The European Commission has approved apalutamide for use in combination with androgen deprivation therapy for the treatment of adult men with metastatic hormone-sensitive prostate cancer.
Axel S. Merseburger, MD, PhD
The European Commission has approved apalutamide (Erleada) for use in combination with androgen deprivation therapy (ADT) for the treatment of adult men with metastatic hormone-sensitive prostate cancer.1
The approval is based on findings from the phase III TITAN trial (NCT02489318), which showed that apalutamide plus ADT led to a 33% reduction in the risk of death compared with placebo and ADT in this patient population (HR, 0.67; 95% CI, 0.51-0.89; P = .0053).2,3 “Prostate cancer is the most prevalent form of cancer in men throughout Europe, and the expanded approval of apalutamide marks a significant advancement for those living with metastatic hormone-sensitive prostate cancer,” Axel S. Merseburger, MD, PhD, chairman of the Department of Urology, Campus Lübeck, University Hospital Schleswig-Holstein, Kiel, Germany, said in a press release.
“In prostate cancer treatment, our primary goal is always to delay progression of disease and prolong survival, to ensure the best possible outcomes for patients. Today’s news is therefore an encouraging development for patients within Europe, for whom the importance of an additional treatment option that can both delay progression and extend survival cannot be underestimated,” added Merseburger.
In the international, multicenter, placebo-controlled, double-blind, randomized TITAN study, 1052 patients were enrolled who had metastatic castration-sensitive prostate cancer who were newly diagnosed, regardless of prognostic risk, volume of disease, had an ECOG performance status of 0 or 1, and had prior therapy with docetaxel or localized treatment. Patients were randomized to receive oral apalutamide at 240 mg once daily plus ADT or placebo combined with ADT until disease progression, unacceptable toxicity, or end of treatment. The coprimary endpoints were rPFS and OS; secondary endpoints included time to chemotherapy, time to pain progression, time to chronic opioid use, and time to skeletal-related event.
Patients with small cell, ductal, or neuroendocrine carcinoma of the prostate, brain metastases, lymphatic metastases, visceral metastases, a prior malignancy within 5 years of randomization, a history of seizures, or prior treatment with other next-generation AR inhibitors or CYP17 inhibitors, immunotherapy, or radiopharmaceutical agents were excluded.
Results also showed that at a median follow-up of 22.7 months, the 2-year overall survival (OS) rate was 82.4% in the apalutamide arm versus 73.5% in patients receiving ADT alone (HR, 0.67; 95% CI, 0.51-0.89; P = .005). The median OS was not yet reached in either arm.
Moreover, the addition of apalutamide also reduced the risk of radiographic progression or death by 52%. The median radiographic progression-free survival (rPFS) was not reached in the apalutamide arm versus 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.
Key secondary and exploratory endpoints with the addition of apalutamide to ADT were also met. 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). 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% risk reduction in the median time to second progression-free survival (HR, 0.66; 95% CI, 0.50-0.87)—the time from randomization to either progressive disease on the first subsequent anticancer treatment, or death.
Regarding safety, grade 3/4 adverse events (AEs) occurred in 42.2% of the apalutamide arm versus 40.8% of the control arm. Serious AEs occurred in 19.8% versus 20.3%, respectively. Discontinuations related to AEs occurred in 8% of the apalutamide group compared with 5.3% in the group receiving ADT alone. There were 10 AE-related deaths in the apalutamide arm versus 16 in the placebo arm.
Grade ≥3 AEs of special interest included 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).
Apalutamide was approved by the FDA in September 2019 for the treatment of patients with metastatic castration-sensitive prostate cancer.
In Europe and the United States, apalutamide is also approved for use in adults with nonmetastatic castration-resistant prostate cancer.