Unpacking prostate-specific antigen dynamics and patient outcomes: insights from the ARASENS trial
Editorial Commentary

Unpacking prostate-specific antigen dynamics and patient outcomes: insights from the ARASENS trial

Hayley Nicole Roberts1 ORCID logo, Corinne Maurice-Dror1,2, Kim Nguyen Chi1,2

1British Columbia Cancer Agency, Vancouver, British Columbia, Canada; 2University of British Columbia, Vancouver, British Columbia, Canada

Correspondence to: Kim Nguyen Chi, MD, FRCP(C), BSc. British Columbia Cancer Agency, 600 W 10th Ave., Vancouver, British Columbia, Canada; University of British Columbia, Vancouver, British Columbia, Canada. Email: kchi@bccancer.bc.ca.

Comment on: Saad F, Hussain MHA, Tombal B, et al. Deep and Durable Prostate-specific Antigen Response to Darolutamide with Androgen Deprivation Therapy and Docetaxel, and Association with Clinical Outcomes for Patients with High- or Low-volume Metastatic Hormone-sensitive Prostate Cancer: Analyses of the Randomized Phase 3 ARASENS Study. Eur Urol 2024;86:329-39.

Keywords: Metastatic castration-sensitive prostate cancer; prostate-specific antigen (PSA); darolutamide

Received: 26 August 2024; Accepted: 09 December 2024; Published online: 21 February 2025.

doi: 10.21037/actr-24-168

The management of metastatic hormone-sensitive prostate cancer (mHSPC) has undergone significant advancements with the advent of intensified androgen deprivation therapy (ADT) strategies. The TITAN, LATITUDE, STAMPEDE, ENZAMET, ARCHES and ARANOTE trials illustrated the benefits of combining ADT with next generation androgen receptor blockade with androgen receptor pathway inhibitors (ARPI) (1-6). More recently, the PEACE-1 and ARASENS trials demonstrated the overall survival (OS) benefit of adding an ARPI to ADT plus docetaxel in a triplet therapy approach (7,8). The concept of achieving “undetectable” prostate-specific antigen (PSA) levels as a prognostic marker was originally introduced in the INT-0162 trial, which randomised mHSPC patients to intermittent or continuous ADT after 7 months of treatment (9). This trial, run in the 1990s, showed that reaching a PSA of ≤0.2 at 6 to 7 months has a strong positive association with OS. PSA nadir has since been explored as both an intermediate clinical outcome and a prognostic biomarker in several ADT intensification trials, most recently in the ARASENS cohort.

ARASENS, an international, double-blind, phase 3 study, evaluated the addition of darolutamide, an ARPI, to ADT and docetaxel in mHSPC patients (8). As previously reported, the ARASENS trial demonstrated a significant improvement in OS with darolutamide, showing a hazard ratio (HR) of 0.68 [95% confidence interval (CI): 0.57 to 0.80; P<0.001] (8). This builds on the OS benefit seen with addition of docetaxel to ADT in the STAMPEDE and CHAARTED trials (10,11). Questions remain as to what the benefit of adding docetaxel is to combination ADT + ARPI, which has not been tested in a prospective randomized manner, and also which patients stand to benefit most from triplet therapy, with many clinicians reserving the addition of docetaxel to ARPI and ADT for patients with poor-prognosis high volume disease (12-17).

Post hoc analysis of PSA kinetics within the ARASENS study highlights the association between “undetectable” PSA and longer OS, delayed time to castration-resistant prostate cancer (CRPC), and prolonged time to PSA progression (18). Notably, patients on darolutamide who reached a PSA of <0.2 ng/mL at 36 weeks had a 3-year OS rate of 79% compared to 47% for those with a PSA of ≥0.2 ng/mL, reflecting a significant survival advantage. This association persisted across both treatment arms, suggesting the prognostic value of reaching an undetectable PSA.

The prespecified exploratory analyses within the ARASENS study underscore the substantial impact of darolutamide on prostate cancer control. The proportion of patients ever achieving PSA <0.2 ng/mL was more than doubled with the addition of darolutamide (67%) compared to placebo (29%). This effect was evident at 24 and 36 weeks, with similar trends observed across both high and low-volume disease subgroups. Darolutamide also significantly delayed the time to PSA progression, indicating that the PSA response was durable.

The ARASENS findings align with similar analyses from other trials, such as CHAARTED, LATITUDE, TITAN, ENZAMET and PEACE-1 supporting that the depth and duration of PSA response are important indicators of treatment efficacy and prognosis (19-24). Despite heterogeneity across studies, the results consistently demonstrate that deep PSA responses are more likely with ADT intensification than with ADT alone, and also indicative of better clinical outcomes.

Comparing PSA nadir analyses across different trials is fraught due to several factors: differing eligibility criteria (for example LATITUDE only enrolled patients with high-risk disease), variable duration of exposure to ADT prior to treatment intensification across trials (ranging from 3 to 6 months), different PSA nadir threshold among trials, and differing timing of PSA nadir assessment. Nevertheless, across all trials the effect of incorporating ARPI with ADT +/− docetaxel is remarkably consistent on the proportion of patients achieving a PSA ≤0.2 (see Table 1).

