Available online 12 March 2026

Author links open overlay panelMahtab Hamidikia a †, Tanja C. van Dijk a †, John W.M. Martens a, Khrystany T. Isebia a, Ronald de Wit a, Nick Beije aShow moreAbstract

Continuous treatment with an androgen receptor pathway inhibitor (ARPI) plus androgen deprivation therapy (ADT) in low-volume metastatic castration-sensitive prostate cancer (mCSPC) may lead to overtreatment, resulting in increased toxicity and higher costs. Evidence to guide a shorter duration of ARPI therapy is currently lacking. The Apa/Enza-short trial evaluates whether a 12-mo course of apalutamide or enzalutamide is noninferior to continuous treatment in low-volume mCSPC. This randomized, open-label, noninferiority study enrolls 400 patients across Dutch hospitals. After 12 mo of ADT + ARPI, eligible patients are randomized to continue or discontinue ARPI treatment, with reinitiation permitted upon prostate-specific antigen (PSA) increase. The primary end point is clinical progression-free survival (cPFS). If noninferiority is demonstrated, this strategy could maintain efficacy while reducing treatment-related toxicity and health care costs.

Introduction

Prostate cancer is a major cause of death worldwide [1], mostly due to complications of metastases [2]. Treatment of metastatic castration-sensitive prostate cancer (mCSPC) is nowadays intensified with androgen receptor pathway inhibitors (ARPI) plus androgen deprivation therapy (ADT), improving overall survival (OS) [3], [4]. However, prolonged ARPI exposure (median 39.3 in the TITAN study) increases toxicity, including higher risk of cardiovascular events, falls, fractures, and cognitive side effects [5], [6], [7], and higher costs for society. In low-volume metastatic disease (CHAARTED definition [8]), durable survival with enzalutamide and apalutamide (∼80% at 4 yr [3], [4]) suggests more indolent disease characteristics and potential overtreatment [8], [9], [10]. We hypothesized that dual targeting of the androgen receptor in low-volume metastatic prostate cancer is most important at the start of treatment. The Apa/Enza-short trial evaluates whether limiting ARPI treatment to 12 mo, with restarting upon a confirmed prostate-specific antigen (PSA) increase, is noninferior to continued ARPI treatment until progression.

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Access through your organizationSection snippetsTrial overview

This randomized, noninferiority, open-label trial is conducted across 28 Dutch hospitals (Fig. 1). Overall, 400 patients are included and when on treatment for 1 yr, randomized 1:1 to ADT + continuous ARPI (apalutamide/enzalutamide), or ADT + 12 mo of ARPI, with reinitiation of ARPI allowed upon confirmed PSA increase (Fig. 2). The approach to start with both ADT and ARPI and de-escalate, rather than to start the ARPI later, was chosen to align with the European Society For Medical Oncology

Participants

Eligible participants are adult men with de novo low-volume mCSPC. Inclusion requires histologically confirmed adenocarcinoma and M1a/b stage not meeting high-volume criteria (≥4 bone lesions with ≥1 beyond spine/pelvis, or visceral metastases), documented by bone/computed tomography scan (CHAARTED) [8], or prostate-specific membrane-antigen positron emission tomography scan. The local multidisciplinary team assesses all imaging that has been performed and has to decide that disease aligns with

Interventions

All patients receive ADT + ARPI (either enzalutamide or apalutamide) during the first year. Randomization occurs after 12 mo, stratified by PSA response (0.2< vs <0.2 ng/ml), disease location (bone/nodal versus bone only), and prior prostate radiotherapy. Patients progressing within the first 12 mo are not randomized. In the experimental arm, ARPI treatment is discontinued after 12 mo, with reinitiation allowed upon a confirmed PSA increase according to protocol-defined retreatment criteria (

Main study parameter/end point

The primary end point is clinical progression-free survival (cPFS, defined as radiological progression, development of cancer-related symptoms, or initiation of other treatment for prostate cancer), considered a surrogate end point for OS [12]. In the stop arm, a cPFS event is recorded after treatment reinitiation. The reason for the cPFS event will be recorded and compared by arm to obtain insight in potential follow-up differences by treatment arm.

Secondary end points include quality of life,

Sample size calculation

The power analysis for a two-sample proportional noninferiority test indicated that with an inclusion period of 2 yr and 5 yr of additional follow-up, 170 events are required, expected within 7 yr if 366 patients are randomized (183 per arm).

The calculation was based on the following parameters: power = 80%, one-sided α = 5%, and a noninferiority margin of 10%, which was deemed acceptable in a national survey among Dutch oncologists and urologists and endorsed by the Dutch prostate cancer

Statistical methods

Baseline and on-treatment parameters will be presented as quantitative data (absolute values and relative changes). cPFS will be estimated using the stratified Kaplan-Meier method and compared between arms using Cox regression with treatment and stratification factors as covariates. The primary analysis will be conducted by the per-protocol principle, with sensitivity analyses on the intention-to-treat population. Repeatedly measured biomarkers will be analyzed using time-dependent Cox

Current status

Recruitment has been ongoing since February 2024, with 197 patients enrolled as of February 2026. Completion is expected by mid-2027. Results are expected after 170 cPFS events, in 2031.

Conclusion

The Apa/Enza-short study evaluates whether a shortened 12-mo course of apalutamide or enzalutamide is safe in low-volume mCSPC, potentially reducing toxicity and treatment costs.

Author contributions: Nick Beije had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design: Beije, Isebia, van Dijk, Hamidikia.

Acquisition of data: None.

Analysis and interpretation of data: None.

Drafting of the

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†

These authors contributed equally.

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