Patients with metastatic castration-resistant prostate cancer who received apalutamide plus androgen deprivation therapy had a 33% reduced risk of death compared with patients taking androgen deprivation therapy alone in the phase III TITAN trial. Topline results from the trial were presented at the 2019 ASCO Annual Meeting and simultaneously published in the <em>New England Journal of Medicine.</em>
Kim N. Chi, MD
Patients with metastatic castration-resistant prostate cancer who received apalutamide (Erleada) plus androgen deprivation therapy (ADT) had a 33% reduced risk of death compared with patients taking ADT alone in the phase III TITAN trial. Topline results from the trial were presented at the 2019 ASCO Annual Meeting and simultaneously published in theNew England Journal of Medicine.
At the median follow-up of 22.7 months, the 2-year overall survival (OS) rate was 82.4% in the apalutamide arm compared with 73.5% in patients receiving ADT alone (HR, 0.67; 95% CI, 0.51-0.89;P= .005).
The addition of apalutamide also significantly reduced the risk of radiographic progression or death by 52%. The median radiographic progression-free survival (rPFS) was not reached in the apalutamide arm compared with 22.1 months in the control arm (HR, 0.48; 95% CI, 0.39-0.60;P<.0001). The 2-year rPFS rates were 68.2% versus 47.5%, respectively. The OS and rPFS benefits were observed across patient subgroups.
“These results support the addition of apalutamide to ADT for a broad range of patients with metastatic castration-sensitive prostate cancer, [such as] those enrolled on the TITAN study, which included patients with high or low disease volume, prior docetaxel, de novo metastatic disease or relapsed metastatic disease after initial diagnosis of localized disease, and those who had received prior treatment for localized disease,” said principal TITAN investigator Kim Chi, MD, a medical oncologist at BC Cancer Vancouver.
From December 2015 to July 2017, the international, double-blind TITAN study enrolled an all-comer population of 1052 patients with metastatic castration-sensitive prostate cancer, regardless of prior docetaxel treatment or the extent of disease. Patient characteristics were well balanced between the 2 treatment arms at baseline. The median patient age overall was 68 years, 10.7% had prior docetaxel, and 16.4% had received prostatectomy or been treated with radiotherapy for localized disease. Overall, 62.7% of patients had high-volume disease, with 37.3% having low-volume disease.
Patients were randomized in a 1:1 ratio to receive oral apalutamide at 240 mg once daily plus ADT (n= 525) or placebo combined with ADT (n = 527) until disease progression, unacceptable toxicity, or end of treatment. The coprimary endpoints were rPFS and OS.
Beyond meeting the two coprimary endpoints, the study met several key secondary and exploratory endpoints with the addition of apalutamide to ADT. Among these were median time to cytotoxic chemotherapy (HR, 0.39; 95% CI, 0.27-0.56;P<.0001) and median time to PSA progression (HR, 0.26; 95% CI, 0.21-0.32). Of note, in the apalutamide arm 68% of patients had their PSA drop to undetectable levels compared with 29% of patients receiving ADT alone.
The additional of apalutamide to ADT also led to a 34% (HR, 0.66; 95% CI, 0.50-0.87) risk reduction in the median time to second progression-free survivalthe time from randomization to either progressive disease on the first subsequent anticancer treatment, or death.
Regarding safety, Chi said, “Treatment was tolerable and the safety profile was consistent with the known side effects of apalutamide.”
Grade 3/4 adverse events (AEs) occurred in 42.2% of the apalutamide arm compared with 40.8% of the control arm. Serious AEs occurred in 19.8% versus 20.3% of the 2 arms, respectively. Discontinuations related to AEs occurred in 8% of the apalutamide group compared to 5.3% in the group receiving ADT alone. There were 10 AE-related deaths in the apalutamide arm compared with 16 in the placebo arm.
Chi listed several grade ≥3 AEs of special interest, including rash (6.3% in the apalutamide arm vs 0.6% in the ADT-alone arm), fatigue (1.5% vs 1.1%, respectively), fall (0.8% in each arm), fracture (1.3% vs 0.8%), and seizure (0.2% vs 0).
Based on the TITAN data, a supplemental new drug application has been submitted to the FDA for the approval of apalutamide for use as a treatment of patients with metastatic castration-sensitive prostate cancer. In February 2018, the FDA approved apalutamide for the treatment of patients with nonmetastatic castration-resistant prostate cancer.