Glucocorticoid regimens explored in mCRPC
medwireNews: Combining abiraterone acetate with a relatively high dose of prednisone or dexamethasone may reduce mineralocorticoid excess toxic effects, but can result in increased metabolic toxicity, study data show.
Gerhardt Attard (UCL Cancer Institute, London, UK) and colleagues carried out the phase II trial among 164 men with metastatic castration-resistant prostate cancer (mCRPC) to “support physician decision making in selecting a glucocorticoid regimen that balances controlling manifestations of endogenous mineralocorticoid excess with the adverse consequences of nonphysiological exposure to exogenous glucocorticoids.”
The men, from 22 hospitals in five countries, were randomly assigned to receive treatment with abiraterone acetate 1000 mg once daily plus one of four glucocorticoid regimens: prednisone 5 mg twice daily, 5 mg once daily, or 2.5 mg twice daily, or dexamethasone 0.5 mg once daily.
Among the 144 evaluable patients, 70.6% of 34 in the prednisone 5 mg twice daily group, 36.8% of 38 in the prednisone 5 mg once daily group, 60.0% of 35 in the prednisone 2.5 mg twice daily group, and 70.3% of 37 in the dexamethasone group achieved the primary endpoint of no mineralocorticoid excess. This was defined as patients being free from both grade 1 or higher hypokalemia and grade 2 or higher hypertension.
However, only the prednisone 5 mg twice daily and dexamethasone groups had a lower 95% confidence interval boundary for no mineralocorticoid excess that was above the predefined cutoff of 50%.
In line with this, the researchers found that plasma adrenocorticotrophic hormone levels increased significantly from baseline to cycle 3 with prednisone 5 mg once daily and 2.5 mg twice daily but did not change significantly in the prednisone 5 mg twice daily group and decreased significantly in the dexamethasone group.
Urinary mineralocorticoid metabolites were also significantly higher in the groups that did not meet the primary end point, relative to those that did.
Prednisone use in general was associated with a decrease in total lean body mass whereas dexamethasone use was associated with increased serum insulin and insulin resistance, and decreased bone mineral density.
In spite of these changes, patient quality of life remained stable in all groups, throughout the study.
Attard and co-authors note in JAMA Oncology that the trial was not powered to make direct comparisons among the four groups. Nonetheless, they observed longer radiographic progression-free survival with prednisone 5 mg twice daily and dexamethasone (18.5 and 26.6 months, respectively) than with prednisone 5 mg once daily or 2.5 mg twice daily (15.3 and 12.8 months, respectively).
In an accompanying commentary, Neeraj Agarwal (University of Utah, Salt Lake City, USA) and co-authors say the next step is to incorporate the results of this and other studies into clinical practice.
“In our view, patients who are expected to be on long-term treatment with abiraterone acetate (as described in LATITUDE trial in which the median radiographic progression-free survival in [metastatic castration-sensitive prostate cancer] was 3 months), should receive prednisone, 5 mg, once daily to mitigate long-term metabolic toxic effects,” they write, recommending close monitoring of serum potassium and blood pressure in this population.
The commentators continue: “In other circumstances, the corticosteroid dose will need to be individualized. For example, a higher dose can be used for men who are nonadherent with close follow-up and when obtaining laboratory tests and close monitoring for mineralocorticoid excess may be difficult.
“On the other hand, a lower dose of prednisone is recommended for men who have considerable cardiovascular or metabolic comorbidities but who are otherwise compliant.”
By Laura Cowen
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