Apalutamide plus androgen deprivation therapy (ADT) significantly improved overall survival (OS) (HR 0.67) and radiographic progression-free survival (rPFS) (HR 0.48) versus placebo plus ADT in patients with mCSPC as shown by the first interim analysis of the TITAN phase 3 randomized trial1. After unblinding, patients without progression on placebo were allowed to cross over to apalutamide. The final analysis of OS was reported at ASCO GU 2021 after 44 months of follow-up (HR 0.65). Dr. Chowdhury and colleagues presented outcomes in patients with high-volume versus low-volume disease at the final analysis.
Overall, there were 1,052 patients with mCSPC randomized to apalutamide (240 mg/d) (n=525) or placebo (n=527) plus ADT. Dual primary endpoints were rPFS and OS. The trial schema for TITAN is as follows:
Apalutamide effect was analyzed by Cox models and Kaplan-Meier methods across high-volume and low-volume groups. High-volume disease definition (modified CHAARTED) included: 1) visceral metastases and ≥1 bone lesion, or 2) ≥4 bone lesions, with ≥1 outside of the vertebral column or pelvis. Low volume disease definition: (presence of) bone lesions not meeting the high-volume definition.
At baseline, 63% of patients had high-volume and 37% had low-volume disease (apalutamide: high-volume n=325, low-volume n=200; placebo: high-volume n=335, low-volume n=192). With 44.0 months median follow-up, 208 patients (39.5%) had crossed over to apalutamide. Both the high-volume and low-volume groups had significantly improved OS with apalutamide vs placebo despite crossover:
Both high-volume and low-volume groups had significantly improved rPFS with apalutamide vs placebo:
Other endpoints also favored apalutamide versus placebo in both high-volume and low-volume groups, including time to PSA progression in both high and low-volume disease:
Additionally, there was a benefit for apalutamide for the outcome of delayed time to castration resistance in both high- and low-disease burden. The safety profile of apalutamide in both high-volume and low-volume groups was consistent with the safety profile in the intent-to-treat (ITT) population reported earlier. Grade 3/4 adverse event rates were higher in the high-volume group with either treatment (high-volume: apalutamide, 53.5%; crossover placebo → apalutamide, 34.8%; placebo, 46.9%; low-volume: apalutamide, 42.7%; placebo→ apalutamide, and 18.8%; placebo, 32.8%).
Dr. Chowdhury concluded this stratified analysis of the TITAN trial with the following take homes messages:
• In TITAN, patients with mCSPC and irrespective of disease volume, apalutamide added to ADT significantly improved rPFS, OS, and time to PSA progression
• The long-term treatment effect of apalutamide was observed despite ~40% placebo to apalutamide crossover after unblinding
• PSA response was similarly rapid and deep after apalutamide treatment regardless of disease volume
• The apalutamide safety profile in both high- and low-volume disease remained consistent with previous reports
Presented by: Simon Chowdhury, MD, Ph.D., Consultant Medical Oncologist, Guy's Hospital and St. Thomas' Hospital NHS Foundation Trust, Dept. of Urological Cancer, and the Joint Lead for the treatment of urological cancers within the Southeast London Cancer Network, London, United Kingdom
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.