Regulatory Decision Summary for Erleada

Clinical efficacy and safety for the proposed indication for apalutamide is supported primarily by a randomized, double-blind, placebo-controlled study (ARN-509-003), in patients with NM-CRPC who were at high risk of developing distant metastases. Treatment with apalutamide plus Androgen Deprivation Therapy (ADT) decreased the risk of distant metastases or death (Metastasis-Free Survival [MFS]) by 70% compared with placebo plus ADT. The median MFS was 2 years longer in patients treated with apalutamide. The improvement in MFS was supported by three secondary efficacy endpoints: time to metastases, progression-free survival and time to symptomatic progression. Overall survival (OS) was insignificant at the time of the primary analysis but not detrimental to patients treated with apalutamide. Time to initiation of cytotoxic chemotherapy could not be evaluated due to the insignificant OS results. Based on the patient population studied and unknown benefit and risk profile in those with low risk of developing metastases, a caveat was added to the approved broad indication to address the concern.

The safety profile of apalutamide plus ADT is manageable for patients with NM-CRPC. Overall incidences of treatment emergent adverse events (AEs) and serious adverse events were comparable between the two treatment arms. Higher incidences of severe AEs and AEs leading to dose modification or discontinuation suggest higher toxicity and lower tolerability of patients treated with apalutamide. Apalutamide also increased risks of known toxicities associated with ADT including falls and fractures, cardiac disorders (including QTc prolongation), and serious infections. Deaths due to AEs (cardiac disorders, infections and cerebrovascular accidents) were also reported with apalutamide but the incidence was low. The Erleada Product Monograph was updated with these safety concerns and risk management information.

Treatment with apalutamide plus ADT in patients with NM-CRPC at high risk of developing metastases demonstrated significant improvement in delaying distant metastases or death over ADT alone. The efficacy results suggest early intervention with apalutamide can delay disease progression in the high risk patient population. Treatment with apalutamide plus ADT was well tolerated with a manageable safety profile. Taken together, the data provided in this dossier establish a favorable benefit/risk profile for the use of apalutamide in the treatment of patients with high risk NM-CRPC.