Darolutamide, undetectable PSA, and prolonged survival: a new standard in prostate cancer treatment?

Oncology

Metastatic hormone-sensitive prostate cancer (mHSPC) is undergoing a therapeutic revolution with the introduction of intensified combination regimens incorporating darolutamide. The ARASENS study, which demonstrated a survival benefit with the addition of darolutamide to androgen deprivation therapy (ADT) and docetaxel, has redefined the standard of care. However, a biological endpoint deserves particular attention: achieving undetectable prostate-specific antigen (PSA) levels — a well-known marker that has rarely been used as a major predictive criterion. This secondary analysis of the ARASENS trial evaluated the depth and durability of PSA responses according to tumor volume and their correlation with clinical outcomes, including overall survival (OS). Is an undetectable PSA response a new prognostic marker? The analysis included 1305 patients from the ARASENS trial (ADT + docetaxel ± darolutamide), stratified by tumor volume (high or low) as defined by the CHAARTED criteria. The main objective of this secondary analysis was to assess the proportion of patients achieving a deep PSA response (≤0.2 ng/mL) at 12 months and its prognostic impact. The results are clear: 86% of patients treated with darolutamide achieved a PSA response, compared with 77% in the placebo arm. The proportion of patients reaching PSA ≤0.2 ng/mL at 12 months was significantly higher in the darolutamide arm (59.1% vs 40.3%; p < 0.0001), and this benefit was observed regardless of tumor volume.

In high-volume disease, 53.5% of darolutamide-treated patients achieved PSA ≤0.2 ng/mL at 12 months, compared with 35.1% in the placebo arm.
In low-volume disease, the difference was even more striking: 71.5% vs 53.4%.

Achieving undetectable PSA at 12 months was strongly associated with improved overall survival and prolonged radiographic progression-free survival (rPFS). Patients who achieved PSA ≤0.2 ng/mL at 12 months had a 63% reduced risk of death (HR = 0.37) across all treatment groups. These findings confirm the prognostic value of the biological response and underscore the relevance of PSA monitoring as an early indicator of therapeutic efficacy. In terms of safety, this analysis identified no new safety signals with the addition of darolutamide. Adverse events were comparable between groups and consistent with the original ARASENS results. Will PSA response guide future treatment strategies? The secondary analysis of ARASENS demonstrates that adding darolutamide to ADT + docetaxel results in a significant and durable reduction in PSA levels, independent of tumor volume. Moreover, achieving a PSA ≤0.2 ng/mL at 12 months is strongly correlated with prolonged survival, establishing this marker as a promising response criterion for guiding future therapeutic decisions. These findings suggest that undetectable PSA could become an intermediate treatment goal to stratify patients, tailor therapy intensity, or even explore de-escalation strategies. This approach would enable a more individualized management of mHSPC, integrating precise biological data beyond traditional clinical parameters (volume, risk, etc.). Prospective studies are needed to validate PSA as a decision-making biomarker, particularly in the context of new triplet regimens or targeted therapies. This strategy paves the way for precision oncology, where biological response dynamics guide treatment intensity — ultimately improving both outcomes and patients’ quality of life.

Source(s) :
Saad F, et al. Deep and Durable Prostate-specific Antigen Response to Darolutamide with Androgen Deprivation Therapy and Docetaxel, and Association with Clinical Outcomes […] : Analyses of the Randomized Phase 3 ARASENS Study. European Urology. 2024. ;

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