A comparison of several glucocorticoid regimens, given in combination with abiraterone acetate, for metastatic castration-resistant prostate cancer (CRPC), found that a once-daily prednisone 5 mg regimen and a once-daily dexamethasone 0.5 mg regimen both were generally safe, though the dexamethasone option may be associated with some adverse metabolic consequences.
Abiraterone acetate is approved in combination with prednisone 5 mg once daily or twice daily, based on previous trials. “When administered without glucocorticoids, abiraterone acetate induces a syndrome of secondary mineralocorticoid excess due to CYP17A1 17α-hydroxylase inhibition, consequently decreased glucocorticoid production, and a compensatory increase in adrenocorticotrophic hormone (ACTH),” wrote study authors led by Gerhardt Attard, MD, PhD, of the University College London Cancer Institute. “In addition to maximizing efficacy for treating prostate cancer, glucocorticoids are combined with abiraterone acetate to prevent this syndrome; however, glucocorticoid exposure may exceed physiological requirements.”
The new study included 164 men with metastatic CRPC, randomized to receive 1 of 4 regimens along with abiraterone acetate: prednisone 5 mg twice daily (34 patients); prednisone 5 mg twice daily (38 patients); prednisone 2.5 mg twice daily (35 patients); or dexamethasone 0.5 mg once daily (37 patients). Results of the comparison were published in JAMA Oncology.
Baseline characteristics were generally well balanced, though, there was a higher rate of hypertension at baseline in the prednisone 5 mg once daily group (46.3%) than in the other groups (26.8% to 33.4%). The mean time from diagnosis to randomization was 101.4 months in the dexamethasone group, compared with a range of 59.6 months to 69.2 months in the other groups.
The primary endpoint was defined as no mineralocorticoid excess (grade 1 or higher hypokalemia or grade 2 or higher hypertension) through 24 weeks of treatment; the endpoint was deemed to have been met if the 95% confidence interval excluded 50% of patients with mineralocorticoid excess.
By that measure, the prednisone 5 mg twice daily and dexamethasone regimens achieved the endpoint. In the prednisone 5 mg twice daily group, 70.6% of patients had no mineralocorticoid excess (95% CI, 53.8%–83.2%); in the dexamethasone group, the rate was 70.3% (95% CI, 54.2%–82.5%). With prednisone 5 mg once daily, 36.8% were free of mineralocorticoid excess (95% CI, 23.4%–52.7%), and with prednisone 2.5 mg twice daily the rate was 60.0% (95% CI, 43.6%–74.4%).
Total lean body mass decreased in the two groups that met the primary endpoint, while total body fat increased. Patients in the dexamethasone group saw an increase in serum insulin and an assessment of insulin resistance, and total bone density was decreased.
The median radiographic progression–free survival was 18.5 months with prednisone twice daily, and 26.6 months with dexamethasone. In the prednisone 5 mg once daily and 2.5 mg twice daily groups, the median progression-free survival was 15.3 months and 12.8 months, respectively.
“This trial provides results consistent with the approved use of abiraterone acetate with prednisone, 5 mg, twice daily for the treatment of metastatic CRPC,” the authors concluded. “Long-term adverse metabolic and musculoskeletal changes are small and do not appear to have a detrimental effect on patient-reported quality of life.”
In an accompanying editorial, authors led by Umang Swami, MD, of the University of Iowa Hospitals and Clinics in Iowa City, noted that the trial was not powered to assess survival outcomes, and thus the progression-free survival results should be interpreted with caution.
They noted that previous trials using prednisone 5 mg twice daily found the incidence of all-grade corticosteroid-associated adverse events following prednisone exposure was 25%, but only 5% of patients had grade 3 or higher such adverse events. “Now the next step is to synthesize the information from these studies and incorporate them into current practice,” they wrote. “In our view, patients who are expected to be on long-term treatment with abiraterone acetate ... should receive prednisone, 5 mg, once daily to mitigate long-term metabolic toxic effects.” Those doses can be tailored, though, based on adherence or the presence of cardiovascular or metabolic comorbidities.