BACKGROUNDApalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. Whether the addition of apalutamide to androgen-deprivation therapy (ADT) would prolong radiographic progression-free survival and overall survival as compared with placebo plus ADT among patients with metastatic, castration-sensitive prostate cancer has not been determined. METHODSIn this double-blind, phase 3 trial, we randomly assigned patients with metastatic, castration-sensitive prostate cancer to receive apalutamide (240 mg per day) or placebo, added to ADT. Previous treatment for localized disease and previous docetaxel therapy were allowed. The primary end points were radiographic progression-free survival and overall survival. RESULTSA total of 525 patients were assigned to receive apalutamide plus ADT and 527 to receive placebo plus ADT. The median age was 68 years. A total of 16.4% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease, and 37.3% had low-volume disease. At the first interim analysis, with a median of 22.7 months of follow-up, the percentage of patients with radiographic progression-free survival at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (hazard ratio for radiographic progression or death, 0.48; 95% confidence interval [CI], 0.39 to 0.60; P<0.001). Overall survival at 24 months was also greater with apalutamide than with placebo (82.4% in the apalutamide group vs. 73.5% in the placebo group; hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005). The frequency of grade 3 or 4 adverse events was 42.2% in the apalutamide group and 40.8% in the placebo group; rash was more common in the apalutamide group. CONCLUSIONSIn this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the sideeffect profile did not differ substantially between the two groups. (Funded by Janssen Research and Development; TITAN ClinicalTrials.gov number, NCT02489318.

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11 Background: TITAN evaluated APA or PBO added to ADT in pts with mCSPC. Pts with high- and low-volume disease, prior docetaxel, prior treatment for localized disease, and prior ADT (≤ 6 mos) were eligible. At the first interim analysis, with 22.7 mos median follow-up, APA significantly improved dual primary end points of overall survival (OS) (hazard ratio [HR] 0.67) and radiographic progression-free survival (rPFS) (HR 0.48) compared with PBO (Chi et al. NEJM. 2019). At that time, OS analysis was first planned interim while rPFS was final. TITAN was unblinded, allowing pts without progression who were still receiving PBO to cross over to APA. Herein, we report the final analysis of efficacy and safety results from TITAN. Methods: 1052 mCSPC pts were randomized 1:1 to receive APA (240 mg QD) or PBO plus ADT. Time-to-event end points were analyzed by Kaplan-Meier method and Cox proportional hazards model. A preplanned sensitivity analysis for OS, accounting for crossover using inverse probability censoring weighted (IPCW) log-rank test, was conducted. No formal statistical retesting was performed; nominal p values were reported without multiplicity adjustment. Change from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score was assessed using a mixed-effect repeated-measures model. Results: With 44 mos median follow-up, 405 OS events had occurred. After unblinding, 208 PBO pts (39.5%) crossed over to APA. Median treatment duration was 39.3 mos for the APA group, 20.2 mos for the entire PBO group, and 15.4 mos for the PBO→APA crossover group. OS was superior in the APA group compared with the PBO group despite crossover (Table). 48-mo survival rates were 65% (APA) vs 52% (PBO). Other end points also favored APA vs PBO (Table). Health-related quality of life (HRQoL), per total FACT-P, was maintained in the APA group through the study and was not different from the PBO group. Safety was consistent with previous reports. Conclusions: With close to 4 yrs of follow-up, the final analysis of TITAN demonstrated that in a broad population of pts with mCSPC, APA plus ADT provides an improvement in OS with a 35% reduction in risk of death, which increased to 48% reduction after adjusting for pts who crossed over from PBO to APA. In addition, there was consistent benefit with APA in other end points, including delaying castration resistance, and HRQoL continued to be maintained with an acceptable safety profile. Clinical trial information: NCT02489318. [Table: see text]

82 Background: TITAN, a phase 3, randomized, double-blind study of apalutamide (APA) vs placebo (PBO) added to androgen deprivation therapy (ADT), demonstrated significant improvement in radiographic progression-free survival and overall survival in a broad pt population with mCSPC who received APA (Chi KN et al. NEJM 2019). This post hoc analysis evaluates whether type of 1st life-prolonging subsequent therapy (hormonal vs taxane) has an effect on PFS2 benefit shown with APA + ADT. Methods: PFS2 (the time from randomization to disease progression on 1st subsequent therapy for prostate cancer or death, whichever occurs first) was evaluated for pts from TITAN based on 1st subsequent life-prolonging therapy (hormonal vs taxane) after study treatment. Analysis censored all other 1st subsequent systemic therapies after start of treatment. Results: 277 pts (APA, 87; PBO, 190) received subsequent systemic therapy for prostate cancer; 86 pts (APA, 24; PBO, 62) received hormonal therapy (abiraterone acetate + prednisone or enzalutamide) and 99 (APA, 30; PBO, 69) received taxane (docetaxel or cabazitaxel) as 1st subsequent therapy. Baseline demographic and disease characteristics were generally similar between groups. The taxane group had a higher proportion of pts with high volume and pts with > 10 bone metastases, and a lower proportion with prior docetaxel exposure when compared with the hormonal group. Median treatment duration with APA and PBO was 11.9 and 11.1 mos in the hormonal group and 11.0 and 11.3 mos in the taxane group. Regardless of subsequent therapy, PFS2 was significantly longer for APA vs PBO (HR 0.66 [95% CI 0.50-0.87], p = 0.0026). Pts in both groups who received APA had a significant reduction in risk of 2nd progression compared with PBO (hormonal: HR 0.68 [0.48-0.97], p = 0.0326; taxane: HR 0.67 [0.48-0.94], p = 0.0189; medians not reached). Safety analyses were not conducted; all pts had discontinued therapy, most due to disease progression. Conclusions: The addition of APA to ADT for treatment of mCSPC results in risk reduction of 2nd progression regardless of choice of hormonal or taxane as the 1st life-prolonging subsequent therapy. Clinical trial information: NCT02489318.