Use of corticosteroids had a negative impact on outcomes with enzalutamide treatment as well as placebo treatment in men with metastatic castrate resistant prostate cancer.
Howard Scher, MD
Use of corticosteroids had a negative impact on outcomes with enzalutamide treatment as well as placebo treatment in men with metastatic castrate resistant prostate cancer (mCRPC), according to a post-hoc analysis of the Phase III AFFIRM trial reported at the 4th Annual Genitourinary Cancers Symposium held February 14-16, 2013, in Orlando, Florida.
The AFFIRM trial randomized 1199 patients with mCRPC post-docetaxel to treatment with enzalutamide versus placebo. Overall results of AFFIRM showed that enzalutamide extended median overall survival (OS) by 4.8 months versus placebo, a 37% reduction in risk of death that was statistically significant in favor of enzalutamide (P <.001).
Research has suggested that corticosteroid use may activate androgen receptor signaling, which is thought to drive prostate cancer. In fact, a multivariate analysis of AFFIRM presented by Howard I. Scher, MD, at the 2012 European Society of Medical Oncology Congress in September, showed that baseline use of corticosteroids was associated with reduced OS (Abstract 899PD). Scher is Chief of the Genitourinary Oncology Service at the Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan-Kettering Cancer Center, New York City, and lead author of the present study to determine if concomitant use of corticosteroids plus enzalutamide would lead to inferior outcomes.
AFFIRM patients were randomized 2:1 to enzalutamide 160 mg/day versus placebo. Patients could choose whether or not to take corticosteroids.
“Corticosteroid use varied widely. Some patients took them, some did not, about 30% were taking them at baseline,” said Scher. “All patients had previously received corticosteroids on docetaxel.”
On-study use of corticosteroids was as follows: 381 (48%) enzalutamide patients and 178 (45%) placebo patients. Baseline prognostic features were better in the group of patients who did not use corticosteroids, suggesting that corticosteroids are generally used in sicker patients.
Regardless of whether patients were taking concomitant corticosteroids, enzalutamide was consistently superior to placebo for OS, radiographic progression-free survival (rPFS), and time-to-PSA-progression (TTPP). But concomitant use of corticosteroids was associated with worse outcomes in both treatment arms.
Overall survival was inferior in patients who used concomitant corticosteroids. Among users of corticosteroids, median OS was 12.8 months in the enzalutamide arm and 9.6 months in the placebo arm (P = .001). In the no corticosteroid group, median OS had not yet been reached in the enzalutamide-treated patients and was 18.8 months in the placebo arm (P <.001).
Median rPFS was 11.1 months with enzalutamide versus 3 months with placebo in those who did not use corticosteroids (P <.001), and 5.6 months versus 2.9 months, respectively, in corticosteroid users (P <.001). Median TTPP was 8.6 months with enzalutamide versus 2.9 months with placebo in the no corticosteroid group (P <.001), and 5.6 months versus 3.1 months, respectively, in on-study corticosteroid users (P <.001).
Patients who used on-study corticosteroids had higher rates of grades 3 and 4 adverse events than those who did not use corticosteroids during the study: 63.3% versus 34.4%, respectively.
“These findings show that on-study use of corticosteroids was associated with reduced overall survival and higher rates of grades 3 and 4 adverse events in mCRPC post-docetaxel. However, enzalutamide was consistently superior to placebo regardless of baseline and/or on-study corticosteroid use,” said Scher. He added that inferior outcomes related to corticosteroid use may be due to unmeasured confounders or to the biologic properties of corticosteroid use itself. Further study would be needed to elucidate this association.
Scher HI, Fizazi K, Saad F, et al. Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor. Presented at: 4th Annual Genitourinary Cancers Symposium; February 14-16, 2013; Orlando, FL. Abstract 6.