Assessment of the Safety of Glucocorticoid Regimens in Combination With Abiraterone Acetate: A Randomized, Open-Label Phase 2 Study.

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.

To evaluate the safety of abiraterone acetate with 4 glucocorticoid regimens.

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.

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).

Primary end point was no mineralocorticoid excess (grade ≥1 hypokalemia or grade ≥2 hypertension) through 24 weeks (6 cycles) from treatment.

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.

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. identifier: NCT01867710.

JAMA oncology. 2019 Jun 27 [Epub ahead of print]

Gerhardt Attard, Axel S Merseburger, Wiebke Arlt, Cora N Sternberg, Susan Feyerabend, Alfredo Berruti, Steven Joniau, Lajos Géczi, Florence Lefresne, Marjolein Lahaye, Florence Nave Shelby, Geneviève Pissart, Sue Chua, Robert J Jones, Bertrand Tombal

University College London Cancer Institute, London, United Kingdom., Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany., Institute of Metabolism and Systems Research (IMSR), Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham Health Partners, NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom., Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy., Studienpraxis Urologie, Nürtingen, Germany., Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy., Department of Urology, University Hospitals Leuven, Leuven, Belgium., National Institute of Oncology, Budapest, Hungary., Janssen Research and Development, Beerse, Belgium., Department of Nuclear Medicine and PET/CT, Royal Marsden NHS Foundation Trust, London, United Kingdom., Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland., Institut de Recherche Clinique, Université Catholique de Louvain, Brussels, Belgium.