Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration-resistant prostate cancer

Abstract

PurposeAbiraterone is the active metabolite of the pro-drug abiraterone acetate (AA) and a selective inhibitor of CYP17, a key enzyme in testosterone synthesis, and improves overall survival in postdocetaxel metastatic castration-resistant prostate cancer (mCRPC). This open-label, single-arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval.MethodsThe study was conducted in 33 patients with mCRPC. Patients received AA 1,000 mg orally once daily + prednisone 5 mg orally twice daily. Electrocardiograms (ECGs) were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle 1 Day-1. Serial ECG recordings and time-matched pharmacokinetic (PK) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1. Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8.ResultsAfter AA administration, the upper bound of the 2-sided 90 % confidence interval (CI) for the mean baseline-adjusted QTcF change was <10 ms; no patients discontinued due to QTc prolongation or adverse events. No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [estimated slope (90 % CI): 0.0031 (−0.0040, 0.0102)].ConclusionsThere is no significant effect of AA plus prednisone on the QT/QTc interval in patients with mCRPC.

Safety of long-term exposure to abiraterone acetate in patients with castration-resistant prostate cancer and concomitant cardiovascular risk factors

“…In an exploratory phase Ib study aimed at assessing the effect of abiraterone plus prednisone on QT/QT c intervals in mCRPC patients by using pharmacokinetic and time-matched ECGs, no clinically significant changes in the QT/QT c interval were observed, suggesting that abiraterone does not substantially affect ventricular repolarization and has, therefore, a low potential for inducing arrhythmias (especially torsade de pointes) [Tolcher et al 2012]. Safety data extracted from both controlled clinical trials and retrospective studies show a good tolerability profile of abiraterone regarding cardiac events, also in elderly patients receiving this drug after multiple lines of previous therapies.…”

Population Pharmacokinetic Analysis of Abiraterone in Chemotherapy-Naïve and Docetaxel-Treated Patients with Metastatic Castration-Resistant Prostate Cancer

“…The total analysis dataset included pooled data from 359 subjects from three phase I studies (COU-AA-008 [13], COU-AA-009, and COU-AA-014), one phase Ib study (COU-AA-006 [16]), and two phase III studies (COU-AA-301 [8] and COU-AA-302 [2]). All studies were approved by the appropriate ethics committees and were conducted in accordance with the ethical standards outlined in the 1964 Declaration of Helsinki and its later amendments.…”

New Therapeutics to Treat Castrate‐Resistant Prostate Cancer

“…Due to the mechanism of action, many of these adverse events were believed to be due to excessive mineralocorticoids and in subsequent trials exogenous corticosteroids such as dexamethasone or prednisone were given with abiraterone acetate. Despite drug-induced hypokalemia, abiraterone acetate had no effect on QT interval [34]. In a Phase II study of 47 docetaxel pre-treated CRPC patients, abiraterone acetate and prednisone was found to be effective at lowering serum PSA level >50% in 51% of patients.…”

“…Given the short path length of alpha emission, the radium-223 located in the hydroxyapatite will expose the metastatic tumor site to radiation, while limiting the damage to the soft tissue and bone marrow [44]. This elegant mechanism of action limits systemic adverse events that are observed with beta-emitting radiopharmaceuticals including strontium-89 and samarium-153 [34, 45]. …”