARP and BLM helicase inhibitors for radiosensitizing NSCLC cells, and supported the model that BLM inhibition sensitizes cells to PARP inhibitor-mediated radiosensitization, as well as providing the basis for the potential clinical development of this combination for tumors intrinsically resistant to PARP inhibitors and radiotherapy.

Assessment of Ovarian Function in Phase III (Neo)Adjuvant Breast Cancer Clinical Trials: A Systematic Evaluation.

BACKGROUND: Loss of ovarian function is a recognized adverse effect of chemotherapy for breast cancer and of great importance to patients. Little is known about the ovarian toxicity of newer cancer treatments. This study examined whether breast cancer clinical trials include assessment of the impact of trial interventions on ovarian function. METHODS: Eligible trials were phase III (neo)adjuvant trials of pharmacologic treatments for breast cancer, recruiting between June 2008 and October 2019, which included premenopausal women. MEDLINE, EMBASE, Clinicaltrials.gov, and EudraCT were searched. Data were extracted from trial publications, protocols, databases, and a survey sent to all trial chairs. Tests of statistical significance were 2-sided. RESULTS: Of 2354 records identified, 141 trials were eligible. Investigational treatments included chemotherapy (36.9%), HER2 targeted (24.8%), endocrine (12.8%), immunotherapy (7.8%), cyclin-dependent kinase 4/6 inhibitors (5.0%), and poly-ADP-ribose polymerase inhibitors (2.8%). Ovarian function was a prespecified endpoint in 13 (9.2%) trials. Forty-five (31.9%) trials collected ovarian function data, but only 33 (23.4%) collected posttrial-intervention data. Common postintervention data collected included menstruation (15.6%), pregnancy (13.5%), estradiol (9.9%), and follicle-stimulating hormone levels (8.5%). Only 4 (2.8%) trials collected postintervention anti-müllerian hormone levels, and 3 (2.1%) trials collected antral follicle count. Of 22 trials investigating immunotherapy, cyclin-dependent kinase 4/6 inhibitors, or poly-ADP-ribose polymerase inhibitors, none specified ovarian function as an endpoint, but 4 (18.2%) collected postintervention ovarian function data. CONCLUSIONS: The impact of pharmacologic interventions on ovarian function is infrequently assessed in phase III breast cancer (neo)adjuvant trials that include premenopausal women. Trialists should consider inclusion of ovarian function endpoints when designing clinical trials, given its importance for informed decision making.

Avatrombopag Optimizes Response to Niraparib by Managing Thrombocytopenia Associated with Poly-ADP Ribose Polymerase (PARP) Inhibition in Ovarian Cancer and Breast Cancer: A Case Series.

BACKGROUND Thrombocytopenia is a potentially treatment-limiting adverse event of particular interest with the PARP inhibitor niraparib. This adverse event may necessitate niraparib dose reduction or treatment discontinuation, resulting in suboptimal treatment outcomes. Here, we report on niraparib dose optimization in 2 patients with breast cancer and 4 patients with ovarian cancer through concurrent administration of the thrombopoietin receptor stimulating agent avatrombopag to mitigate thrombocytopenia, enabling niraparib reescalation and improved clinical response. CASE REPORT Three of 6 patients received niraparib 300 mg daily, the highest recommended dose, for a sustained period. Avatrombopag therapy enabled niraparib dose escalation that led to reductions in biomarkers associated with disease progression. Before initiation of avatrombopag, increases in CA-125 levels, a marker for ovarian cancer, were observed in association with niraparib dose interruption, and in 2 patients with ovarian cancer CA-125 levels fell in response to niraparib dose escalation enabled by concurrent avatrombopag therapy. Further, in 2 patients with metastatic breast cancer, intracranial response was observed in association with avatrombopag-enabled niraparib therapy. In 1 patient with metastatic breast cancer, niraparib induced an intracranial response, while previous use of talazoparib had not, confirming preclinical findings of superior blood-brain-barrier penetrance with niraparib. CONCLUSIONS Avatrombopag is currently approved for use in chronic immune thrombocytopenia and thrombocytopenia associated with chronic liver disease in patients undergoing a surgical procedure. A clinical trial of avatrombopag for chemotherapy-induced thrombocytopenia is ongoing. Preliminary results in these 6 patient cases demonstrate the need for a confirmatory trial of avatrombopag for optimizing the dose of niraparib.

Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy.

BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPis) specifically target homologous recombination deficiency (HRD) cells and display good therapeutic effect in women with advanced-stage BRCA1/2-mutated breast and epithelial ovarian cancer (EOC). However, about 50% of high grade serous ovarian cancers (HGSOC) present with HRD due to epigenetic BRCA1 inactivation, as well as genetic/epigenetic inactivation(s) of other HR genes, a feature known as "BRCAness". Therefore, there is a potential for extending the use of PARPis to these patients if HR status can be identified. METHODS: We have developed a 3D (spheroid) functional assay to assess the sensitivity of two PARPis (niraparib and olaparib) in ascites-derived primary cell cultures (AsPCs) from HGSOC patients. A method for AsPCs preparation was established based on a matrix (agarose), allowing for easy isolation and successive propagation of monolayer and 3D AsPCs. Based on this method, we performed cytotoxicity assays on 42 AsPCs grown both as monolayers and spheroids. RESULTS: The response to PARPis treatment in monolayer AsPCs, was significantly higher, compared to 3D AsPCs, as 88% and 52% of the monolayer AsPCs displayed sensitivity to niraparib and olaparib respectively, while 66% of the 3D AsPCs were sensitive to niraparib and 38% to olaparib, the latter being more consistent with previous estimates of HRD (40%-60%) in EOC. Moreover, niraparib displayed a significantly stronger cytotoxic effect in both in 3D and monolayer AsPCs, which was confirmed by consecutive analyses of the HR pathway activity (γH2AX foci formation) in PARPis-sensitive and resistant AsPCs. Global gene expression comparison of 6 PARPi-resistant and 6 PARPi-sensitive 3D AsPCs was indicative for the predominant downregulation of numerous genes and networks with previously demonstrated roles in EOC chemoresistance, suggesting that the PARPis-sensitive AsPCs could display enhanced sensitivity to other chemotherapeutic drugs, commonly applied in cancer management. Microarray data validation identified 24 potential gene biomarkers associated with PARPis sensitivity. The differential expression of 7 selected biomarkers was consecutively confirmed by immunohistochemistry in matched EOC tumor samples. CONCLUSION: The application of this assay and the potential biomarkers with possible predictive significance to PARPis therapy of EOC patients now need testing in the setting of a clinical trial.

The efficacy and safety of the addition of poly ADP-ribose polymerase (PARP) inhibitors to therapy for ovarian cancer: a systematic review and meta-analysis.

BACKGROUND: The purpose of this study was to explore the efficacy and tolerability of poly ADP-ribose polymerase (PARP) inhibitors in patients with ovarian cancer. METHODS: The meta-analysis searched the PubMed, Web of Science, EBSCO, and Cochrane libraries from inception to February 2020 to identify relevant studies. And the main results of this study were long-term prognosis and treatment-related adverse events. RESULTS: The results showed that the addition of PARP inhibitors could significantly prolong progression-free survival (PFS) and overall survival (OS) for patients with ovarian cancer (HR 0.44, 95% CI 0.34-0.53, p < 0.001; HR, 0.79, 95% CI 0.65-0.94, p < 0.001, respectively). In the BRCA 1/2 mutation patients, the HR of PFS was 0.29 (p < 0.001), and the HR was 0.51 (p < 0.001) in the no BRCA 1/2 mutation patients. The HR of PFS was 0.40 (p < 0.001) in the homologous recombination deficiency (HRD) mutation patients, while the HR was 0.80 (p < 0.001) in the no HRD mutation patients. Moreover, the analysis found that the use of PARP inhibitors did not significantly increase the risk of all grade adverse events (AEs) (RR = 1.04, p = 0.16). But the incidence of grade 3 or higher AEs was increased (RR = 1.87, p = 0.002). In general, the AEs were mainly manifested in the blood system. CONCLUSIONS: PARP inhibitors can improve the prognosis of ovarian cancer patients with and without genetic mutations (BRCA 1/2 or HRD). Furthermore, PARP inhibitors were tolerable to patients when added to their current therapy, although it inevitably adds the grade 3 and higher AEs.

Ribose cysteine protects against acetaminophen-induced hepatic and renal toxicity.

Ribose cysteine (RibCys) is a cysteine prodrug that increases both hepatic and renal glutathione with documented antagonism of acetaminophen (APAP)-induced hepatotoxicity. To determine if RibCys could also protect against APAP-induced kidney damage, mice were injected with APAP (600 mg/kg) or APAP and RibCys (1.0 g/kg) (APAP/RIB) followed by additional RibCys injections 1 and 2 hours later. Mice were euthanatized 10-12 hours after APAP administration, and liver and kidney toxicity were assessed by plasma sorbitol dehydrogenase (SDH) activity and blood urea nitrogen (BUN), respectively, and by histopathology. APAP treatment resulted in elevation of SDH activity and BUN to 2,490 U/ml and 47 mg/dl, respectively. By contrast, SDH and BUN values for APAP/RIB-treated mice were not different from controls, 0 U/ml and 31 mg/dl, respectively. Histopathologic examination revealed moderate to severe hepatic centrilobular necrosis in 9/11 and renal proximal tubular necrosis in 10/11 APAP-treated mice. However, no evidence of hepatic or renal toxicity was noted in any of the 12 APAP/RIB-treated mice. Utilizing the same treatment regimen, APAP covalent binding to hepatic and renal cytosolic proteins was assessed 4 hours after APAP challenge. RibCys cotreatment decreased covalent binding to the 58-kDa acetaminophen-binding protein in both liver and kidney. RibCys decreased both toxicity and covalent binding after APAP administration, and in addition to protecting the liver, this cysteine prodrug can also effectively protect the kidney from APAP-induced injury.