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Darolutamide Improved Survival in Phase 3 Trials for Patients With Metastatic Hormone-Sensitive Prostate Cancer
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Key Takeaways
- Darolutamide combined with SOC therapies significantly improves progression-free and overall survival in mHSPC patients, as shown in ARANOTE and ARASENS trials.
- The ARANOTE trial demonstrated darolutamide's superior efficacy in both high and low disease volume subgroups, reducing radiological progression or death risk.
The data were presented at the 2025 ASCO Genitourinary Cancers Symposium in San Francisco, California.
Darolutamide (Nubeqa, Bayer) in conjunction with standard of care (SOC) therapy showed clinically significant increases in progression-free survival (PFS), overall survival (OS), tolerability, and safety for patients with metastatic hormone-sensitive prostate cancer (mHSPC). The data from the phase 3 ARANOTE (NCT04736199) and ARASENS trials (NCT02799602) were presented at the 2025 ASCO Genitourinary Cancers Symposium.1,2
Conceptual image of prostate cancer cells | Image Credit: © Dr_Microbe - stock.adobe.com
The SOC treatment for patients with mHSPC has traditionally been monotherapy androgen deprivation therapy (ADT) or ADT and docetaxel, which blocks the production of androgens by the testicles. However, emerging studies over the past decade have revealed the superior clinical benefit of adding other agents, such as docetaxel (Docefrez; Bayer HealthCare Pharmaceuticals Inc) or darolutamide, significantly improved PFS and OS for patients.3
Darolutamide is a hormone therapy that has been FDA-approved as a monotherapy and in combination with docetaxel. In 2019, it was approved as a monotherapy for patients with non-metastatic castration-resistant prostate cancer. This was followed by darolutamide’s approval for use in combination with docetaxel for patients with mHSPC. Continued studies have begun to explore the potential addition of darolutamide to the SOC treatment.3-5
ARANOTE
In the randomized, double-blind, placebo-controlled phase 3 ARANOTE study, researchers assessed the safety and efficacy of darolutamide in combination with ADT in 699 patients with mHSPC. They were randomized 2:1 to receive either 600 mg twice daily of darolutamide plus ADT or placebo and ADT. The researchers used the CHAARTED criteria to characterize the trial participants as either high volume (HV; n = darolutamide n = 315; placebo n = 157) or love volume (LV; darolutamide n = 131; placebo n = 66) disease.6
The primary end point was radiological progression-free survival (rPFS), with secondary endpoints of time to metastatic castration-resistant prostate cancer (mCRPC), time to prostate-specific antigen (PSA) progression, and safety.6
Darolutamide plus ADT significantly improved rPFS, reducing the risk of progression or death by 46%, according to the trial data. Superior prognostic variables were seen in individuals with LV disease (e.g., lower baseline median PSA levels, a higher number of patients with ECOG PS 0, Gleason <8, and prior local therapy). In all the HV and LV subgroups, darolutamide plus ADT outperformed placebo plus ADT in terms of rPFS. With neither group reaching the median rPFS, the darolutamide combination decreased the risk of radiographic progression or mortality in the LV subgroup by 70% (HR 0.30; 95% CI: 0.15–0.60).6
ADT on block letters | Image Credit: © photoopus - stock.adobe.com
“Consistent with the overall population, darolutamide plus ADT improved rPFS versus placebo plus ADT in both the high-volume and low-volume subgroups, with a larger treatment effect in the low-volume subgroup,” explained Fred Saad, MD, FRCS from the Centre Hospitalier de l'Université de Montréal, Université de Montréal, in his presentation. “Darolutamide plus ADT reduced the risk of radiological progression or death by 40% in the high-volume subgroup and by 70% in the low-volume subgroup.”6
For the secondary end points, a greater percentage of the HV and LV subgroups achieved PSA <0.2 ng/mL with darolutamide compared to placebo (HV: 54.6% vs 15.5%; LV: 82.6% vs 25.4%), and darolutamide delayed time to mCRPC (HV: HR 0.46; 95% CI: 0.36–0.60; LV: HR 0.21; 95% CI: 0.12–0.37) and time to PSA progression (HV: HR 0.34; 95% CI: 0.25–0.46; LV: HR 0.19; 95% CI: 0.10–0.37). Overall survival results were immature but suggestive of a benefit with darolutamide versus placebo.6