Table 1

mCSPC ADT intensification trials reporting on PSA nadir as outcome and prognostic biomarker

Paper Intervention Control “Undetectable” PSA definition (ng/mL) “Undetectable” PSA timeframe Proportion of patients reaching “undetectable” PSA in intervention arm (%) Proportion of patients reaching “undetectable” PSA in control arm (%) HR for OS
ARASENS (18) Darolutamide + ADT + docetaxel Placebo + ADT + docetaxel <0.2 At any time 67 29 0.49†; 0.36‡
CHAARTED (19) Docetaxel + ADT ADT alone ≤0.2 At 7 months 45 29 0.18
LATITUDE (20) AAP + ADT Placebo + ADT <0.2 At 12 months 55 9 0.26§
TITAN (21,24) Apalutamide + ADT Placebo + ADT ≤0.2 By 12 months 64 23 0.22†,¶
ENZAMET (22) Enzalutamide + ADT +/− docetaxel ADT + NSAA +/− docetaxel ≤0.2 At 7 months 67 48 Not reported^
PEACE-1 (23) AAP + ADT +/− docetaxel ADT +/− docetaxel ≤0.2 At 8 months 54 25 Not reported^

Multiple landmark timepoints reported for each trial. Latest timepoint chosen in each study. †, hazard ratio reported for intervention arm; ‡, hazard ratio reported for control arm; §, hazard ratio reported for the outcome of reaching PSA <0.1 (rather than 0.2) at 12 months; , hazard ratio reported for composite measure called “deep PSA decline”, defined as PSA decline by 90% and/or reaching PSA ≤0.2, at 12 months; ^, hazard ratio not available in published abstract, but statistically significant benefit reported for this clinical outcome. mCSPC, metastatic castration-sensitive prostate cancer; ADT, androgen deprivation therapy; PSA, prostate-specific antigen; AAP, abiraterone acetate and prednisone; NSAA, non-steroidal antiandrogen; HR, hazard ratio; OS, overall survival.

The concept of achieving an “undetectable” PSA potentially provides a more immediate measure of treatment success compared to longer-term endpoints like progression-free survival or OS. As an indicator of prognosis during treatment which is readily available in the clinical setting, it facilitates early identification of clinical benefit. For patients who do not achieve substantial PSA reductions, closer monitoring for progression becomes essential given the poor outcomes of these patients. The attainment of PSA ≤0.2 ng/mL is also a potential intermediate endpoint in clinical trials. However, caution should be used when interpreting PSA nadir as an endpoint for non-AR targeting drugs: the proportion of patients that achieve a PSA ≤0.2 in the triplet therapy intervention arms of the PEACE-1 and ARASENS trials does not appear to be substantially higher than those in other trials receiving ARPI + ADT doublet therapy (see Table 1). This suggests that docetaxel may not be adding to the proportion of patients achieving a low PSA nadir, with the caveat that the benefit from adding docetaxel to ADT + ARPI remains undefined.

The aforementioned landmark trials all combined ARPIs with ADT given continuously until evidence of castration resistance, with implications for cumulative toxicity, health-related quality of life and financial impacts. Given that many patients diagnosed with mCSPC have prolonged OS, but a minority have rapidly progressive disease, identification of a predictive biomarker to enable personalizing treatment is a priority. Ongoing and future trials are exploring the clinical utility of PSA kinetics as a predictive biomarker in guiding treatment decision, including de-escalation and escalation strategies. Trials such as A-DREAM (NCT05241860) (25), LIBERTAS (NCT05884398) (26) and EORTC 2238 De-escalate (NCT05974774) (27) are investigating treatment interruption and intermittent therapy based on achieving undetectable PSA, aiming to reduce treatment burden while maintaining efficacy. Conversely, studies such as PR26 TRIPLE-SWITCH (NCT06592924) (28) are assessing further intensification for patients with inadequate PSA responses.

In conclusion, the ARASENS trial and the recent analysis of PSA declines reinforces the benefit of adding darolutamide to ADT and docetaxel, particularly in achieving deeper PSA responses. These responses are strongly associated with improved clinical outcomes across all treatment intensification trials, supporting the use of PSA nadir as a key prognostic biomarker for both clinical practice and research.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-168/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-168/coif). C.M.D. reports consulting fees from Biomica, payments or honoraria from Pfizer, Janssen, Merck, and Eisai, support for attending meetings and/or travel from Janssen, and GlaxoSmithKline. K.N.C. reports grants from Amgen, AstraZeneca, Janssen, Novartis, Point Biopharma, Bayer, and Roche, consulting fees from Amgen, Astellas, AstraZeneca, BMS, Janssen, Merck, Novartis, Pfizer, Point Biopharma, and Roche, payments or honoraria from Astellas, and Janssen. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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doi: 10.21037/actr-24-168
Cite this article as: Roberts HN, Maurice-Dror C, Chi KN. Unpacking prostate-specific antigen dynamics and patient outcomes: insights from the ARASENS trial. AME Clin Trials Rev 2025;3:10.

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