Final TITAN results highlight apalutamide-ADT efficacy on survival in mCSPC

Final analysis of the phase III TITAN* trial, presented at ASCO GU 2021, has shown that the addition of apalutamide to androgen deprivation therapy (ADT) improves overall survival (OS) in patients with metastatic castration-sensitive prostate cancer (mCSPC).

Participants in this international, double-blind study were 1,052 patients with mCSPC and ECOG performance score 0–1 who were receiving ADT. They were randomized 1:1 to receive apalutamide (240 mg QD) or placebo plus ADT.

At a median follow-up of 44 months, duration of treatment was 39.3 and 20.2 months in the apalutamide-ADT and placebo-ADT groups, respectively. A 35 percent reduction in the risk of death was noted with the apalutamide-ADT compared with the placebo-ADT combination (median not reached vs 52.2 months; hazard ratio [HR], 0.65, 95 percent confidence interval [CI], 0.53–0.79; p<0.0001). [ASCO GU 2021, abstract 11]

After adjusting for the approximately 40 percent of placebo recipients who crossed over to receive open-label apalutamide at unblinding (median apalutamide treatment duration of 15.4 months), the risk of death was reduced by 48 percent in the apalutamide-ADT vs the placebo-ADT group (HR, 0.52, 95 percent CI, 0.42–0.64; p<0.0001).

The OS findings favoured the apalutamide-ADT over the placebo-ADT group for all subgroups analysed with the exception of prior docetaxel use (HR, 1.12), though this comprised only 10 percent of patients, with relatively few events.

Second progression-free survival was also longer with apalutamide-ADT compared with placebo-ADT (median not reached vs 44.0 months; HR, 0.62, 95 percent CI, 0.51–0.75; p<0.0001). Patients in the apalutamide-ADT group also had a longer time to castration resistance than those in the placebo-ADT group (median not reached vs 11.4 months; HR, 0.34, 95 percent CI, 0.29–0.41; p<0.0001).

These findings add on to the results of the primary analysis which was undertaken after a median follow-up of 22.7 months. In this analysis, patients who received apalutamide-ADT had a 33 percent reduced risk of death (82.4 percent vs 73.5 percent; HR, 0.67, 95 percent CI, 0.51–0.89; p=0.0053) compared with placebo-ADT, as well as a 52 percent reduced risk of radiographic progression or death (68.2 percent vs 47.5 percent; HR, 0.48, 95 percent CI, 0.39–0.60; p<0.0001). [N Engl J Med 2019;381:13-24]

In this updated analysis, treatment-emergent adverse events (TEAEs; excluding grade 5 events) occurred in a comparable proportion of patients in the apalutamide-ADT, placebo-ADT, and crossover (placebo to apalutamide) groups (97.3, 96.8, and 83.7 percent, respectively), with 49.4, 41.7, and 27.4 percent, respectively, experiencing grade 3–4 TEAEs, and 29.2, 21.8, and 13.9 percent, respectively, experiencing serious TEAEs.

TEAEs led to treatment discontinuation in 11.8, 5.7, and 7.7 percent, respectively, and to death in 3.8, 3.2, and 3.4 percent, respectively. Three COVID-19-related AEs occurred in the crossover group. Common grade ≥3 AEs among apalutamide recipients included skin rash (6.3 and 3.8 percent in the apalutamide-ADT and crossover groups, respectively), fracture (3.4 percent in the apalutamide-ADT group), ischaemic heart disease (3.1 percent in the apalutamide-ADT group), and ischaemic cerebrovascular disorder (2.4 percent in the crossover group).

“[T]he final analysis of TITAN, with almost 4 years of median follow-up and nearly 40 percent of patients in the placebo group crossing over to receive apalutamide, demonstrates the continued benefit and OS with the addition of apalutamide to ADT for a broad population of patients with mCSPC,” presented Professor Kim Chi from the BC Cancer and Vancouver Prostate Centre, Vancouver, British Columbia, Canada, at ASCO GU 2021.

“The benefit of apalutamide was consistent across other endpoints, and health-related quality of life was maintained with apalutamide. Treatment was tolerable and there were no new safety signals. These results confirmed the favourable benefit-risk profile of apalutamide,” he concluded.