ACIS Trial: Addition of Apalutamide to Abiraterone Acetate/Prednisone for Metastatic Castration-Resistant Prostate Cancer

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As reported in The Lancet Oncology by Fred Saad, MD, FRCS, and colleagues, the phase III ACIS trial has shown that the addition of apalutamide to abiraterone acetate and prednisone significantly prolonged radiographic progression–free survival in men with metastatic castration-resistant prostate cancer.

As stated by the investigators, “The majority of patients with metastatic castration-resistant prostate cancer will have disease progression of a uniformly fatal disease. Metastatic castration-resistant prostate cancer is driven by both activated androgen receptors and elevated intratumoral androgens; however, the current standard of care is therapy that targets a single androgen-signaling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen-signaling axis in a different way, vs standard [of] care in metastatic castration-resistant prostate cancer.”

Fred Saad, MD, FRCS

Fred Saad, MD, FRCS

Study Details

The double-blind trial included 982 patients from sites in 17 countries with no prior androgen biosynthesis–signaling inhibitor therapy who were also receiving ongoing androgen-deprivation therapy. They were randomly assigned between December 2014 and August 2016 to receive apalutamide at 240 mg once daily, abiraterone acetate at 1,000 mg once daily, and prednisone at 5 mg twice daily (n = 492) or placebo plus abiraterone/prednisone (n = 490) in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression–free survival in the intention-to-treat population.

Radiographic Progression–Free Survival

At primary analysis, with a median follow-up of 25.7 months (interquartile range [IQR] = 23.0­–28.9 months) at data cutoff (March 2018), median radiographic progression–free survival was 22.6 months (95% confidence interval [CI] = 19.4–27.4 months) in the apalutamide group vs 16.6 months (95% CI = 13.9–19.3 months) in the control group (hazard ratio [HR] = 0.69, 95% CI = 0.58–0.83, P < .0001).   

At a median follow-up of 54.8 months (IQR = 51.5–58.4 months) at data cutoff (September 2020) for final overall survival analysis, median radiographic progression–free survival was 24.0 months (95% CI = 19.7–27.5 months) in the apalutamide group vs 16.6 months (95% CI = 13.9–19.3 months) in the control group (HR = 0.70, 95% CI = 0.60–0.83, P < .0001). 

Median overall survival was 36.2 months (95% CI = 32.8–38.8 months) in the apalutamide group vs 33.7 months (95% CI = 31.2–38.3 months) in the control group (HR = 0.95, 95% CI = 0.81–1.11, P = .50).

No significant differences between groups were observed for time to initiation of cytotoxic chemotherapy, time to chronic opioid use, time to pain progression, time to prostate-specific antigen (PSA) progression, or objective response rate (58% vs 53% among patients with measurable disease). More patients in the apalutamide group had PSA declines to undetectable levels (25% vs 19%, P = .04) and declines ≥ 50% (79% vs 73%, P = .015), with no difference in declines ≥ 90% (53% vs 49%).


  • The addition of apalutamide to abiraterone/prednisone significantly prolonged radiographic progression–free survival.
  • At primary analysis, median radiographic progression–free survival was 22.6 vs 16.6 months.

Adverse Events

Grade 3 or 4 adverse events occurred in 60% of patients in the apalutamide group vs 51% of the control group, with hypertension being the most common in both groups (17% vs 10%) Serious adverse events occurred in 40% vs 37%. Cardiac adverse events occurred in 19% vs 19% of patients and led to death in 6 patients (1%) vs 13 patients (3%). Treatment-related adverse events led to death in three patients (1%) in the apalutamide group (pulmonary embolism in two, cardiac failure in one) and five patients (1%) in the control group (cardiac failure, cardiac arrest, mesenteric arterial occlusion, seizure, and sudden death in one patient each).

The investigators concluded, “Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone/prednisone improved radiographic progression–free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of metastatic castration-resistant prostate cancer.”

Dr. Saad, of the Centre Hospitalier de l’Université de Montréal, Université de Montréal, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Janssen Research & Development. For full disclosures of the study authors, visit

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