ARASEC: Darolutamide plus ADT reduces progression risk in mHSPC

Darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) demonstrated statistically significant improvements in progression-free survival (PFS), overall survival (OS), and prostate-specific antigen (PSA) response rates compared with ADT alone in US patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to results from the phase 2 ARASEC trial (NCT05059236) presented at the 2026 American Urological Association (AUA) Annual Meeting in Washington, DC.¹

Background and study design

Darolutamide carries FDA and European Medicines Agency approval for mHSPC based on the global phase 3 ARANOTE study (NCT04736199), in which darolutamide significantly improved radiological PFS (rPFS) vs placebo (HR 0.54; 95% CI 0.41–0.71; P <.0001).² By 2020, the treatment landscape for mHSPC had undergone a rapid evolution, with combination therapy emerging as the standard of care. Data on darolutamide plus ADT were being requested in the US setting; however, as Rana R. McKay, MD, FASCO, noted during her presentation at AUA 2026, “An ADT control arm was really not possible in the US because ADT was no longer the standard of care.”

To address this gap, investigators designed ARASEC, a US open-label study that compared a prospectively enrolled darolutamide-plus-ADT arm against the ADT arm from the historic phase 3 CHAARTED trial (NCT00309985).³ Inclusion and exclusion criteria were aligned with those of CHAARTED, and the assessment schedule mirrored that trial. The primary end point was PFS, defined per CHAARTED.

Propensity score-matching methodology

To account for differences in baseline characteristics between arms, propensity scores were calculated from 6 key baseline criteria: age, ECOG performance status, extent of disease, prior local therapy, Gleason score, and baseline PSA level. Patients with similar propensity scores were then matched 1:1 between arms. In the primary analysis, propensity score matching identified 160 patients per arm with well-balanced baseline characteristics across all key variables. With respect to PSA, there was a slightly higher PSA in the ADT-alone arm (9.8 ng/mL) compared with 6.0 ng/mL in the darolutamide-plus-ADT arm.

US patients with mHSPC were enrolled to receive darolutamide 600 mg twice daily plus ADT (n = 223) and were matched 1:1 to patients in the CHAARTED ADT arm (n = 393). Secondary end points included OS, time to metastatic castration-resistant prostate cancer (mCRPC), rPFS, PSA less than 0.2 ng/mL response rates, and safety.

Primary and key secondary efficacy results

At the primary data cut-off (median follow-up: darolutamide arm, 26 months; ADT arm, 28 months), ARASEC met its primary end point. Darolutamide plus ADT significantly improved PFS vs ADT (HR 0.29; 95% CI 0.20–0.40; P <.001).¹

Darolutamide plus ADT also significantly improved OS vs ADT (HR 0.50; 95% CI 0.30–0.82; P = .003), a key secondary end point. The 24-month OS rates were 89% in the combination arm and 80% in the ADT arm. Notably, this OS benefit was achieved despite proportionately more patients in the ADT arm receiving subsequent life-prolonging therapies compared with the darolutamide arm (65% vs 26%, respectively).

Darolutamide plus ADT also significantly delayed time to mCRPC (HR 0.26; 95% CI 0.18–0.38; P <.001) and rPFS (HR 0.30; 95% CI 0.19–0.48; P <.001) vs ADT. PSA response rates favored the darolutamide arm at all time points: 59% vs 23% in the ADT arm achieved a PSA less than 0.2 ng/mL at 6 months (P < .001), and 68% vs 33%, respectively, at any time on study (P <.001).

Sensitivity analyses

Two prespecified sensitivity analyses were conducted to address the limitations of the trial design. The first compared the darolutamide arm with the contemporary ARANOTE ADT arm using the same propensity score matching as the primary analysis. In this sensitivity analysis, darolutamide plus ADT prolonged PFS (HR 0.30; 95% CI 0.21–0.44) and OS (HR 0.55) vs ADT, with all confidence intervals for the primary and key secondary end points falling below 1.

The second sensitivity analysis included all match-eligible patients from ARASEC and CHAARTED, applying inverse probability of treatment weighting to adjust for baseline differences. This broader analysis also strongly supported the primary findings; the PFS HR in the ARASEC–CHAARTED match-eligible population was 0.28 (95% CI 0.23–0.33). All HRs for the primary and key secondary end points continued to favor the combination.

Safety

Safety data were not recorded in detail in the CHAARTED ADT arm, so safety comparisons were contextualized against the ARANOTE trial. In the darolutamide arm (n = 223), treatment-emergent adverse events were mostly grade 1 or 2 (58%) and led to discontinuation in 8% of patients, a rate McKay described as low. The overall frequency and severity of adverse events were generally similar to ADT alone.

Conclusions and implications

McKay emphasized the broader significance of ARASEC’s novel design: “This is the first study, to our knowledge, in prostate cancer that uses propensity score matching with external phase 3 trial control arms. This innovative approach really offers a potentially practice-changing paradigm to accelerate enrollment, enhance operational efficiency, and expedite patient access to emerging therapies in a rapidly evolving landscape.”

References

1. McKay R, Ross AE, Preston MA, et al. ARASEC: A novel pragmatic trial design comparing darolutamide plus ADT versus ADT in US patients with metastatic hormone-sensitive prostate cancer using propensity score matching with an external phase 3 trial control arm. J Urol. 2025;213(5S). doi:10.1097/01.JU.0001109788.ARASEC

2. Saad F, Efstathiou E, Attard G, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. Ann Oncol. 2024;42(36):4271-4281. doi:10.1200/JCO-24-01798.

3. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. doi:10.1056/NEJMoa1503747