After adjusting for crossover using a preplanned sensitivity analysis, investigators for the pivotal phase 3 TITAN trial found a 48% reduction in the risk of death in patients treated with apalutamide plus ADT versus ADT alone.
The final analysis of the phase 3 randomized, double-blind, placebo-controlled TITAN trial found that treatment with apalutamide (Erleada) plus androgen-deprivation therapy (ADT) reduced the risk of death by 35% versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC).1
The findings were presented at the 2021 Genitourinary Cancers Symposium by investigator Kim N. Chi, MD, chief medical officer and vice president of BC Cancer, Vancouver, Canada.
For the TITAN trial (NCT02489318), 1052 patients with mCSPC were randomized 1:1 to receive apalutamide plus ADT or placebo plus ADT. Dual primary end points were radiographic progression-free survival (rPFS) and overall survival (OS).
Findings from the primary analysis of the trial were published in 2019.2 At a median follow-up of 22.7 months, both rPFS and OS reached statistical significance, according to Chi. The 2-year OS rates at the primary analysis was 82.4% in the apalutamide arm versus 73.5% in the control arm, translating to a 33% reduction in the risk of death (HR, 0.67; P = .005). Based on the primary TITAN analysis, the FDA approved apalutamide in September 2019 for the treatment of patients with mCSPC.
The primary TITAN analysis marked the final analysis for rPFS and first interim analysis for OS. Upon recommendation of the independent data monitoring committee, the trial was unblinded, and 39.5% of patients in the placebo group who had not progressed went on to receive open-label apalutamide.
Final analysis of the TITAN trial occurred at a median follow-up of 44.0 months. A total of 405 OS events had occurred. The median duration of treatment in the apalutamide plus ADT, crossover apalutamide plus ADT, and placebo plus ADT groups was 39.3 months, 20.2 months, and 15.4 months, respectively.
At the long-term follow-up, treatment with apalutamide plus ADT reduced the risk of death by 35% (HR, 0.65; 95% CI, 0.53-0.79; P <.0001). After adjusting for crossover using a preplanned sensitivity analysis, investigators found a 48% reduction in the risk of death (HR, 0.52; 95% CI, 0.42-0.64; P <.0001).
The treatment effect on OS was found to favor apalutamide plus ADT across all prespecified subgroups except for patients who had received prior docetaxel. “However, this subgroup comprised only 10% of patients, and among them, there have been relatively few events. A post hoc interaction analysis between treatment and prior use of docetaxel showed no significant interaction,” Chi noted.
Health-related quality of life (HRQOL) was measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score. Chi reported that HRQOL was maintained in the treatment group, with no difference between the treatment and placebo groups.
The safety profile of apalutamide plus ADT was found to be consistent with previous reports, according to Chi.
“Importantly, cumulative incidence of any-grade treatment-emergent falls, fractures, and fatigue was similar between groups. The cumulative incidence of grade 3/4 treatment-emergent adverse events and serious adverse events were also similar between groups. As expected, the incidence of any-grade rash was higher in the apalutamide group than in the placebo group, but reached a plateau after about 6 months,” Chi said.
1. Chi KN, Chowdhury S, Bjartell A, et al. Final analysis results from TITAN: A phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT). J Clin Oncol. 2021;39(suppl 6):11. doi: 10.1200/JCO.2021.39.6_suppl.11
2. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307