No Overall Survival Benefit of Adding Orteronel to Prednisone in Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer


Key Points

  • The addition of orteronel to prednisone increased radiographic progression-free survival in chemotherapy-naive patients with metastatic castration-resistant prostate cancer.
  • No improvement in overall survival was observed.

In the phase III ELM-PC 4 trial reported in The Lancet Oncology, Saad et al found that the addition of the CYP 17,20 lyase inhibitor orteronel to prednisone did not improve overall survival in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. Improvement in radiographic progression-free survival was observed with orteronel-prednisone treatment, which was also associated with greater toxicity. The development of orteronel in this setting has been halted.

Study Details

In this double-blind trial, 1,560 patients from 324 sites in 43 countries were randomly assigned between October 2010 and June 2012 to receive orteronel 400 mg and prednisone 5 mg twice daily (n = 781) or placebo and prednisone 5 mg twice daily (n = 779). Approximately half of the patients in each group had radiographic progression at baseline, and approximately one-fifth in each group had visceral disease. The two primary endpoints were radiographic progression-free survival and overall survival in the intention-to-treat population.

Radiographic Progression-Free Survival

At interim analysis, the planned final analysis for radiographic progression-free survival, median radiographic progression-free survival was 11.0 months (95% confidence interval [CI] = 9.1–13.6 months) in the orteronel-prednisone group vs 8.3 months (95% CI = 8.2–8.6 months) in the control group (hazard ratio [HR] = 0.70, P < .0001). Updated analysis at the time of overall survival analysis showed median radiographic progression-free survival of 13.8 months (95% CI = 13.1–14.9 months) vs 8.7 months (95% CI = 8.3–10.9 months; HR = 0.71, P < .0001).

Overall Survival

Overall, 353 (45%) patients treated with orteronel plus prednisone and 395 (51%) patients treated with placebo plus prednisone received subsequent therapy for prostate cancer.

After median follow-up of 20.7 months, median overall survival was 31.4 months (95% CI = 28.6 months to not estimable) vs 29.5 months (95% CI = 27.0 months to not estimable; HR = 0.92, P = .31). Outcome was consistent across subgroups except for a significant improvement with orteronel-prednisone among patients with baseline prostate-specific antigen level > 50 ng/mL (HR = 0.81, 95% CI = 0.67–0.99).


Grade 3 or 4 adverse events occurred in 59% of the orteronel group and 40% of the control group; the most common effects were increased lipase (17% vs 2%), increased amylase (10% vs 1%), fatigue (6% vs 2%), and pulmonary embolism (5% vs 4%). Serious adverse events occurred in 46% vs 38%. Adverse events led to discontinuation of treatment in 30% vs 18%.

The investigators concluded: “In chemotherapy-naive patients with metastatic castration-resistant prostate cancer, radiographic progression-free survival was prolonged with orteronel plus prednisone vs placebo plus prednisone. However, no improvement was noted in the other primary endpoint, overall survival. Orteronel plus prednisone was associated with increased toxic effects compared with placebo plus prednisone. On the basis of these and other data, orteronel is not undergoing further development in metastatic castration-resistant prostate cancer.”

Fred Saad, MD, of Centre Hospitalier de l’Universite de Montreal/CRCHUM, is the corresponding author of The Lancet Oncology article.

The study was funded by Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. 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®.