Charles Ryan, MD
For decades, the standard of care for men with advanced prostate cancer has been the depletion or inhibition of androgens. While androgen-deprivation therapy (ADT) often results in temporary tumor regression or symptom relief in some patients, disease progression ultimately occurs over time.1
For patients with metastatic disease, the median overall survival (OS), until very recently, had been less than 2 years after chemotherapy.2
While tumor progression with ADT was previously believed to be hormone-refractory or androgen-independent, a large body of evidence supports that metastatic castration-resistant prostate cancer (mCRPC) is commonly driven by elevated steroid synthesis, increased expression or splice variants of the androgen receptor (AR), or AR ligand promiscuity, indicating the ongoing need for targeted androgen therapies.3
Abiraterone acetate (AA), the prodrug of abiraterone, alone or in combination with low-dose steroids, has been intensely investigated in recent years for the treatment of progressive CRPC in patients who have received prior chemotherapy or who were treatment-naïve. Abiraterone is a selective and potent inhibitor of cytochrome P450 c17 (CYP17), an enzyme that is critical for testosterone synthesis in the adrenal glands.4
Despite the established clinical utility of steroids in mCRPC and other tumor types to manage adverse events (AEs) of chemotherapy and cancer-associated pain, long-term use of high doses of glucocorticoids, such as prednisone, have a number of associated AEs. As such, an analysis of the frequency and severity of AEs in patients treated with long-term dosing of AA and prednisone is of interest.
Long-Term Analysis of Abiraterone Plus Prednisone
Data sets from the COU-AA-301 and COU-AA-302 phase III clinical trials were used to determine whether long-term use of low-dose prednisone with or without AA would lead to significant AEs in patients with mCRPC. Karim Fizazi, MD, PhD, from the Institut Gustave Roussy in Villejuif, France, and colleagues reported their findings in the March 7, 2016, issue of European Urology.5
Investigators analyzed AEs in 1195 patients from the COU-AA-301 trial and 1088 patients from the COU-AA-302 trial. All patients received prednisone 5 mg twice daily for a median of 8.3 months. Investigators utilized the Standardized MedDRA Queries to identify preferred terms known for glucocorticoid-associated AEs.
For all patients, those treated with AA and prednisone (AA + P), and those treated with prednisone alone (P alone), the overall incidence of any-grade AEs for any prednisone exposure was 24.6%, 25.5%, and 23.3%, respectively. The most common any-grade AEs were hyperglycemia (7.4%, 7.8%, and 6.9% for all patients, those treated with AA + P, and those treated with P alone, respectively) and weight increase (4.3%, 3.9%, and 4.8%, respectively). Among any-grade AEs, ecchymosis, rib fracture, Cushingoid state, cataract, diabetes mellitus, and skin atrophy occurred at rates ≥1%. The incidence of grade ≥3 AEs for any prednisone exposure was 4.5%, 5.1%, and 3.7% for all patients, AA + P, and P alone, respectively. Hyperglycemia (48%) and cataract (10%) were the 2 most common grade ≥3 AEs. No discernable trends were observed in any-grade or grade ≥3 AEs when examined by duration of exposure.5
These results indicate that treatment with low-dose prednisone, administered with or without AA, is associated with few glucocorticoid-related AEs, and that the incidence of AEs is not directly related to prednisone exposure duration. As such, long-term treatment with AA plus prednisone is safe and tolerable for most patients.5
Charles Ryan, MD, from the University of California, San Francisco, and lead investigator of the COU-AA-302 study, stressed that the addition of prednisone to AA therapy has a triple purpose. “First, steroids have been traditionally used as a palliative treatment to control bone pain from the disease. Prednisone has always been included in the packets of treatments that included chemotherapy. That formed the basis for the FDA saying that prednisone is an acceptable treatment for some CRPC,” Ryan said. “Second, patients respond to steroids. The number of patients who have shown a clinical response to steroids alone is somewhere between 20% and 30%. So steroids have therapeutic efficacy as well as palliative benefits. Third, prednisone reduces the mineralocorticoid excess that can occur from abiraterone monotherapy. As such, AA is made safer with the addition of prednisone.”