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ESMO 2025 ENZARAD (ANZUP 1303), randomized phase II trial of ADT + radiation therapy +/- enzalutamide, localized prostate cancer.

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IMPORTANCE: Complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT).<br/><br/>OBJECTIVE: To determine if stereotactic ablative radiotherapy (SABR) improves oncologic outcomes in men with oligometastatic prostate cancer.<br/><br/>DESIGN, SETTING, AND PARTICIPANTS: The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized study accrued participants from 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6 months of enrollment or 3 or more years total were randomized.<br/><br/>INTERVENTIONS: Patients were randomized in a 2:1 ratio to receive SABR or observation.<br/><br/>MAIN OUTCOMES AND MEASURES: The primary outcome was progression at 6 months by prostate-specific antigen level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at 6 months with SABR, progression-free survival, Brief Pain Inventory (Short Form)-measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)-targeted positron emission tomography in the identification of metastatic disease.<br/><br/>RESULTS: In the 54 men randomized, the median (range) age was 68 (61-70) years for patients allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at 6 months occurred in 7 of 36 patients (19%)&#x2009;receiving SABR and 11 of 18 patients (61%) undergoing observation (P&#x2009;=&#x2009;.005). Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P&#x2009;=&#x2009;.002). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months (16% vs 63%; P&#x2009;=&#x2009;.006). No toxic effects of grade 3 or greater were observed. T-cell receptor sequencing identified significant increased clonotypic expansion following SABR and correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P&#x2009;=&#x2009;.03).<br/><br/>CONCLUSIONS AND RELEVANCE: Treatment with SABR for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by PSMA-targeted positron emission tomography. SABR induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates.<br/><br/>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02680587.

PURPOSE: ARTO (ClinicalTrials.gov identifier: NCT03449719) is a multicenter, phase II randomized clinical trial testing the benefit of adding stereotactic body radiation therapy (SBRT) to abiraterone acetate and prednisone (AAP) in patients with oligometastatic castrate-resistant prostate cancer (CRPC).<br/><br/>MATERIALS AND METHODS: All patients were affected by oligometastatic CRPC as defined as three or less nonvisceral metastatic lesions. Patients were randomly assigned 1:1 to receive either AAP alone (control arm) or AAP with concomitant SBRT to all the sites of disease (experimental arm). Primary end point was the rate of biochemical response (BR), defined as a prostate-specific antigen (PSA) decrease &#x2265;50% from baseline measured at 6 months from treatment start. Complete BR (CBR), defined as PSA < 0.2 ng/mL at 6 months from treatment, and progression-free survival (PFS) were secondary end points.<br/><br/>RESULTS: One hundred and fifty-seven patients were enrolled between January 2019 and September 2022. BR was detected in 79.6% of patients (92% v 68.3% in the experimental v control arm, respectively), with an odds ratio (OR) of 5.34 (95% CI, 2.05 to 13.88; P = .001) in favor of the experimental arm. CBR was detected in 38.8% of patients (56% v 23.2% in the experimental v control arm, respectively), with an OR of 4.22 (95% CI, 2.12 to 8.38; P < .001). SBRT yielded a significant PFS improvement, with a hazard ratio for progression of 0.35 (95% CI, 0.21 to 0.57; P < .001) in the experimental versus control arm.<br/><br/>CONCLUSION: The trial reached its primary end point of biochemical control and PFS, suggesting a clinical advantage for SBRT in addition to first-line AAP treatment in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Oligometastatic disease represents the proximal end of a metastatic spectrum. Metastasis-directed therapy (MDT) is increasingly used to treat oligometastatic disease despite the absence of level 1 evidence. We amalgamated individual patient data across trials to evaluate the effectiveness of MDT for oligometastatic prostate cancer.<br/><br/>METHODS: We conducted a systematic review and individual patient data meta-analysis. We systematically searched Embase, PubMed, CENTRAL, MEDLINE, and ClinicalTrials.gov to identify randomised trials of MDT enrolling patients with oligometastatic prostate cancer. Inclusion criteria were published randomised prospective trials enrolling patients with oligometastatic (up to five metastases) prostate cancer, in which investigators recorded sufficient data to evaluate progression-free survival and overall survival. This systematic review was conducted from database creation to Nov 3, 2023, and was updated on May 4, 2025. Data appraisal was conducted using Covidence with two investigators (CT and ADS) performing independent screens. Studies were evaluated using the Cochrane Collaboration's risk-of-bias assessment (version 2.0). Individual patient data were provided by investigators. Coprimary endpoints were progression-free survival and overall survival. Secondary endpoints were radiographic progression-free survival and castration resistance-free survival. The primary analysis was conducted in the subset of studies in which patients were randomly assigned to MDT plus standard of care (SOC) versus SOC. The primary analysis included a trial-level analysis using a random effects model and a patient-level analysis stratifying by trial. This meta-analysis is registered with PROSPERO (CRD42023479078).<br/><br/>FINDINGS: Of 2975 studies identified for screening, seven phase 2 studies randomly assigning 574 men were included. Six trials randomly assigning 472 patients to MDT plus SOC (n=248) versus SOC (n=224) were used to evaluate MDT and had a median follow-up time of 40&#xb7;7 months (IQR 25&#xb7;6-53&#xb7;7). MDT was associated with improved progression-free survival (trial-level hazard ratio [HR] 0&#xb7;44, [95% CI 0&#xb7;35-0&#xb7;56], p<0&#xb7;0001; patient-level HR 0&#xb7;45 [0&#xb7;35-0&#xb7;57], p<0&#xb7;0001), radiographic progression-free survival (trial-level HR 0&#xb7;60 [0&#xb7;42-0&#xb7;85], p=0&#xb7;0039; patient-level HR 0&#xb7;59 [0&#xb7;46-0&#xb7;76], p<0&#xb7;0001), and castration resistance-free survival (trial-level HR 0&#xb7;58 [95% CI 0&#xb7;37-0&#xb7;92], p=0&#xb7;019; patient-level HR 0&#xb7;58 [95% CI 0&#xb7;37-0&#xb7;91], p=0&#xb7;017). The association between MDT and overall survival showed an HR of 0&#xb7;63 (95% CI 0&#xb7;39-1&#xb7;00, p=0&#xb7;051) in trial-level analyses and 0&#xb7;64 (95% CI 0&#xb7;40-1&#xb7;01, p=0&#xb7;057) in patient-level analyses.<br/><br/>INTERPRETATION: WOLVERINE showed a benefit with MDT for oligometastatic prostate cancer in progression-free survival, radiological progression-free survival, and castration resistance-free survival. Overall survival benefit was not significant and further research is needed.<br/><br/>FUNDING: Philanthropic gift and National Cancer Institute.

