Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5

Abstract

Purpose: Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy.

Patients and methods: In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant.

Results: The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%).

Conclusion: Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.

Trial registration: ClinicalTrials.gov NCT01193257.

Fig 1.

CONSORT diagram. (*) One patient allocated to placebo-prednisone received orteronel plus prednisone. This patient is included in the orteronel plus prednisone safety population. ITT, intent to treat.

Fig 2.

Kaplan-Meier estimates of (A) overall survival, (B) radiographic progression-free survival (PFS), and (C) time to prostate-specific antigen (PSA) progression. (B) Radiographic progressive disease (rPD) was determined by a central imaging center based on protocol definition, not per identification by investigator. Alt, alternate.

Fig 3.

Overall survival by subgroups. BPI, Brief Pain Inventory; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LDH, lactate dehydrogenase; NE, not estimable; PSA, prostate-specific antigen.

Fig 4.

Waterfall plots of prostate-specific antigen (PSA) response at 12 weeks in the evaluable patients with baseline and postbaseline assessments in the (A) orteronel-prednisone group (n = 559) and the (B) placebo-prednisone group (n = 283). Plots are truncated at 200%.

Fig A1.

Kaplan-Meier estimates of overall survival in (A) Europe, (B) non-Europe/North America, and (C) North America. NE, not evaluable.

Fig A2.

Radiographic progression-free survival by subgroups. BPI, brief pain inventory; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LDH, lactate dehydrogenase; PSA, prostate-specific antigen.