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Exploring and comparing adverse events between PARP inhibitors.

ABSTRACT: Ovarian cancer remains one of the most challenging malignancies to treat. Targeted therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as one of the most exciting new treatments for ovarian cancer, particularly in women with BRCA1 or BRCA2 mutations or those without a functional homologous recombination repair pathway. Perhaps the most advantageous characteristic of PARP inhibitors is their mechanism of action, which targets cancer cells on the basis of their inherent deficiencies while seemingly avoiding normally functioning cells. Although health-care providers might assume a low toxicity profile because of their specific mechanism of action, PARP inhibitors are not completely benign and overall show a class effect adverse-event profile. Further complicating this situation, three different PARP inhibitors have been approved by the US Food and Drug Administration since 2014, each with their own specific indications and individual toxicity profiles. The diversity of adverse events seen both within and across this class of drug underscores the importance of having a comprehensive reference to help guide clinical decision making when treating patients. This Review characterises and compares all toxicities associated with each PARP inhibitor, both in monotherapy and in novel combinations with other drugs, with a particular focus on potential management strategies to help mitigate toxic effects. Although the excitement surrounding PARP inhibitors might certainly be warranted, a thorough understanding of all associated toxicities is imperative to ensure that patients can achieve maximal clinical benefit.

SUBMITTER: LaFargue CJ

PROVIDER: S-EPMC7292736 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Exploring and comparing adverse events between PARP inhibitors.

LaFargue Christopher J CJ Dal Molin Graziela Z GZ Sood Anil K AK Coleman Robert L RL

The Lancet. Oncology 20190101 1

Ovarian cancer remains one of the most challenging malignancies to treat. Targeted therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as one of the most exciting new treatments for ovarian cancer, particularly in women with BRCA1 or BRCA2 mutations or those without a functional homologous recombination repair pathway. Perhaps the most advantageous characteristic of PARP inhibitors is their mechanism of action, which targets cancer cells on the basis of their inherent d ...[more]

PMID: 30614472

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Project description:Aim and background: This study attempted to identify similarities and differences in adverse events (AEs) between human epidermal growth factor receptor 2 (HER2) inhibitors, especially those related to hemorrhagic events and nervous system disorders. Methods: This study summarized the types, frequencies, and system organ classes (SOCs) of AEs of HER2 inhibitors. The US Food and Drug Administration Adverse Event Reporting System (FAERS) data from January 2004 through March 2022 was collected and analyzed. Disproportionality analyses were conducted to detect AEs signals for every HER2 inhibitor. The chi-square test, Wilcoxon test, and descriptive analysis were used to compare the differences of AEs for specific SOCs or drugs. Results: A total of 47,899 AE reports were obtained for eight HER2 inhibitors. Trastuzumab-related AEs were reported in the highest number and combination of regimens. In monotherapy, trastuzumab had the highest reported rate of cardiac disorders-related AEs (24.0%). However, small-molecule drugs exceeded other drugs in the reported rates of AEs related to gastrointestinal disorders, metabolism and nutrition disorders. The highest reported rates of respiratory disorders (47.3%) and hematologic disorders (22.4%) were associated with treatment with trastuzumab deruxtecan (T-DXd). Patients treated with trastuzumab emtansine (TDM-1) had the highest reported rate (7.28%) of hemorrhagic events, especially intracranial haemorrhage events. In addition, patients treated with TDM-1 with concomitant thrombocytopenia were likely to experience hemorrhagic events compared to other HER2 inhibitors (p < 0.001). The median time to onset of intracranial haemorrhage associated with trastuzumab (0.5 months) and TDM-1 (0.75 months) was short. However, there was no significant difference in median time to onset intracranial haemorrhage between patients in different age groups or with different outcomes. Disproportionality analysis results reveal that cerebral haemorrhage is a positive signal associated with T-DXd and TDM-1. In addition, tucatinib was the drug with the highest rate of reported nervous system disorders (31.38%). Memory impairment (83 cases) is a positive signal for tucatinib. Conclusion: The types and reporting rates of AEs associated with different HER2 inhibitors vary across multiple systems. In addition, hemorrhagic events concomitant with TDM-1 treatment and nervous system disorders concomitant with tucatinib treatment may be worthy of attention.

Project description:BackgroundPoly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) provided significant antitumor activity in various tumors, mainly carrying deleterious mutations of BRCA1/BRCA2 genes. Only few data are available regarding the cardiac and vascular safety profile of this drug class. We carried out a meta-analysis for assessing the incidence and relative risk (RR) of major adverse cardiovascular events (MACEs), hypertension, and thromboembolic events in patients with solid tumors treated with PARPi-based therapy.MethodsProspective studies were identified by searching the Medline/PubMed, Cochrane Library, and ASCO Meeting abstracts. Data extraction was conducted according to the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) statement. Combined odds ratios (ORs), RRs, and 95% confidence intervals (CIs) were calculated using fixed- or random-effects methods, depending on studies heterogeneity. RevMan software for meta-analysis (v.5.2.3) was used to carry out statistical analyses.ResultsThirty-two studies were selected for the final analysis. The incidence of PARPi-related MACEs of any and high grade was 5.0% and 0.9%, respectively, compared with 3.6% and 0.9% in the control arms, corresponding to a significant increased risk of MACEs of any grade (Peto OR 1.62; P = 0.0009) but not of high grade (P = 0.49). The incidence of hypertension of any grade and high grade was 17.5% and 6.0% with PARPi, respectively, compared with 12.6% and 4.4% in the controls. Treatment with PARPi significantly increased the risk of hypertension of any grade (random-effects, RR = 1.53; P = 0.03) but not of high grade (random-effects, RR = 1.47; P = 0.09) compared with controls. Finally, PARPi-based therapies significantly increased the risk of thromboembolic events of any grade (Peto OR = 1.49, P = 0.004) and not of high grade (Peto OR = 1.31; P = 0.13) compared with controls.ConclusionsPARPi-based therapy is associated with a significantly increased risk of MACEs, hypertension, and thromboembolic events of any grade compared with controls. The lack of a significant increased risk of high-grade events together with the absolute low incidence of these adverse events led not to consider routine cardiovascular monitoring as recommended in asymptomatic patients.

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Exploring and comparing adverse events between PARP inhibitors.

Publications

Exploring and comparing adverse events between PARP inhibitors.

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