Introduction:

Apalutamide, darolutamide, and enzalutamide are androgen receptor pathway inhibitors (ARPIs) approved to treat non-metastatic castration-resistance prostate cancer (nmCRPC) in combination with androgen deprivation therapy (ADT). Central nervous system (CNS) conditions, such as cognitive impairment, falls, seizures, fatigue, pain, or headaches, are important clinical considerations among nmCRPC patients treated with an ARPI due to either pre-existing patient medical history or potential for treatment-related adverse events. Despite the growing use of ARPIs, real-world evidence on CNS-related clinical outcomes in patients with nmCRPC remains limited. This retrospective study aimed to describe CNS outcomes among patients with nmCRPC treated with apalutamide, darolutamide, or enzalutamide in a real-world setting.

Methods:

A retrospective analysis was conducted using linked clinical data from US community urology practices and administrative claims data (PPS Analytics and Komodo Research Database; 1/1/2016-08/31/2024). Patients were assigned to exclusive treatment cohorts based on the first apalutamide, darolutamide or enzalutamide dispensation or pharmacy claim on or after 07/30/2019 (index date). Patients were included if they had evidence of castration resistance in the absence of metastasis and had ≥12 months of pre-index clinical activity. Follow-up spanned from index date until the earliest of index ARPI discontinuation or switch, initiation of an advanced PC-related medication (i.e., chemotherapy, radiopharmaceuticals, poly ADP-ribose polymerase [PARP] inhibitors, or immunotherapy), or end of clinical activity/data availability (08/31/2024). The occurrence of a newly diagnosed CNS-related condition during the follow-up period that was not observed during the 12-month baseline period was considered an event and was described using a Kaplan-Meier analysis. Descriptive statistics were used to evaluate patient characteristics.

Results:

Overall, 253 apalutamide (mean age: 77.6 years, white: 61.3%, Black: 24.5%, Medicare-insured: 87.0%, prior ADT use: 97.2%, mean follow-up: 12.4 months), 544 darolutamide (mean age: 78.7 years, white: 65.8%, Black: 21.5%, Medicare-insured: 93.6%, prior ADT use: 97.2%, mean follow-up: 14.0 months), and 645 enzalutamide (mean age: 77.7 years, white: 62.8%, Black: 24.2%, Medicare-insured: 92.4%, prior ADT use: 96.1%, mean follow-up: 12.3 months) patients with nmCRPC were identified. New onset of any CNS-related condition was observed by a numerically lower proportion of apalutamide patients (25.7%) than darolutamide (31.4%) and enzalutamide patients (40.8%) patients at 12 months post index (Figure 1). This trend persisted at 24 months post index with numerically lower proportion of apalutamide patients (46.6%) than darolutamide (54.6%) and enzalutamide (59.7%) patients (Figure 1). The median time-to-new onset (months) of any CNS-related condition was descriptively longer for apalutamide (29.2), relative to darolutamide (21.3) and enzalutamide (18.1) patients (Figure 2).

Conclusion:

In this real-world study of patients with nmCRPC treated with ARPIs, a smaller proportion of patients treated with apalutamide were observed to have new onset of any CNS-related condition than those treated with darolutamide or enzalutamide by 12 months and 24 months post-index. Additionally, the median time-to-new onset of any CNS-related condition was descriptively longer for apalutamide compared to darolutamide or enzalutamide patients. As ARPIs continue to be widely used in the management of nmCRPC, understanding their impact on neurological outcomes is critical. These findings suggest a clinical difference in the real-world incidence of CNS-related conditions among patients treated with different ARPIs, suggesting that apalutamide may have a more favorable profile that minimizes the risk of CNS-related conditions in patients with nmCRPC. Continued research and long-term surveillance will be essential to better characterize CNS-related conditions across treatment options and inform clinical management.

Funding: Johnson & Johnson