Kim Nguyen Chi MD Of The University Of British Colombia Discusses TITAN Study: Phase III Double-Blind, Randomized Study Of Apalutamide Versus Placebo In Patients With (mCSPC).
TITAN was designed to determine whether APA, a selective next-generation androgen receptor inhibitor, plus ADT improves radiographic progression-free survival (rPFS) and overall survival (OS) compared with PBO plus ADT in pts with mCSPC.
In this randomized, double-blind phase 3 study, pts with mCSPC regardless of extent of disease were randomized (1:1) to APA (240 mg/d) or PBO, added to ADT, in 28-day cycles. Pts with prior treatment (tx) for localized disease or prior docetaxel for mCSPC were allowed. All pts received continuous ADT. Dual primary end points were rPFS and OS. Secondary end points were time to a) initiation of cytotoxic chemotherapy, b) pain progression, c) chronic opioid use, d) skeletal-related event. Time-to-event end points were estimated by Kaplan-Meier and Cox proportional hazards methods. This first planned OS interim analysis took place after ~50% of expected events.
525 pts were randomized to APA and 527 to PBO. Median age was 68 y; 8% had prior tx for localized disease; 11% had prior docetaxel. 63% and 37% had high- or low-volume disease, respectively. At median 22.6 mo follow-up, 66% APA and 46% PBO pts remained on tx. APA significantly improved rPFS (HR, 0.48; 95% CI, 0.39-0.60; p < 0.0001), with a 52% reduction in risk of death or radiographic progression; benefit was observed across all subgroups analyzed. Median rPFS was not reached in the APA group and 22.1 mos in the PBO group. APA also significantly improved OS (HR, 0.67; 95% CI, 0.51-0.89; p = 0.0053), with a 33% reduction in risk of death. Median OS was not reached in the APA or PBO group. Time to initiation of cytotoxic chemotherapy was significantly improved with APA (HR, 0.39; 95% CI, 0.27-0.56; p < 0.0001). Based on these results, the independent data monitoring committee recommended unblinding to allow crossover of PBO pts to receive APA. Rates of grade 3/4 adverse events (AEs) (42% APA, 41% PBO) were similar, and discontinuations due to AEs (8% APA, 5% PBO) were low.
In the TITAN study in pts with mCSPC, including pts with high- and low-volume disease and prior docetaxel, addition of APA to ADT significantly improved rPFS and OS, and the safety profile was tolerable. These results support the addition of APA to ADT for tx of pts with mCSPC. Clinical trial information: NCT02489318