Monitoring initial dose to navigate ARPI treatment outcomes (MINATO study)

Abstract Androgen receptor pathway inhibitors (ARPIs: apalutamide, enzalutamide, darolutamide, abiraterone) are central to the first-line treatment of castration-sensitive prostate cancer (CSPC). Although their efficacy has been established in large-scale clinical trials, real-world evaluations of drug tolerability and related outcomes remain scarce. Using a large prescription database, this study analyzed the continuation of ARPIs in CSPC and the impact of dose reduction on time to castration-resistant prostate cancer (CRPC). This was a retrospective cohort study using a medical information database (MDV). Among patients with prostate cancer, those who initiated a first-line ARPI while in the CSPC state (no CRPC diagnosis) were included. First, as indicators of treatment continuation, same-drug dose reduction among patients starting at the standard dose and switching to another agent were evaluated from the date of first-drug initiation using the Kaplan-Meier method and the log-rank test; the timing of dose reduction and the distribution of the final administered dose were also described. Next, as an indicator of prognosis, the time from first-drug initiation to the first CRPC diagnosis was evaluated by first-line agent using the Kaplan-Meier method and the log-rank test. Time to CRPC was examined in two cohorts: a full-period cohort and a post-approval cohort comprising patients who initiated treatment on or after the approval date of darolutamide plus docetaxel (February 24, 2023). In addition, for apalutamide and enzalutamide, time to CRPC was compared by starting dose (full dose vs. reduced-dose start) and by the presence or absence of on-treatment dose reduction. The first-line agents were enzalutamide in 8,254 patients (50%), abiraterone in 4,896 (30%), apalutamide in 2,318 (14%), and darolutamide in 951 (6%). Regarding dose reduction, the proportion of patients reducing the dose among standard-dose starters was highest for apalutamide (28%), versus 10% for enzalutamide, 12% for darolutamide, and 7% for abiraterone (log-rank P < 0.001). Apalutamide dose reductions were concentrated within the first 0–6 months. The proportion maintaining the standard dose as the final dose was only 52% for apalutamide, compared with 70–87% for the other agents. In contrast, switching was infrequent for all agents, with no significant difference among them (P = 0.060). Next, in the full-period cohort, the time to CRPC differed significantly among the agents (overall log-rank P < 0.001) and was longest for apalutamide; the same ordering was observed in the post-approval cohort, in which all four agents were simultaneously available ( P < 0.001). Of note, apalutamide had the highest proportion of censoring (76% in the full-period and 90% in the post-approval cohort), and follow-up was uneven across agents. With respect to dose, apalutamide showed no significant difference in time to CRPC by either starting dose or the presence or absence of on-treatment reduction (starting dose P = 0.74; 6-month landmark P = 0.12). Enzalutamide showed a difference by starting dose ( P < 0.001) but no difference by the presence or absence of on-treatment reduction (landmark P = 0.72). Because the four agents are prescribed to different patient populations under Japanese reimbursement rules, these between-agent differences are descriptive and are not efficacy comparisons. This study evaluated the continuation and dose-reduction patterns of various ARPIs as first-line treatment for CSPC. It also evaluated the association between dose reduction and time to CRPC.