3-weekly docetaxel 75 mg/m 2 vs 2-weekly docetaxel 50 mg/m 2 in combination with darolutamide + ADT in patients with mHSPC: Subgroup analyses from the randomised phase 3 ARASAFE trial.

153 Background: Triple therapy with androgen deprivation therapy (ADT), darolutamide (DARO), and docetaxel (DOCE) is approved for metastatic hormone-sensitive prostate cancer (mHSPC). DARO triple therapy with DOCE 50 mg/m² Q2W is hypothesized to reduce grade 3-5 adverse events (AEs) vs standard 75 mg/m² Q3W. Methods: In this academic, randomized, open-label, multicenter phase 3 trial (NCT05676203), 250 men with mHSPC were randomized 1:1 (JUN 2023 – DEC 2024) to receive ADT, DARO, and 6 cycles of DOCE 75 mg/m 2 Q3W (3-week cycle; D75) or 50 mg/m² Q2W (4-week cycle; D50). Primary objective was to compare grade 3-5 AE rates 26 weeks after last patient first DOCE dose (LPFD) in the safety population, followed by the rate of grade 3/4 neutropenia or death from any cause (NAER) as secondary safety variable. We herein report primary endpoint data of pre-specified subgroups. Results: In the safety population, 128 patients received DOCE in the D75 arm and 121 in the D50 arm. ARASAFE met its primary endpoint (rate of grade 3-5 AEs p=0.0024; NAER p<0.00001, previously published). The benefits in favor of D50 were maintained across all subgroups and independent of extent of disease (low vs high volume), ALP levels (< vs ≥ upper limit of normal ULN), age (< vs ≥ median 68 years, see table), ECOG performance status at study entry (0 vs 1, see table), baseline PSA (< vs ≥ median), Gleason score at study entry (<8 vs ≥8), and presence of metastases at primary diagnosis ( de novo vs metachronous metastatic disease). The PSA response rate (PSA≤0.2 ng/ml, 26 weeks after LFPD) was higher in D75 (48.8% vs. 41.3%), the 1 year post-LPFD rate will be available at the time of presentation. Conclusions: The benefits of the D50 approach in reducing grade 3-5 AE rate and NAER (primary endpoints) were independent of patients' age and performance status, as well as of surrogate markers of tumor load. The ARASAFE approach (D50) may therefore represent a potential new standard of care for triple therapy across all mHPSC subgroups. Further follow-up is ongoing to determine its efficacy in terms of oncological outcomes. Clinical trial information: NCT05676203 (and EU CT number: 2022-502634-52-00) . Primary endpoint parameters per age and ECOG subgroups. Outcome parameter Characteristic Subgroup D75: N D75: Rate (95% CI), % D50: N D50: Rate (95% CI), % High grade (3-5) adverse events Age <68 yrs* 60 76.7 (64.0, 86.6) 61 55.7 (42.4, 68.5) ≥68 yrs* 68 80.9 (69.5, 89.4) 60 66.7 (53.3, 78.3) ECOG 0 100 77.0 (67.5, 84.8) 105 58.1 (48.1, 67.7) 1 28 85.7 (67.3, 96.0) 16 81.2 (54.4, 96.0) High grade (3-4) neutropenia or death Age <68 yrs* 60 60.0 (46.5, 72.4) 61 18.0 (9.4, 30.0) ≥68 yrs* 68 67.6 (55.2, 78.5) 60 30.0 (18.8, 43.2) ECOG 0 100 65.0 (54.8, 74.3) 105 22.9 (15.2, 32.1) 1 28 60.7 (40.6, 78.5) 16