At any time, the incidence of treatment-emergent adverse events (TEAEs) was similar between treatment arms across HV and LV subgroups. The LV subgroup experienced lower rates of fatigue and treatment discontinuations as a result of TEAEs with darolutamide compared to placebo: 2.3% vs. 13.8% and 3.1% vs. 10.8%, respectively.6
“In conclusion, efficacy outcomes with darolutamide plus ADT were improved versus placebo plus ADT, regardless of disease volume,” said Saad. “Darolutamide plus ADT was well tolerated in both high-volume and low-volume subgroups, with low treatment discontinuation rates, consistent with the overall population, and reconfirming the established tolerability of darolutamide.”6
ARASENS
ARASENS is a phase 3 randomized, double-blind, placebo-controlled, multicenter trial evaluating darolutamide plus SOC ADT and docetaxel in 1305 patients with mHSPC who were randomized to receive darolutamide 600 mg orally twice daily (n = 651) or placebo (n = 654), with ADT and docetaxel. The relative dosage intensity (RDI) of docetaxel was used to examine baseline patient characteristics, G-CSF use, safety, overall survival, and time to prostate-specific antigen (PSA) progression. All treatment groups had similar baseline characteristics, except for regional distribution.7
“More than 97% of patients received an efficacious dose of docetaxel, defined as an RDI greater than 80%, with over 80% receiving an RDI greater than 85%,” explained Michael Ong, MD, BSc, FRCPC, from the Ottawa Hospital Cancer Centre, in his poster presentation. “This indicates that darolutamide did not affect docetaxel dose intensity.”7
In 63% of the trial participants, docetaxel dose adjustments were necessary, and 44% needed G-CSF. Compared to 37% of patients without dose modifications, 47% of patients with dose modifications needed G-CSF. This suggests that docetaxel dosage adjustments, with or without G-CSF, can maximize the triplet regimen's delivery in both the general population and the Asia-Pacific region.7
Molecular model of docetaxel | Image Credit: © Alexey Novikov - stock.adobe.com
For both cohorts, OS and time to PSA progression were comparable across RDI cycles. The placebo arm's median OS was 46 months in the lower RDI subgroup compared to the higher RDI subgroup, while the darolutamide treatment arm's median was not attained for either of the RDI subgroups. The median time to PSA progression in the placebo arm was 22 months, compared with 19 months for the lower versus higher RDI subgroups. However, it was not reached for either of the RDI subgroups in the darolutamide arm.7
The lower RDI subgroup had higher rates of grade 3 or 4 TEAEs, including neutropenia and febrile neutropenia, and treatment-emergent adverse events (TEAEs) that resulted in docetaxel dose changes. Seldom was febrile agranulocytosis seen. All groups had low rates of docetaxel discontinuation (greater than or equal to 85%: DARO 7%, PBO 11%; greater than 85%: darolutamide 8%, placebo 11%), suggesting that darolutamide had no influence on docetaxel tolerance and that proper use of G-CSF enabled efficient docetaxel delivery.7
These results underscore darolutamide’s role in improving treatment outcomes for patients with mHSPC without compromising quality of life,” Ong concluded. “The combination of darolutamide with standard treatments offers a well-tolerated, efficacious option that delays disease progression and improves survival, making it a promising addition to the therapeutic landscape for this challenging disease.”7
The ARANOTE and ARASENS phase 3 trials provide compelling evidence supporting the addition of darolutamide to SOC therapies for patients with mHSPC. Both trials demonstrated that the combination of darolutamide with ADT or ADT plus docetaxel significantly improved PFS and OS, showcasing darolutamide’s potential to become a cornerstone treatment for this patient population. As further data emerges, darolutamide may become a key player in the management of mHSPC.
