Τίτλος:
Orteronel plus prednisone in patients with chemotherapy-naive metastatic
castration-resistant prostate cancer (ELM-PC 4): a double-blind,
multicentre, phase 3, randomised, placebo-controlled trial
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Background Orteronel is an investigational, partially selective
inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a
validated therapeutic target for metastatic castration-resistant
prostate cancer. We assessed orteronel in chemotherapy-naive patients
with metastatic castration-resistant prostate cancer.
Methods In this phase 3, double-blind, placebo-controlled trial, we
recruited patients with progressive metastatic castration-resistant
prostate cancer and no previous chemotherapy from 324 study centres (ie,
hospitals or large urologic or group outpatient offices) in 43
countries. Eligible patients were randomly assigned in a 1: 1 ratio to
receive either 400 mg orteronel plus 5 mg prednisone twice daily or
placebo plus 5 mg prednisone twice daily. Randomisation was done
centrally with an interactive voice response system and patients were
stratified by region (Europe, North America, and not Europe or North
America) and the presence or absence of radiographic disease progression
at baseline. The two primary endpoints were radiographic
progression-free survival and overall survival, determined in the
intention-to-treat population. This trial is registered with
ClinicalTrials.gov, number NCT01193244.
Findings From Oct 31, 2010, to June 29, 2012, 2353 patients were
assessed for eligibility. Of those, 1560 were randomly assigned to
receive either orteronel plus prednisone (n=781) or placebo plus
prednisone (n=779). The clinical cutoff date for the final analysis was
Jan 15, 2014 (with 611 deaths). Median follow-up for radiographic
progression-free survival was 8.4 months (IQR 3.7-16.6). Median
radiographic progression-free survival was 13.8 months (95% CI
13.1-14.9) with orteronel plus prednisone and 8.7 months (8.3-10.9) with
placebo plus prednisone (hazard ratio [HR] 0.71, 95% CI 0.63-0.80;
p<0.0001). After a median follow-up of 20.7 months (IQR 14.2-25.4),
median overall survival was 31.4 months (95% CI 28.6-not estimable)
with orteronel plus prednisone and 29.5 months (27.0-not estimable) with
placebo plus prednisone (HR 0.92, 95% CI 0.79-1.08; p=0.31). The most
common grade 3 or worse adverse events were increased lipase (137
[17%] of 784 patients in the orteronel plus prednisone group vs 14
[2%] of 770 patients in the placebo plus prednisone group), increased
amylase (77 [10%] vs nine [1%]), fatigue (50 [6%] vs 14
[2%]), and pulmonary embolism (40 [5%] vs 27 [4%]). Serious
adverse events were reported in 358 [46%] patients receiving
orteronel plus prednisone and in 292 [38%] patients receiving placebo
plus prednisone.
Interpretation In chemotherapy-naive patients with metastatic
castration-resistant prostate cancer, radiographic progression-free
survival was prolonged with orteronel plus prednisone versus 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.
Συγγραφείς:
Saad, Fred
Fizazi, Karim
Jinga, Viorel
Efstathiou, Eleni and
Fong, Peter C.
Hart, Lowell L.
Jones, Robert
McDermott,
Raymond
Wirth, Manfred
Suzuki, Kazuhiro
MacLean, David B.
and Wang, Ling
Akaza, Hideyuki
Nelson, Joel
Scher, Howard I.
and Dreicer, Robert
Webb, Iain J.
de Wit, Ronald
ELM-PC 4
Investigators
Περιοδικό:
The lancet oncology
Εκδότης:
EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC
DOI:
10.1016/S1470-2045(15)70027-6
