Assessment of the safety of glucocorticoid regimens in combination with abiraterone acetate formetastatic castration-resistant prostate Cancer: a randomized, open-label phase 2 study

Attard, G. et al. (2019) Assessment of the safety of glucocorticoid regimens in combination with abiraterone acetate formetastatic castration-resistant prostate Cancer: a randomized, open-label phase 2 study. JAMA Oncology, 5(8), pp. 1159-1167. (doi: 10.1001/jamaoncol.2019.1011) (PMID:31246234) (PMCID:PMC6604092)

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Abstract

Importance: Abiraterone acetate is combined with prednisone, 5 mg, twice daily for metastatic castration-resistant prostate cancer (mCRPC) and with prednisone, 5 mg, once daily for newly diagnosed, high-risk, metastatic castration-sensitive prostate cancer. Understanding the physiological effects of these and other regimens is important. Objective: To evaluate the safety of abiraterone acetate with 4 glucocorticoid regimens. Design, Setting, and Participants: Open-label, randomized clinical trial (1:1:1:1) of 164 men with mCRPC from 22 hospitals in 5 countries who were randomly assigned to 1 of 4 intervention groups between June 2013 and October 2014. Analyses were conducted from August 2017 to June 2018. Interventions: Abiraterone acetate, 1000 mg, once daily with prednisone, 5 mg, twice daily (n = 41), 5 mg once daily (n = 41), 2.5 mg twice daily (n = 40), or dexamethasone, 0.5 mg, once daily (n = 42). Main Outcomes and Measures: Primary end point was no mineralocorticoid excess (grade ≥1 hypokalemia or grade ≥2 hypertension) through 24 weeks (6 cycles) from treatment. Results: Of 164 men (median [range] age, 70 [50-90] years) randomized to receive abiraterone acetate, 1000 mg, daily with prednisone, 5 mg, twice daily, once daily, or 2.5 mg twice daily, or dexamethasone, 0.5 mg, once daily, 24 (70.6%) of 34 patients (95% CI, 53.8%-83.2%), 14 (36.8%) of 38 patients (95% CI, 23.4%-52.7%), 21 (60.0%) of 35 patients (95% CI, 43.6%-74.4%), and 26 (70.3%) of 37 patients (95% CI, 54.2%-82.5%), respectively, had no mineralocorticoid excess. Plasma adrenocorticotrophic hormone and urinary mineralocorticoid metabolites after 8 weeks were higher with prednisone, 2.5 mg, twice daily and 5 mg once daily than with 5 mg twice daily or dexamethasone, 0.5 mg, once daily. The level of urinary glucocorticoid metabolites appeared higher in patients who did not meet the primary end point, regardless of glucocorticoid regimen. Total lean body mass decreased in the prednisone groups and total body fat increased in the prednisone, 5 mg, twice daily and dexamethasone groups. In the dexamethasone group, there was an increase in serum insulin and homeostatic model assessment of insulin resistance, while total bone mineral density decreased. In the prednisone, 5 mg, twice daily, 5 mg once daily, 2.5 mg twice daily, and dexamethasone groups, median radiographic progression-free survival was 18.5, 15.3, 12.8, and 26.6 months, respectively. Conclusions and Relevance: Abiraterone acetate with prednisone, 5 mg, twice daily or dexamethasone, 0.5 mg, once daily met the prespecified threshold for the primary end point (95% CI excluded 50% mineralocorticoid excess); abiraterone acetate with prednisone, 5 mg, once daily or 2.5 mg twice daily did not meet the threshold. Abiraterone acetate in combination with dexamethasone appeared to be particularly active but may be associated with adverse metabolic consequences.

Item Type:Articles
Additional Information:The study was funded by Janssen EMEA. Dr Attard is a Cancer Research UK Advanced Clinician Scientist fellow supported by grant No. A22744.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jones, Professor Robert
Authors: Attard, G., Merseburger, A. S., Arlt, W., Sternberg, C. N., Feyerabend, S., Berruti, A., Joniau, S., Géczi, L., Lefresne, F., Lahaye, M., Shelby, F. N., Pissart, G., Chua, S., Jones, R. J., and Tombal, B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:JAMA Oncology
Publisher:American Medical Association
ISSN:2374-2437
ISSN (Online):2374-2445
Published Online:27 June 2019
Copyright Holders:Copyright © 2019 Attard G et al.
First Published:First published in JAMA Oncology 5(8):1159-1167
Publisher Policy:Reproduced under a Creative Commons license

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