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Benefits seen with apalutamide plus ADT in metastatic castration-sensitive prostate cancer

Presented by
Dr Kim N. Chi, BC Cancer Agency, Canada
ASCO 2019
Phase 3, TITAN
Medical writer: Tim Donald, ELS

The addition of apalutamide to androgen-deprivation therapy (ADT) significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-sensitive prostate cancer (mCSPC) in the TITAN trial, according to a presentation on May 31 during a Genitourinary (Prostate) Cancer Oral Abstract Session (Abstract 5006). The safety profile of the regimen was tolerable in the trial, according to presenter Kim N. Chi, MD, FRCPC, of BC Cancer Agency, Canada.

“These results support the addition of apalutamide to ADT for a broad range of patients with mCSPC, such as those in the TITAN study, which included patients with high- and low-volume disease, with prior docetaxel treatment, those who had metastatic disease at diagnosis or relapsed metastatic disease, and those who had received prior treatment for localized disease,” Dr. Chi said.

The results he presented were based on a final analysis of rPFS and, coincidentally, the first planned interim analysis of OS in the trial. Based on results of the analysis, in January the trial’s independent data monitoring committee recommended unblinding and amending the study protocol to allow crossover of patients receiving placebo to receive apalutamide.

“For the dual primary endpoint, apalutamide significantly reduced the risk of radiographic progression or death by 52%,” Dr. Chi said. “At 2 years, there was an absolute 20% difference in the rate of rPFS, with 68% of patients on the apalutamide arm remaining free of progression, vs. 48% of patients on the placebo arm. The rPFS benefit from apalutamide was consistent across subgroups.”

Apalutamide also significantly reduced the risk of death in the study by 33%, with 82% OS at 2 years in the apalutamide arm compared with 74% in the placebo arm. The OS benefit was also consistent across subgroups.

TITAN (NCT02489318) was designed to evaluate apalutamide, an androgen-receptor inhibitor, vs. placebo in a broad population of patients with mCSPC who would also receive continuous ADT. The trial tested the proposition that direct inhibition of androgen receptors may provide a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes.

The randomized, double-masked, phase III study included patients with mCSPC regardless of extent of disease, randomly assigned 1:1 to apalutamide 240 mg/d or placebo, added to continuous ADT, in 28-day cycles. The study’s dual primary endpoints were rPFS and OS.

Secondary endpoints in TITAN included time to initiation of cytotoxic chemotherapy, time to pain progression, time to chronic opioid use, and time to skeletal-related event. Exploratory endpoints included time to prostate-specific antigen (PSA) progression, second PFS (PFS2), and time to symptomatic progression. Results for secondary and exploratory endpoints also favoured apalutamide.

Regarding the exploratory endpoint of time to PFS2, defined as the time from randomization to progression on next subsequent treatment, Dr. Chi commented that the difference favoring apalutamide (HR 0.66, 95% CI [0.50, 0.87]; P = 0.0026) “supports the earlier use of apalutamide.”

Treatment with apalutamide was tolerable, and the safety profile was consistent with the known side effects of the drug, Dr. Chi said. Health-related quality of life was maintained and not different from placebo.

Discussant Michael A. Carducci, MD, FASCO, of the Sidney Kimmel Cancer Centre at Johns Hopkins, noted that the OS benefit was not consistent in all subgroups, notably in patients with prior docetaxel use (about 10% of the study population), patients over age 75, and those with low disease volume.

It will be important, he said, in deciding which drug is appropriate for which patient, to consider these factors. There is a clear benefit in OS with apalutamide in patients with high-volume disease, “but there may be these subpopulations that may not derive benefit,” he said.

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