Re: Mandel P, Wenzel M, Chun F, et al. Role of Local Treatment to the Prostate in Patients with De Novo Low-volume Metastatic Hormone-sensitive Prostate Cancer Receiving Androgen Receptor Pathway Inhibitors. Eur Urol Open Sci 2026;87:16–24

We read Mandel et al with great interest. Their multinational ARON-3 analysis is timely, as the role of prostate-directed local treatment (LT) in men receiving androgen receptor pathway inhibitor (ARPI)-based therapy for de novo low-volume metastatic hormone-sensitive prostate cancer remains clinically unsettled [1]. The observed association between LT and longer overall survival is provocative, particularly in light of prior evidence from STAMPEDE and PEACE-1 [2], [3].

The most clinically useful next step, however, may not be another broad question of LT yes versus no, but defining the biologic state in which LT is being delivered. In Table 1 of Mandel's referenced manuscript, patients undergoing LT had markedly lower baseline prostate-specific antigen (PSA) than those who were not undergoing LT, alongside fewer bone-metastatic presentations and greater use of apalutamide. Although the authors adjusted for prespecified covariates, this numerical pattern has bedside meaning: clinicians usually offer prostate-directed therapy not merely to low-volume patients but to patients in whom systemic disease appears controllable. Because the investigators collected PSA response during treatment, an analysis anchored on early PSA kinetics, such as PSA decline or nadir before or within the 6-mo landmark, could distinguish whether LT benefit is retained among patients with suboptimal systemic response. Such an analysis would make the result more actionable than a volume-based definition alone, especially because Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) low-volume disease still includes biologically heterogeneous M1a-only and bone-metastatic states [4].

A second issue concerns the clinical interpretation of time on treatment (ToT). In this cohort, ToT favored LT less strongly than overall survival, whereas first-line progression was similar between groups. Since ToT can end because of radiographic progression, toxicity, patient preference, physician sequencing, access, or frailty, it may mix biological failure with treatment-management decisions. Reporting cause-specific ARPI discontinuation, castration resistance-free survival, and the proportion of patients requiring subsequent systemic therapy before 24 or 36 mo would help clarify whether LT delayed systemic escape or mainly selected patients already destined to remain on ARPI longer. This distinction matters because PEACE-1 showed gains in radiographic progression-free and castration resistance-free survival with prostate radiotherapy, but not a clear overall survival advantage in low-volume disease [3], whereas the present survival signal is strikingly large.

Finally, the study would be strengthened by separating oncologic control from local-palliation value. Local events, including urinary obstruction, hematuria, catheterization, transurethral intervention, or pelvic pain requiring treatment, are often what patients and clinicians weigh when deciding whether to add prostate-directed therapy to ARPI. STAMPEDE established that prostate radiotherapy can be beneficial in low-burden disease [2], and smaller radical local therapy trials have supported a cytoreductive rationale [5], but the real-world decision increasingly depends on identifying patients whose systemic response and local-risk profile justify treatment intensification.

Mandel et al therefore provide an important dataset. A response-conditioned and end point-decomposed analysis would help convert this association into a more clinically interpretable framework for discussing LT with patients receiving ARPI-based therapy.



Conflicts of interest: The authors have nothing to disclose.