Darolutamide: Will it redefine the initial treatment strategy in metastatic prostate cancer?

  For many years, metastatic castration-sensitive prostate cancer (mCSPC) was treated exclusively with androgen deprivation therapy (ADT). However, recent therapeutic advances have led to the emergence of combination strategies, particularly those involving androgen receptor signaling inhibitors (ARSi). Among these agents, darolutamide, already validated in non-metastatic castration-resistant prostate cancer, has gained increasing attention for earlier use in treatment. The ARANOTE study, recently published, assessed the efficacy of darolutamide combined with ADT compared with ADT alone in patients with mCSPC who had not received prior chemotherapy, addressing a clinical gap left by major trials such as ARASENS.   Darolutamide + ADT: a sufficient alternative without chemotherapy? The ARANOTE study was a phase III, multicenter, randomized, double-blind trial that enrolled 553 chemotherapy-naïve patients with mCSPC. Participants were randomized to receive darolutamide plus ADT or placebo plus ADT. Most patients presented with high-volume disease according to CHAARTED criteria (72%), and 70% had de novo metastatic disease. The primary endpoint, radiographic progression-free survival (rPFS), was achieved, showing a 55% reduction in the risk of progression or death in the darolutamide arm (HR = 0.45; 95% CI: 0.34–0.59; p < 0.001). At 12 months, 87.8% of patients treated with darolutamide remained progression-free, compared with 72.7% in the placebo group. Overall survival (OS) at 12 months was high in both groups, reaching 96.9% with darolutamide versus 93.2% with placebo. Although the OS data are still immature, a favorable trend was observed for darolutamide. In terms of safety, grade ≥3 adverse events occurred at similar rates in both arms (25.4% versus 25.7%). The most common adverse events were fatigue, hypertension, and musculoskeletal pain. No new safety signals emerged, and the safety profile of darolutamide remained favorable, particularly regarding neurological effects, due to its low blood–brain barrier penetration. When compared with the ARASENS study (ADT plus darolutamide and docetaxel), ARANOTE targeted a distinct population—patients without an initial indication for chemotherapy. This design offers a chemotherapy-free alternative that combines proven clinical efficacy with improved tolerability.   Can chemotherapy now be avoided upfront? The ARANOTE results position darolutamide combined with ADT as a robust first-line therapeutic option for mCSPC, particularly for patients ineligible for or unwilling to receive docetaxel. The objective of maintaining efficacy comparable to triplet therapy while improving tolerability appears to have been achieved. This strategy may redefine the therapeutic paradigm, especially in patients with low-volume metastatic disease or those considered fragile. Future studies will need to refine stratification criteria to determine which patients derive the greatest benefit from darolutamide combination therapy and whether response biomarkers can be integrated to personalize treatment further. Darolutamide’s position within the therapeutic arsenal for mCSPC is strengthening. Yet, the key question remains: can chemotherapy now be safely omitted at diagnosis for certain patients while ensuring durable disease control?