First-line treatment for metastatic hormone-sensitive prostate cancer (mHSPC) has been established as dual therapy including androgen-deprivation therapy (ADT) and second-generation androgen receptor inhibitors (ARIs). Recently, triplet therapies incorporating ADT, Docetaxel and ARIs with Darolutamide or Abiraterone have shown the potential to improve clinical outcomes. However, the effectiveness and safety of separated regimen of ARI in triplet therapies remain a question in urology oncology, without randomized study to compare different regimens head to head. We therefore emulated the hypothetical target clinical trial to compare Darolutamide with Abiraterone in the triplet therapy for mHSPC.

We conducted a retrospective cohort study using the TriNetx database from 2021-2025 to emulate a target population as ARASEN study. To reduce potential bias in baseline characteristics, we employed Propensity score (PS) 1:1 matched analysis based on important prognostic variables to create comparable treatment groups. The primary outcomes were overall survival (OS) and time to mCRPC(metastatic castration resistant prostate cancer). Secondary outcomes include time to PSA progression, time to skeletal adverse event, time to pain progression, time to subsequent therapy and adverse event between the two patient groups.

A total of 2,396 mHSPC patients in the database received one of the two triplet therapies. After PS matching, 1,648 patients were included in each treatment group. With a median follow-up of one year, the Darolutamide group demonstrated significantly improved overall survival compared to the Abiraterone group (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.21–0.92). The Darolutamide group also exhibited a significantly longer time to mCRPC (HR 0.39, 95% CI 0.25–0.62), time to PSA progression (HR 0.64, 95% CI 0.54–0.77), and time to subsequent therapy (HR 0.36, 95% CI 0.26–0.48), with a lower incidence of adverse events (p < 0.0001) compared to the Abiraterone group. No significant differences were observed between the two groups in time to skeletal adverse events, time to pain progression (opioid use), or incidence of major adverse cardiac events (MACE).

This real-world study using propensity score matching suggests that, for patients with mHSPC, first-line treatment with Darolutamide + ADT + docetaxel may be associated with better overall survival, longer time to mCRPC, delayed PSA progression, longer time to subsequent therapy, and fewer adverse events compared to Abiraterone + ADT + docetaxel. These findings provide valuable real-world evidence to guide clinical decision-making in triplet therapy selection for mHSPC. However, given the retrospective nature of this study, further validation through prospective trials is necessary.