As reported in The New England Journal of Medicine by Kim N. Chi, MD, of BC Cancer and Vancouver Prostate Centre, and colleagues, the first analysis of the phase III TITAN trial has shown that the addition of apalutamide to androgen-deprivation therapy improved radiographic progression-free and overall survival among men with metastatic castration-sensitive prostate cancer.1
Kim N. Chi, MD
In the double-blind trial, 1,052 patients from 260 sites in 23 countries were randomly assigned between December 2015 and July 2017 to receive apalutamide at 240 mg/d (n = 525) or placebo (n = 527) in addition to continuous androgen-deprivation therapy. Patients could not have been receiving antiandrogen therapy at randomization. Previous treatment of localized disease and previous docetaxel therapy were allowed. Randomization was stratified by Gleason score at diagnosis (≤ 7 vs > 7), geographic region (North America and European Union vs all other regions), and previous treatment with docetaxel. The primary endpoints were radiographic progression-free survival and overall survival.
Patients with severe angina, myocardial infarction, congestive heart failure, arterial or venous thromboembolic events, a history of or predisposition to seizure, or recent ventricular arrhythmia were excluded from the trial.
For the apalutamide vs placebo groups, the median age was 69 vs 68 years; Eastern Cooperative Oncology Group performance status was 0 or 1 in all but one patient; Gleason score at diagnosis was up to 7 in 7.8% vs 7.4%, 7 in 25.3% vs 24.7%, and higher than 7 in 66.9% vs 67.9%; metastatic stage was M1 in 78.3% vs 83.7%; disease volume was high in 61.9% vs 63.6%; 11.0% vs 10.4% had prior docetaxel; and 17.9% vs 15.0% had radiotherapy or prostatectomy for localized disease.
Progression-Free and Overall Survival
At the final analysis for radiographic progression-free survival, with a median follow-up of 22.7 months, 24-month radiographic progression-free survival was 68.2% in the apalutamide group vs 47.5% in the placebo group (hazard ratio [HR] = 0.48, P < .001). Median progression-free survival was not reached vs 22.1 months. Hazard ratios favored apalutamide across subgroups, including Gleason score up to 7 (HR = 0.53, 95% confidence interval [CI] = 0.36–0.78) and Gleason score higher than 7 (HR = 0.53, 95% CI = 0.37–0.61); geographic region of North America and European Union (HR = 0.43, 95% CI = 0.28–0.66) and all others (HR = 0.51, 95% CI = 0.40–0.65); previous docetaxel (HR = 0.47, 95% CI = 0.22–1.01) and no previous docetaxel (HR = 0.49, 95% CI = 0.39–0.62); and high (HR = 0.53, 95% CI = 0.41–0.67) and low disease volume (HR = 0.36, 95% CI = 0.22–0.57).
A total of 87 patients in the apalutamide group and 190 in the placebo group received subsequent treatment of prostate cancer.
The first interim analysis for overall survival was performed when 200 deaths had occurred (83 in the apalutamide group and 117 in the placebo group). Overall survival at 24 months was 82.4% vs 73.5% (HR = 0.67, P = .005). Median overall survival was not reached in either group. Hazard ratios favored apalutamide across subgroups, including Gleason score up to 7 (HR = 0.56, 95% CI = 0.33–0.97) and Gleason score higher than 7 (HR = 0.73, 95% CI = 0.52–1.01); geographic region of North America and European Union (HR = 0.71, 95% CI = 0.40–1.25) and all others (HR = 0.66, 95% CI = 0.48–0.91); and high (HR = 0.68, 95% CI = 0.50–0.92) and low disease volume (HR = 0.67, 95% CI = 0.34–1.32). Hazard ratios were 1.27 (95% CI = 0.52–3.09) for prior docetaxel use and 0.63 (95% CI = 0.47–0.85) for no prior docetaxel.
Secondary efficacy endpoints were formally tested for statistical significance in a hierarchical manner. Hazard ratios for apalutamide vs placebo were 0.39 (P < .001) for time to cytotoxic chemotherapy, 0.83 (P = .12) for time to pain progression, 0.77 (95% CI = 0.54–1.11) for time to chronic opioid use, and 0.80 (95% CI = 0.56–1.15) for time to skeletal-related event. For other efficacy endpoints, hazard ratios were 1.20 (95% CI = 0.71–2.02) for time to symptomatic local disease progression, 0.26 (95% CI = 0.21–0.32) for time to prostate-specific antigen disease progression, and 0.66 (95% CI = 0.50–0.87) for second progression-free survival.
The most common adverse events of any grade in the apalutamide group were rash (27.1% vs 8.5% in the placebo group), hot flush (22.7% vs 16.3%), fatigue (19.7% vs 16.7%), and hypertension (17.7% vs 15.6%). Grade 3 or 4 adverse events occurred in 42.2% of the apalutamide group vs 40.8% of the placebo group, with the most common events in the apalutamide group including hypertension (8.4% vs 9.1% in the placebo group) and rash (6.3% vs 0.6%). Serious adverse events occurred in 19.8% vs 20.3% of patients. Adverse events led to treatment discontinuation in 8.0% vs 5.3%. A total of 10 patients in the apalutamide group (1.9%) and 16 in the placebo group (3.0%) died as the result of adverse events.
The investigators concluded: “In this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival and radiographic progression–free survival were significantly longer with the addition of apalutamide to androgen-deprivation therapy than with placebo plus androgen-deprivation therapy, and the side effect profile did not differ substantially between the two groups.”
DISCLOSURE: The study was funded by Janssen Research and Development. Dr. Chi has received honoraria from Astellas Pharma, Bayer, Janssen, and Sanofi; has served as a consultant or advisor to Amgen, Astellas Pharma, AstraZeneca, Bayer, ESSA Pharma, Janssen, Roche, and Sanofi; and has received institutional research funding from Astellas Pharma, Bayer, Bristol Myers Squibb, Janssen, Lilly/ImClone, Merck, Roche, Sanofi, and Tokai Pharmaceuticals.
1. Chi KN, Agarwal N, Bjartell A, et al: Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med 381:13-24, 2019.