Regulatory Decision Summary for Nubeqa

Clinical efficacy and safety for the proposed indication is supported primarily by a randomized, double-blind, placebo-controlled study, ARAMIS, conducted in 1,509 patients with nmCRPC who were at high risk for developing metastatic disease. The primary endpoint was Metastasis-Free Survival (MFS), defined as the time from randomization to confirmed evidence of distant metastasis or death from any cause, whichever occurred first. Treatment with Nubeqa plus Androgen Deprivation Therapy (ADT) decreased the risk of MFS events by 59% compared with placebo plus ADT alone. The median MFS was 22 months longer in patients treated with Nubeqa. The secondary endpoints of overall survival, time to pain progression, time to initiation of first cytotoxic chemotherapy for prostate cancer, and time to first symptomatic skeletal event were not statistically significant, however no decrement of these endpoints was apparent in the Nubeqa arm.

Because all patients enrolled in the pivotal study were at high risk of developing metastatic disease, and the benefit/risk profile of Nubeqa treatment in those with low risk of developing metastases unknown, a caveat was added to the approved broad indication to better reflect the patient population studied. It was considered reasonable not to limit the indication in a manner that would exclude treatment of low-risk patients based on the significant positive effect of Nubeqa, the androgen receptor target of darolutamide, and because the precise definition of high risk nmCRPC is still evolving.

Adverse drug reactions reported at a higher incidence in the Nubeqa arm compared to the placebo arm (≥2 percentage point difference) were fatigue, rash, and pain in extremity. Incidences of adverse drug reactions were below 10% in both treatment arms, with the exception of fatigue (12.1% Nubeqa vs. 8.7% placebo). Nubeqa was generally well tolerated, with treatment-emergent AEs leading to permanent study drug discontinuation occurring at a similar rate in both study arms. The primary tool for risk mitigation is the Nubeqa Product Monographs (PM).

A Risk Management Plan was submitted by the sponsor and considered acceptable by the Marketed Health Products Directorate.

Treatment with Nubeqa plus ADT in patients with nmCRPC at high risk of developing metastases demonstrates significant improvement in delaying distant metastases or death over ADT alone. The efficacy results that suggest early intervention with Nubeqa can delay disease progression in the high-risk patient population. Treatment with Nubeqa plus ADT is well tolerated with a manageable safety profile. Taken together, the data provided in the submission establishes a favorable benefit/risk/uncertainty profile for the use of Nubeqa in the treatment of patients with nmCRPC, with the caveat that Nubeqa has not been studied in patients with nmCRPC at low risk of developing metastases.