A new analysis presented at the 2025 American Urological Association Annual Meeting in Boston has revealed that a combination of darolutamide and androgen-deprivation therapy (ADT) significantly boosts ultra-low prostate-specific antigen (PSA) responses in men with metastatic hormone-sensitive prostate cancer (mHSPC), offering a promising new approach to delay disease progression.

NOTE: there is no randomized clinical trial that compared darolutamide to other ARSi therapies (like enzalutamide, apalutamide,…).

The findings, drawn from the phase 3 ARANOTE trial, show that this treatment achieves PSA levels below 0.02 ng/mL—considered an ultra-low threshold—far more frequently than ADT alone, leading to longer periods without cancer progression.

The ARANOTE trial involved 669 men with mHSPC, randomly assigned to receive either darolutamide (600 mg twice daily) alongside ADT or a placebo with ADT. Researchers tracked radiographic progression-free survival as the primary goal, alongside secondary measures like overall survival and time to PSA progression or metastatic castration-resistant prostate cancer (mCRPC). The post hoc analysis focused on ultra-low PSA responses and their link to clinical outcomes, examining patients across three baseline PSA groups: below 4.1 ng/mL, 4.1 to under 21.3 ng/mL, and 21.3 ng/mL or higher.
Results were striking. Men receiving darolutamide plus ADT achieved ultra-low PSA levels at much higher rates than those on ADT alone, with benefits seen at 24, 36, and 48 weeks. For those with the highest baseline PSA (≥21.3 ng/mL), 30.5% reached ultra-low PSA at some point, compared to under 2% in the placebo group. These ultra-low PSA levels were tied to significant clinical advantages, including a 91% reduced risk of radiological progression or death for those achieving PSA below 0.02 ng/mL, and a 59% risk reduction for those with PSA between 0.02 and 0.2 ng/mL. Overall, the combination therapy tripled the rate of undetectable PSA (below 0.2 ng/mL) compared to ADT alone, reaching 62.6% versus 18.5%.
Importantly, the treatment was well-tolerated. Side effects were comparable between the darolutamide and placebo groups, with fewer patients stopping darolutamide (6.1%) than placebo (9%) due to adverse events. This favorable safety profile supports the therapy’s potential for long-term use, a critical factor for men managing mHSPC, a disease where cancer grows despite hormone-suppressing treatments.
The implications are profound for mHSPC patients, who face limited options as their disease progresses. Achieving ultra-low PSA levels is emerging as a key indicator of better disease control, delaying the onset of more aggressive mCRPC. By offering a chemotherapy-free regimen, darolutamide plus ADT addresses a pressing need for effective, tolerable treatments. Researchers emphasized that these findings position the combination as a potential new standard of care, with ongoing studies set to explore how ultra-low PSA responses can shape future treatment plans.

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