Investigators demonstrated that the benefit of androgen deprivation therapy was extended with the addition of apalutamide for patients with metastatic castration-sensitive prostate cancer regardless of disease volume.
Investigators demonstrated that the benefit of androgen deprivation therapy (ADT) was extended with the addition of apalutamide (Erleada) for patients with metastatic castration-sensitive prostate cancer (mCSPC) regardless of disease volume. Data from an analysis of the final survival outcomes of the phase 3 TITAN trial (NCT02489318) were presented during the 2021 European Association of Urology (EAU) Congress.1
In total, 1052 patients were enrolled to the TITAN study and at baseline 63% had high-volume (HV) disease and 37% had low-volume (LV) disease. Patients were randomized 1:1 to either apalutamide (n = 525) or placebo (n = 527) plus ADT.
When stratified by disease volume, the median overall survival (OS) for patients with HV-disease treated with apalutamide (n = 325) were not estimable (NE) vs 38.7 months for those who received placebo plus ADT (n = 335); HR, 0.70; 95% CI, 0.56-0.88; P = .0017). Median OS was NE for patients in the LV cohort treated with apalutamide (n = 200) and those who received placebo (n = 192) with a reported HR of 0.53 (95% CI, 0.35-0.79; P = .0019).
Moreover, the radiographic progression-free survival (rPFS) outcomes were significantly improved with addition of apalutamide. For patients with HV disease, the median rPFS was NE in the apalutamide cohort vs 14.9 months in the placebo cohort (HR, 0.52; 95% CI, 0.40-0.66; P < .0001). In the LV cohorts, the median rPFS was NE in the apalutamide group vs 30.5 months in the placebo group (HR, 0.36; 95% CI, 0.22-0.57; P < .0001).
Apalutamide also delayed the development of castration resistance for those with HV and LV disease. Time to castration resistance was NE for patients in the HV cohort who received apalutamide compared with 8.3 months for those who received placebo (HR, 0.40; 95% CI, 0.32-0.48; P < .0001). In the LV cohort, time to castration resistance was NE in the apalutamide group vs 18.5 months in the placebo group (HR, 0.23; 95% CI, 0.16-0.33; P < .0001).
Finally, apalutamide improved time to prostate-specific antigen (PSA) progression in those with HV and LV disease. Time to progression was not reached in either apalutamide arm and was 9.2 months (HR, 0.32; 95% CI, 0.26-0.41; P < .0001) and 18.5 months (HR, 0.15; 95% CI, 0.09-0.23; P < .0001) in the placebo arms for HV and LV disease, respectively.
“In our post hoc analysis we assessed apalutamide efficacy and safety in patients who had high or low volume disease at baseline, the definition of high-volume disease was adapted from the CHAARTED study [NCT00309985],” Simon Chowdhury, MBBS, MRCP, PhD, MA, said in a virtual presentation of the data. Chowdhury is a consultant medical oncologist for the London Clinic in the England.
Disease volume for patients at baseline was determined by factors including presence of visceral metastases and bone lesions. Specifically, for a patient’s disease to be considered HV there must either be visceral metastases and at least 1 bone lesion or at least 4 bone lesions with at least 1 of which is located outside of the vertebral column or pelvis. In total, 59% of patients with HV disease had greater than 10 bone lesions and 41% had 10 or fewer lesions. Only 3% of patients considered to have LV disease had more than 10 lesions at baseline.
TITAN was an international, randomized, placebo-controlled phase 3 study that enrolled a broad population of patients with mCSPC. Following randomization, patients received either apalutamide 240 mg daily plus standard ADT or placebo plus ADT. The dual primary end points were OS or rPFS and the primary analysis was conducted after a median follow-up of 22.7 months.
“[At the time of primary analysis] both the rPFS and OS met statistical significance,” Chowdhury said. “The primary analysis was the final analysis for rPFS and the first interim analysis for OS. The TITAN study was unblinded at that time on the recommendation of the Independent Data Monitoring Committee and 39.5% of patients in the placebo group who had not progressed crossed over to receive apalutamide.”
The median rPFS for the intention-to-treat (ITT) population at the time of primary analysis was NR in patients who received apalutamide (n = 525) vs 22.1 months for those who received placebo (n = 527; HR, 0.48; 95% CI, 0.39-0.60; P < .0001).1,2 At 44.0 months follow-up, the median OS in the ITT population was not reached in the apalutamide cohort compared with 52.2 months in the placebo cohort (HR, 0.65; 95% CI, 0.53-0.79; P < .0001).1,2
“Apalutamide improved clinical outcomes in a broad population of patients with mCSPC in both high- and low-volume disease at baseline despite approximately 40% crossover [from placebo to apalutamide after unblinding],” Chowdhury said. “After adjusting for crossover in a preplanned sensitivity analysis, using the inverse probability censoring weighted method, the treatment effect of apalutamide on OS increased in both the overall TITAN population and in patients with high- and low-volume of disease.”
The HRs favoring apalutamide for the ITT population, HV population, and the LV population were 0.52 (95% CI, 0.42-0.64; P < .0001), 0.61 (95% CI, 0.49-0.78; P <. 0001), and 0.34 (95% CI, 0.22-0.53; P < .0001), respectively.1
In a detailed analysis of PSA reduction across patient populations, Chowdhury noted, “[treatment with] apalutamide resulted in a rapid and deep PSA response in both high- and low-volume disease subgroups,” Chowdhury said.
Specifically, PSA reduction of at least 50% was reported at 3-, 6-, and 12-month intervals for 87%, 88%, and 88%, of patients with HV disease treated with apalutamide compared with 41%, 48%, and 50% of those who received placebo. For those with LV disease, the PSA reduction rates were 93% at all time points for apalutamide compared with 41%, 51%, and 54% for placebo.
Deep PSA reduction, defined as reduction of at least 90%, occurred within a majority of patients within 3 months of apalutamide treatment, regardless of disease volume at baseline, Chowdhury said. At the 3-, 6-, and 12-month intervals the rate of deep response for those with HV treated with apalutamide were 55%, 65%, and 67%, respectively, compared with 13%, 18%, and 21% with placebo. For those with LV disease the rates with apalutamide were 64%, 72%, and 78% vs 13%, 19%, and 22% with placebo.
A third end point that was explored was the PSA of 0.2 ng/mL or less at 3-, 6-, and 12-months. For those in the HV group treated with apalutamide the rates of response were 40%, 51%, and 55%, respectively; with placebo the rates were 15%, 18%, and 19%, respectively. In the LV cohort, the rates of response with apalutamide were 68%, 77%, and 80%, at 3-, 6-, and 12-month intervals compared with 22%, 27%, and 29% with placebo.1
Chowdhury concluded with a safety analysis of the disease-burden subgroups. “The safety profile of apalutamide for patients with high- and low-risk disease was consistent with previous reports,” he said. The cumulative incidence of grade 3/4 treatment-emergent adverse events and serious adverse events were also similar between groups, he added.
“Importantly, cumulative incidence of any-grade treatment-emergent falls, fractures, and fatigue were similar between groups,” Chowdury said. In previously reported analysis, the rates of any-grade falls, fractures, and fatigue for patients in the ITT population who received apalutamide were 9.4%, 10.3%, and 20.4%, respectively, compared with 7.0%, 4.9%, and 16.9%, with placebo.2
“As expected, the incidence of any-grade rash was higher in the apalutamide group than the placebo group, but reached a plateau after approximately 6 months,” he said. In previously reported data for the ITT population, these rates were 29.2% and 9.3%, respectively.2