Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study
Mené dans 17 pays sur 982 patients atteints d'un cancer métastatique de la prostate résistant à la castration, cet essai de phase III évalue l'efficacité, du point de vue de la survie sans progression mesurée par radiographie, et la toxicité de l'ajout de l'apalutamide à un traitement combinant acétate d'abiratérone et prednisone
Background : The majority of patients with metastatic castration-resistant prostate cancer (mCRPC)will have disease progression of a uniformly fatal disease. mCRPC is driven by bothactivated androgen receptors and elevated intratumoural androgens; however, the currentstandard of care is therapy that targets a single androgen signalling mechanism. Weaimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way,versus standard care in mCRPC.
Methods : ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region,Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) withmCRPC who had not been previously treated with androgen biosynthesis signalling inhibitorsand were receiving ongoing androgen deprivation therapy, with an Eastern CooperativeOncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-ShortForm question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients wererandomly assigned (1:1) via a centralised interactive web response system with a permutedblock randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plusoral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamideplus abiraterone–prednisone group) or placebo plus abiraterone acetate and prednisone(abiraterone–prednisone group), in 28-day treatment cycles. Randomisation was stratifiedby presence or absence of visceral metastases, ECOG performance status, and geographicalregion. Patients, the investigators, study team, and the sponsor were masked to groupassignments. An independent data-monitoring committee continually monitored data toensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population.Safety was reported for all patients who received at least one dose of study drug.This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736.
Findings : 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492to apalutamide plus abiraterone–prednisone; 490 to abiraterone–prednisone). At theprimary analysis (median follow-up 25·7 months [IQR 23·0–28·9]), median radiographicprogression-free survival was 22·6 months (95% CI 19·4–27·4) in the apalutamide plusabiraterone–prednisone group versus 16·6 months (13·9–19·3) in the abiraterone–prednisonegroup (hazard ratio [HR] 0·69, 95% CI 0·58–0·83; p<0·0001). At the updated analysis(final analysis for overall survival; median follow-up 54·8 months [IQR 51·5–58·4]),median radiographic progression-free survival was 24·0 months (95% CI 19·7–27·5) versus16·6 months (13·9–19·3; HR 0·70, 95% CI 0·60–0·83; p<0·0001). The most common grade3–4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receivingapalutamide plus abiraterone–prednisone and 49 [10%] of 489 receiving abiraterone–prednisone).Serious treatment-emergent adverse events occurred in 195 (40%) patients receivingapalutamide plus abiraterone–prednisone and 181 (37%) patients receiving abiraterone–prednisone.Drug-related treatment-emergent adverse events with fatal outcomes occurred in three(1%) patients in the apalutamide plus abiraterone–prednisone group (2 pulmonary embolism,1 cardiac failure) and five (1%) patients in the abiraterone–prednisone group (1 cardiacfailure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 suddendeath).
Interpretation : Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone–prednisone improved radiographic progression-free survival. Additionalstudies to identify subgroups of patients who might benefit the most from combinationtherapy are needed to further refine the treatment of mCRPC.
The Lancet Oncology , résumé, 2020