At a median follow-up of 44 months, the median overall survival (OS) was not reached in patients who received apalutamide plus standard androgen deprivation therapy (ADT), but the median OS was 52.2 months in patients who received placebo plus ADT.
“In the final analysis, the risk of death with apalutamide was reduced by 35%, with a hazard ratio of 0.65 and P value of less than .0001. This was similar to the hazard ratio of 0.67 in the primary analysis of TITAN, despite an almost 40% crossover rate from the placebo group to the apalutamide,” said Kim N. Chi, MD, a medical oncologist at BC Cancer Vancouver Prostate Centre.
Dr. Chi reported these results at the 2021 Genitourinary Cancer Symposium (Abstract 11).
Study details
The international, double-blind TITAN trial compared apalutamide (240 mg daily) with placebo, both added to standard ADT, in 1,052 patients with metastatic castration-sensitive prostate cancer, including those with high- and low-volume disease, prior docetaxel use, prior treatment for localized disease, and prior ADT for no more than 6 months.
At the primary analysis, reported in the New England Journal of Medicine in 2019, the dual primary endpoints of radiographic progression-free survival and OS met statistical significance at a median follow up of 22.7 months.
At the final analysis, the median treatment duration was 39.3 months for the apalutamide arm, 20.2 months for the placebo arm, and 15.4 months for patients who crossed over from placebo to apalutamide.
After adjusting for crossover, the effect of apalutamide on OS increased (HR, 0.52), indicating a reduction in the risk of death by 48% versus placebo, Dr. Chi said. He noted that the treatment effect on OS favored apalutamide in both high- and low-volume disease.
“Treatment with apalutamide also significantly prolonged second progression-free survival on next subsequent therapy and delayed development of castration resistance,” Dr. Chi said.
The median second progression-free survival was 44.0 months in the placebo arm and was not reached in the apalutamide arm. The median time to castration resistance was 11.4 months in the placebo arm and was not reached in the apalutamide arm.
Health-related quality of life was also maintained in the apalutamide group throughout the study and did not differ from the placebo group. Safety was consistent with previous reports.
“Importantly, the cumulative incidence of treatment-related falls, fracture, and fatigue was similar between groups, as was the cumulative incidence of treatment-related adverse events and serious adverse events,” Dr. Chi said.
An increased incidence of any-grade rash that was seen in the apalutamide group was expected but plateaued after about 6 months.
“These results confirm the favorable risk-benefit profile of apalutamide,” Dr. Chi concluded.
Implications for practice
The study results raise questions about how to best incorporate the findings into practice, including how to use docetaxel or other androgen receptor inhibitors in treatment strategies for this patient population and if they should be used in high-volume patients, said Elisabeth Heath, MD, session cochair and associate director of translational science at Wayne State University in Detroit.
Dr. Chi said a number of studies over the past 5 years have demonstrated OS benefit when combining ADT with additional therapy.
“Really, this should be considered the standard of care,” he said. “However, real-world studies ... suggest that only a minority of patients are actually receiving this additional therapy.”
Although there are challenges with comparing outcomes across studies to determine which treatments to use, the TITAN data reinforce apalutamide plus ADT as a good option, including in high-volume patients, Dr. Chi said.
Funding for TITAN was provided by Janssen Research & Development. Dr. Chi and Dr. Heath disclosed relationships with Janssen and many other companies. sworcester@mdedge.com