BACKGROUND: Metastasis-directed therapy by stereotactic body radiotherapy (SBRT) has been shown to improve clinical outcomes in the oligometastatic prostate cancer setting. We aimed to investigate whether short-course androgen deprivation therapy (ADT) and SBRT at all oligometastatic sites versus SBRT alone improves clinical progression-free survival in men with metachronous oligorecurrent hormone-sensitive prostate cancer.<br/><br/>METHODS: The RADIOSA study was a single-centre, randomised, open-label, controlled phase 2 trial done in the European Institute of Oncology, IRCCS, Milan, Italy. Key eligibility criteria were histologically proven initial diagnosis of adenocarcinoma of the prostate, biochemical progression after radical local prostate treatment, nodal relapse in the pelvis, extra-regional nodal relapse, bone metastases at next-generation imaging with a maximum of three lesions, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and age 18 years or older. Participants were stratified according to prostate-specific membrane antigen doubling time (&#x2264;3 vs >3 months), metastases localisation (node vs bone), and diagnostic imaging (positron emission tomography vs MRI) and were randomly assigned (1:1) using a computer-generated random number to SBRT alone or SBRT in combination with 6 months of ADT. For SBRT treatment, a schedule of 30 Gy in three fractions every other day (with the equivalent dose in 2 Gy fractions being 98&#xb7;6 Gy, considering &#x3b1;/&#x3b2; ratio of 1&#xb7;5 Gy and biologically effective dose of >100 Gy), or equivalent regimens depending on disease site location, was administered. Patients in the SBRT with ADT group received 6 months of ADT with a luteinising hormone-releasing hormone analogue within 1 week before the start of SBRT. The allocated treatment was not masked. The primary outcome measure was clinical progression-free survival. All analyses followed a modified intention-to-treat principle, consisting of all patients assigned to a treatment group who had available data. The trial is registered at ClinicalTrials.gov, NCT02680587, and is complete.<br/><br/>FINDINGS: Between Aug 1, 2019, and April 30, 2023, 218 patients were assessed for eligibility, 113 were excluded, and 105 were enrolled and randomly assigned to an intervention (52 to SBRT only and 53 to SBRT with ADT). Three patients were lost to follow-up and 51 patients in each group were assessed for the primary outcome. The median age at study enrolment was 70 years (IQR 65-75); data on race and ethnicity were not collected. With a median follow-up of 31 months (IQR 16-36) for both groups, the median clinical progression-free survival was 15&#xb7;1 months (95% CI 12&#xb7;4-22&#xb7;8) for the SBRT group versus 32&#xb7;2 months (22&#xb7;4-not reached) for the SBRT with ADT group (hazard ratio 0&#xb7;43 [95% CI 0&#xb7;26-0&#xb7;72], p=0&#xb7;0010]). One gastrointestinal grade 1 adverse event (SBRT group) and one genitourinary grade 3 adverse event (left ureter stenosis, SBRT with ADT group) were reported, with no late toxicities observed. 22 grade 1 ADT-related adverse events were reported, all of which had resolved at the last follow-up. No treatment-related deaths were recorded.<br/><br/>INTERPRETATION: To our knowledge, the RADIOSA trial represents the first randomised trial in the metachronous oligometastatic hormone-sensitive prostate cancer setting to report improved clinical progression-free survival with the combination of SBRT and a short course of ADT, although carefully selected patients might still benefit from SBRT alone. By demonstrating improved clinical progression-free survival, the RADIOSA trial reinforces the role of metastasis-directed therapy in delaying systemic treatment escalation. Additionally, it underscores the need for further studies to determine the optimal duration of ADT and identify biomarkers predicting response to SBRT alone.<br/><br/>FUNDING: Italian Association of Cancer Research.