Addition of Orteronel to Prednisone in Metastatic Castration-Resistant Prostate Cancer Does Not Meet Overall Survival Endpoint in Phase III Trial


Key Points

  • Overall survival analysis crossed the futility boundary at interim analysis.
  • Orteronel was associated with improved radiographic progression-free survival and PSA response.

In a phase III trial (ELM-PC 5) reported in the Journal of Clinical Oncology, Fizazi et al found that the addition of the 17,20-lyase inhibitor orteronel to prednisone in patients with metastatic castration-resistant prostate cancer progressing after docetaxel therapy resulted in an overall survival comparison that crossed the prespecified futility boundary at interim analysis. Orteronel treatment was associated with improved radiographic progression-free survival, prostate-specific antigen (PSA) reduction, and time to PSA progression.

Orteronel targets the effects of CYP17A1, an enzyme important to androgen synthesis that exhibits 17α-hydroxylase and 17,20-lyase activities.

Study Details

In the double-blind trial, 1,099 men from 260 centers in 42 countries were randomly assigned  2:1 to receive orteronel at 400 mg plus prednisone at 5 mg twice daily (n = 734) or placebo plus prednisone at 5 mg twice daily (n = 365). The primary endpoint was overall survival.

The orteronel and placebo groups were generally balanced for age (median, 70 years in both), race (84% white in both), region (Europe for 54% in both, non-Europe/non–North America for 36% in both), Eastern Cooperative Oncology Group performance status (0 or 1 in 92% and 93%), Brief Pain Inventory worst pain score (median, 3 in both), Gleason score (≤ 6 in 14% and 17%, 7 in 29% in both, 8–10 in 51% and 47%), disease extent (bone in 95% and 93%, lymph nodes in 47% in both, visceral disease in 27% in both, lung in 12% and 11%, liver in 9% and 12%), prior chemotherapy regimens (at least two in 22% and 28%), prior radiotherapy (67% and 61%), and prior androgen-deprivation therapy (96% and 95%).

Overall Survival Analysis

Median treatment duration was 5.7 months in the orteronel group and 4.6 months in the placebo group. Median follow-up at data cutoff was 10.6 and 10.7 months.

At the second interim analysis (performed after 79% of events required for final analysis), it was determined that the futility boundary (P ≥ .1775) had been crossed. Median overall survival was 17.0 months in the orteronel group vs 15.2 months in the placebo group (hazard ratio [HR] = 0.886, 95% confidence interval = 0.739–1.062, P = .190).

Subsequent therapy was received by 45% of the orteronel group and 54% of the placebo group, including abiraterone (Zytiga; 20% and 21%), cabazitaxel (Jevtana; 15% and 18%), docetaxel (5% and 9%), and enzalutamide (Xtandi; 5% and 4%).

Other Efficacy Outcomes

The orteronel group had improved median radiographic progression-free survival (8.3 vs 5.7 months, HR = 0.760, P < .001), a greater proportion of patients with ≥ 50% reduction in PSA  (25% vs 10%, P < .001), and prolonged time to PSA progression (median, 5.5 vs 2.9 months, P < .001); no difference in pain response rate was observed (12% vs 9%, P = .128).

Adverse Events

The most common adverse events of any grade in the orteronel group were nausea (42% vs 26% in placebo group), vomiting (36% vs 17%), fatigue (29% vs 23%), and constipation (29% vs 18%). The most common grade ≥ 3 adverse events in the orteronel group were increased lipase (13%) and increased amylase (8%). Serious adverse events occurred in 48% vs 39%, and adverse events led to discontinuation of treatment in 30% vs 24%.

The investigators concluded: “Our study did not meet the primary end point of [overall survival]. Longer [radiographic progression-free survival] and a higher [≥ 50% PSA reduction] rate with orteronel-prednisone indicate antitumor activity.”

Karim Fizazi, MD, PhD, of Institut Gustave Roussy, University of Paris Sud, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by Takeda Pharmaceuticals International. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.