Triple therapy with androgen deprivation therapy (ADT), darolutamide (daro), and docetaxel (doce) is approved for metastatic hormone-sensitive prostate cancer (mHSPC). The pivotal ARASENS trial (NCT02799602) used doce 75 mg/m2 Q3W. Daro triple therapy with doce 50 mg/m2 Q2W is hypothesized to reduce grade 3-5 adverse events (AEs) vs 75 mg/m2 Q3W.
In this academic, randomised, open-label, multicentre phase 3 trial (NCT05676203), 250 men with mHSPC were randomised 1:1 (JUN 2023 – DEC 2024) to receive ADT, daro, and 6 cycles of doce 75 mg/m2 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.
In the safety population, 128 patients received doce in the D75 arm and 121 in the D50 arm. Patient populations were well balanced between the two treatment arms (Table). Mean cumulative docetaxel doses were 842.8 mg for D75 (standard deviation ±181.7 mg) and 1073.5 mg (±240.4 mg) for D50, respectively. The study met its primary endpoints, demonstrating a significantly lower incidence of grade 3-5 AEs for D50 (D50: 61.2% [95% CI 51.9, 69.9] vs D75: 78.9% [70.8, 85.6]; p=0.0024). Also NAER was significantly reduced for D50 (D50: 24.0% [16.7, 32.6] vs D75: 64.1% [55.1, 72.3]; p<0.00001). At 26 weeks after LPFD, median PSA was 0.26 ng/ml (IQR 0.05, 1.55) and 0.16 ng/ml (0.03, 1.00) for D50 and D75, respectively. The PSA-response rate (PSA≤0.2 ng/ml) was higher in D75 (41.3% vs 48.8%).
| Docetaxel 75 mg/m2 Q3W, N=129 | Docetaxel 50 mg/m2 Q2W, N=121 | |
| Age, median (IQR), years | 68.0 (63.0, 74.0) | 67.0 (63.0, 73.0) |
| Metastases at primary diagnosis, n (%) | 102 (79.7) | 108 (89.3) |
| Metastasis pattern at study entry, n (%) | ||
| – Non-regional lymph node only | 1 (0.8) | 0 (0.0) |
| – Bone / non-visceral | 108 (83.7) | 107 (88.4) |
| – Visceral / other | 20 (15.5) | 14 (11.6) |
| High volume disease, n (%) | 108 (83.7) | 104 (86.0) |
| Alkaline phosphatase ≥ ULN, n (%) | 73 (56.6) | 73 (60.3) |
| Serum PSA, median (IQR), ng/ml | 12.2 (2.2, 75) | 14.7 (3.6, 57.7) |
ARASAFE demonstrates a statistically highly significant and clinically meaningful reduction in the incidence of grade 3-5 AE rate and NAER for the D50 approach, which may be considered a potential new standard of care. Further follow-up is ongoing to determine its efficacy in terms of oncological outcomes.
EU CT:2022-502634-52-00; NCT05676203.