BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but may also trigger autoimmune adverse drug reactions (ADRs) referred to as immune-related adverse events (irAEs). Although endocrinopathies are among the most common form of irAEs, primary adrenal insufficiency (PAI) is infrequent and has only been published in case reports. The aim of this study was to identify and characterize the main features of PAI-irAE. MATERIALS AND METHODS: Suspected PAI-irAE cases were identified using VigiBase, the World Health Organizations pharmacovigilance database of individual case safety reports. RESULTS: From September 2, 2008, through October 5, 2018, a total of 50,108 ICI-associated ADRs were reported. Since 2008, there were 451 cases of PAI-irAE identified of which 45 were definite PAI and 406 possible PAI. Patients were mainly male (58.1%) with a median age of 66 years (range, 30-95). Indications of ICI were predominantly for melanoma (41.2%) and lung cancer (28.6%). The majority of patients were treated with ICI monotherapy (nivolumab: 44.3%, pembrolizumab: 11.7%, ipilimumab: 23.6%), and 17.9% were treated with ICI combination therapy. These events occurred with a median time to onset of 120 days (range, 6-576). ICI-associated PAI was associated with significant morbidity (≥90% severe) and mortality (7.3%). Fatality rates were similar in the subgroups of combination therapy versus monotherapy. There were no relevant differences in clinical or demographical characteristics and outcomes between definite versus possible PAI group. CONCLUSION: Our study represents the largest clinical description and characterization of PAI-irAE. Although ICI-associated PAI is a rare adverse event, early recognition is important to implement corticosteroid treatment. Further studies are required to elucidate risk factors and reversibility of this rare but severe irAE. Clinical trial identification number. NCT03492242 IMPLICATIONS FOR PRACTICE: Immune checkpoint inhibitor (ICI)-associated primary adrenal insufficiency (PAI) is a rare adverse event that is important to recognize because it may be severe and life-threatening, requiring emergent and often lifelong hormonal replacement therapy. Awareness regarding this ICI-related endocrinopathy is strongly encouraged among clinicians in addition to patient education about common PAI symptoms that should prompt urgent medical evaluation. In clinical practice, close monitoring and investigation for PAI is crucial to allow for early management and to further define the pathophysiology and prognosis of ICI-PAI. Corticotrophin (adrenocorticotrophic hormone) circulating level evaluation may be often lacking but should be considered as part of the diagnostic workup to differentiate PAI from secondary (central) adrenal insufficiency.

OBJECTIVE: A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status. METHODS: We performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ2) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed. RESULTS: SERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11-8.55), p<0.001). SERMs were also associated with higher proportion of TdP and ventricular arrhythmia reports versus AIs (6/8318 vs 2/14851, ROR: 5.4 (1.29-26.15), p:0.02; 16/8318 vs 12/14851, ROR: 2.38 (1.15-4.94), p:0.02, respectively). Mortality was 38% in patients presenting ventricular arrhythmias associated with SERMs. CONCLUSIONS: SERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs. TRIAL REGISTRATION NUMBER: NCT03259711.

BACKGROUND: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. METHODS: We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. RESULTS: Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7; P<0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P<0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25 µM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5 Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9 ms (chronic; P<0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30 nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. CONCLUSIONS: QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.