(A-145) The comparative risk of diagnosed depression among older men with metastatic castration resistant prostate cancer initiating enzalutamide versus abiraterone

Background: Enzalutamide and abiraterone are both androgen receptor pathway inhibitors (ARPIs) used in the first-line treatment of metastatic castration-resistant prostate cancer (mCRPC) but possess different mechanisms of action. Enzalutamide, which crosses the blood-brain barrier, may have higher depressogenic effects than abiraterone, though this hypothesis has not yet been evaluated.

Objectives: To determine if use of enzalutamide, compared to abiraterone, is associated with a higher one-year risk of incident depression diagnosis in a population of older adult men diagnosed with mCRPC.

Methods: We designed a cohort study using SEER cancer registry data linked with Medicare administrative claims data. Eligible individuals initiated enzalutamide or abiraterone between September 2012 – June 2017, a period during which mCRPC was the only indication for these two ARPI regimens. Those with a diagnosis of depression or use an anti-depressant in the twelve months prior to the index date (first drug dispensation) were excluded. For intent-to-treat analysis, individuals were censored at loss of continuous insurance enrollment, end of one-year risk period without event, or administrative censoring (December 31st, 2020). For per protocol analysis, we additionally censored at discontinuation of index ARPI or switching regimens. Depression was identified using a previously developed and validated claims-based algorithm with 94.3% specificity. Inverse-probability of treatment weighting (IPTW) was used to balance measured confounders between the comparison groups, which included tumor, demographic, and clinical characteristics. A weighted Aalen-Johansen estimator was used to estimate the cumulative incidence of depression.

Results: The cohort consisted of 1,386 enzalutamide and 2,387 abiraterone initiators (total n=3,773). The median age was 78.2 years (range: 66 – 99 years) and 33% had distant (de novo metastatic) disease at diagnosis. In an intention-to-treat analysis, there was a slightly higher one-year cumulative incidence of depression in patients treated with enzalutamide (5.2%; 95% CI: 3.9%, 6.5%) compared to those receiving abiraterone (4.2%; 95% CI: 3.3%, 5.1%), though the risk ratio of 1.24 was compatible with the null (95% CI: 0.83, 1.64). Similarly, in a per-protocol analysis, enzalutamide-treated patients had a higher one-year cumulative incidence of depression (4.7%; 95% CI: 3.2%, 6.2%) than those on abiraterone (3.1%; 95% CI: 2.2%, 4.0%, Risk Ratio = 1.54; 95% CI: 0.87, 2.21).

Conclusions: Point estimates suggest that enzalutamide may be associated with an increased risk of an incident depression diagnosis, compared to abiraterone use. However, statistical precision was limited, and effects were compatible with the null.