The safety profile of combination abiraterone acetate (Zytiga) and glucocorticoid therapy in men with metastatic castration-resistant prostate cancer (mCRPC) hinged on the specific steroid regimen, according to a phase 2 open-label randomized controlled trial.
Glucocorticoids are added to abiraterone in part to prevent mineralocorticoid excess, but can also have adverse effects of their own, noted lead investigator Gerhardt Attard, MD, of the University College London Cancer Institute, London, and colleagues. Understanding of the comparative physiologic effects of various regimens is limited.
In the trial, the investigators randomized 164 men with mCRPC from 22 centers in 5 countries (median age 70 years) to 4 glucocorticoid regimens, each combined with abiraterone acetate, 1,000 mg, daily: prednisone, 5 mg, twice daily; prednisone, 5 mg, once daily; prednisone, 2.5 mg, twice daily; and dexamethasone, 0.5 mg, once daily.
Results reported in JAMA Oncology showed that the proportion of patients who had not developed toxicity (hypotension or hypokalemia) from mineralocorticoid excess during the first 24 weeks of treatment was highest, at about 70%, with prednisone, 5 mg, twice daily, and with dexamethasone, and only these regimens had confidence intervals excluding occurrence of this toxicity in at least half of patients. However, patients in the dexamethasone group had significantly heightened risks of insulin resistance and bone mineral density loss at the end of follow-up.
The median radiographic progression-free survival was 18.5 months in the group given prednisone, 5 mg, twice daily; 15.3 months in the group given prednisone, 5 mg, once daily; 12.8 months in the group given prednisone, 2.5 mg, twice daily; and 26.6 months in the group given dexamethasone, 0.5 mg, once daily.
“Different glucocorticoid regimens make distinct compromises on control of mineralocorticoid excess, changes in body composition, and development of insulin resistance,” Dr. Attard and coinvestigators summarized. “This trial provides results consistent with the approved use of abiraterone acetate with prednisone, 5 mg, twice daily for the treatment of mCRPC. Long-term adverse metabolic and musculoskeletal changes are small and do not appear to have a detrimental effect on patient-reported quality of life.”
At the same time, lower-dose prednisone regimens – with their more modest long-term risks of insulin resistance, increased body fat, and bone mineral density loss – can still be used, with caution. “With careful monitoring, the risk of hypokalemia with lower glucocorticoid doses can be mitigated, as demonstrated in the LATITUDE and STAMPEDE trials where no major safety concerns were raised,” they elaborated.
Dr. Attard disclosed personal fees, research support, and travel support from Janssen during the conduct of the study; as well as personal fees research, and/or travel support from numerous other pharmaceutical companies. The study was funded by Janssen EMEA.
SOURCE: Attard G et al. JAMA Oncol. Published online June 27, 2019. doi:10.1001/jamaoncol.2019.1011.