The final analysis of the TITAN demonstrates that the long-term use of apalutamide plus androgen deprivation therapy (ADT) provided significant improvement in overall survival (OS) and delayed onset of progression despite almost 40% crossover from placebo to apalutamide after the study was unblinded. With substantially longer follow-up and exposure than at the primary analysis, apalutamide treatment had a safety profile consistent with previous reports and patients maintained health-related quality of life (HRQoL) under treatment with apalutamide.
The authors, who published the study results on 29 April 2021 in the Journal of Clinical Oncology, emphasized that the patients with metastatic castration-sensitive prostate cancer (mCSPC) can benefit from early treatment intensification with the addition of apalutamide to ADT.
Kim N. Chi of the BC Cancer and Vancouver Prostate Centre in Vancouver, BC, Canada and Neeraj Aqarwal of the Huntsman Cancer Institute, University of Utah in Salt Lake City, UT, US and TITAN investigators randomly assigned patients with mCSPC (n = 1,052) to receive apalutamide plus ADT or placebo plus ADT. They wrote that the first interim analysis of this phase III, randomised, placebo-controlled study showed that apalutamide significantly improved OS and radiographic progression-free survival (rPFS) in patients with mCSPC receiving ongoing ADT.
The treatment effect on OS consistently favoured apalutamide over placebo across patient subgroups, including those with low-volume disease, regardless of whether patients had metastases at primary diagnosis or had previous treatment of localised disease.
All secondary endpoints favoured apalutamide plus ADT, with time to cytotoxic chemotherapy being significantly longer for patients treated with apalutamide than with placebo plus ADT. The other clinically relevant endpoints of time to prostate-specific antigen progression and second progression-free survival (PFS2) also favoured apalutamide treatment. The safety of apalutamide was manageable, and HRQoL was preserved during apalutamide treatment.
On the basis of these results, the independent data-monitoring committee recommended unblinding TITAN to allow patients receiving placebo to receive apalutamide (crossover).
In this prespecified, event-driven final analysis of TITAN, with matured data and long-term follow-up, the study team report updated results for OS and for the secondary and other clinically relevant endpoints, patient-reported HRQoL, and safety data with longer follow-up.
With a median follow-up of 44.0 months, 405 OS events had occurred and 208 placebo-treated patients (39.5%) had crossed over to apalutamide. The median treatment duration was 39.3 (apalutamide), 20.2 (placebo), and 15.4 months (crossover).
Compared with placebo, apalutamide plus ADT significantly reduced the risk of death by 35% (median OS not reached vs 52.2 months; hazard ratio [HR) 0.65; 95% confidence interval [CI] 0.53 to 0.79; p < 0.0001) and by 48% after adjustment for crossover (HR 0.52; 95% CI 0.42 to 0.64; p < 0.0001).
Apalutamide plus ADT delayed PFS2 and castration resistance (p < 0.0001 for both).
According total Functional Assessment of Cancer Therapy-Prostate, HRQoL in both groups was maintained through the study. Safety was consistent with previous reports.
The authors concluded that the final analysis of TITAN and its long-term results demonstrate that apalutamide plus ADT consistently provides significant improvements in OS and delays onset of progression despite a large number of placebo-treated patients crossing over to active treatment with apalutamide during the study. Apalutamide benefit was robustly supported by other efficacy endpoints, including delayed castration resistance and prolonged PFS2. Apalutamide maintained HRQoL and had an acceptable safety profile confirmed with substantially longer follow-up and exposure. The results support the early addition of apalutamide to ADT in patients with mCSPC.
The study was supported by Janssen Research & Development.
Chi KN, Chowdhury S, Biartell A, et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. Journal of Clinical Oncology; Published online 29 April 2021. DOI: 10.1200/JCO.20.03488.