Background Understanding the molecular features that underlie metastatic prostate cancer (PCa) is essential to develop prognostic markers and improve treatment decisions. However, such studies are hampered by substantial intratumor and interpatient heterogeneity. Methods To cope with this heterogeneity, we propose a unique study design that leverages the statistical power of multifocal bulk transcriptome profiling with the resolution of a single-cell analysis to identify processes and cell types associated with regional metastatic lymph node seeding in PCa. Results Elaborate analysis of these data allowed identifying a metric to distinguish, based on the multifocal expression data between lesions with high and low potential for regional metastatic lymph node seeding. Subsequently comparing the expression profiles of these lesions with respectively high and low metastatic potential identified an aggressiveness signature. Overlaying this signature with single cell data identified proliferative luminal cells, an adipose derived cancer-associated fibroblast (CAF) state and a specific subtype of arterial endothelial cells. Assessing the prognostic value of these cell states in an independent dataset (TCGA-PRAD) confirmed their association with regional metastatic lymph node seeding and progression free survival and unveiled a complementary role for the proliferative luminal cells and the adipose derived CAF state in driving regional metastatic lymph node seeding. Conclusions Based on our analysis, we hypothesize that lesions with high potential for regional metastatic lymph node seeding are mostly characterized by the presence of highly proliferative luminal cells and a transitioning towards an aggressive adipose derived CAF state. Markers associated with these cell states largely explain the prognostic signal of currently used commercial signatures in PCa, further supporting the role of the identified cell states in driving regional metastatic lymph node seeding and providing an in depth understanding of the success of the currently used commercial signatures.

BACKGROUND:For over a decade the Advanced Prostate Cancer Consensus Conference (APCCC) covers a variety of topics that greatly impact daily practice. In 2025, a dedicated event was organised to discuss key questions in clinical management of patients with prostate cancer (PC) related to diagnostic tools (APCCC Diagnostics). Here we present the voting results of the APCCC Diagnostics questions. OBJECTIVE; DESIGN, SETTING, AND PARTECIPANTS: APCCC Diagnostics 2025 is a pilot project. The scientific committee for APCCC Diagnostics 2025 developed 88 multiple-choice consensus questions on six different topics. Prior to the conference, the panel members (''panellists'') voted on these questions via a web-based survey. Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS:Consensus was only reached on 17 of 88 questions (19%), of which six (7%) received a strong consensus. Specifically, consensus was reached for two of 17 questions (14%) in "how to diagnose PC"; seven of 16 (44%) in "how to stage PC"; three of 14 (21%) in "Biochemical Recurrence Scenario"; two of 11 (18%) in "metastatic disease: what to do?"; zero of 18 (0%) in "monitoring metastatic PC"; and three of 12 (25%) in "radioligand therapy and imaging." CONCLUSIONS:The voting results and their discussion may assist physicians in navigating controversial areas of clinical management related to diagnosis, staging, and restaging in the different clinical settings for PC, particularly where high-level evidence is scarce or conflicting. The findings can also help funders and policymakers in prioritising areas for future research.

BACKGROUND AND PURPOSE:Metastasis-directed stereotactic body radiotherapy (SBRT), in combination with systemic therapy, is increasingly used in patients with oligometastatic disease (OMD), supported by international guidelines. However, real-world data on health-related quality of life (HRQoL) following SBRT remain limited. This study aimed to describe baseline HRQoL, evaluate changes over time, and identify clinical factors associated with HRQoL and its evolution. MATERIALS AND METHODS:OligoCare is a pragmatic, prospective cohort study within the E2-RADIatE registry, including patients with oligometastatic breast, colorectal, non-small cell lung cancer (NSCLC), and prostate cancer treated with SBRT. An optional HRQoL sub-study assesses patient-reported outcomes at baseline and within 6 months post-SBRT. Analyses included descriptive assessment of baseline HRQoL, multivariable regression to identify factors associated with baseline global health status (GHS), and longitudinal evaluation of HRQoL changes. Clinically meaningful changes were defined using a minimal clinically important difference (MCID) of ≥ 10 points. RESULTS:Of 2,041 patients, 1,033 (50.6%) completed baseline HRQoL questionnaires and 450 (22%) had follow-up data. The median time to follow-up HRQoL assessment was 2.7 months (range 0.5-6.1). Median baseline GHS was 75. Higher baseline GHS was associated with prostate cancer and good performance status (p < 0.0001). At follow-up, mean GHS remained stable (71, SD 19). Among patients with follow-up data, 23% reported worsened HRQoL, 15% improved. No significant associations were found between HRQoL changes and clinical variables. CONCLUSION:Early findings support that SBRT for OMD maintains overall HRQoL in most patients, reinforcing its role in multimodal treatment without compromising patient-reported outcomes.

In cases of biochemical recurrence (BCR) after radical prostatectomy, salvage radiotherapy (RT) is a well-established standard-of-care treatment. Stereotactic body radiotherapy (SBRT) may offer a shorter treatment duration and favorable radiobiological characteristics, but evidence in the postoperative setting remains limited. This trial aims to compare genitourinary and gastrointestinal patient-reported outcomes after salvage SBRT with standard-of-care schedules. Two-hundred eighty-four patients with persistent or rising PSA levels after radical prostatectomy will be randomized in a 1:1 ratio to receive either a normofractionated or mildly hypofractionated RT schedule (64–70 Gy in 32–35 fractions or 52.5 Gy in 20 fractions, Arm A), or a SBRT schedule (32 Gy in 5 fractions, Arm B). Randomization will be stratified by study center and by the investigator’s treatment choices regarding standard-of-care androgen deprivation therapy (ADT; 6 months) and whole-pelvis radiotherapy (WPRT). The co-primary endpoints are the two-year change from baseline in the urinary and bowel domains of the EPIC-26 questionnaire. Secondary endpoints include patient-reported outcomes across all EPIC-26 domains, IPSS and EQ-5D-5 L scores up to 5 years, physician-reported toxicity according to CTCAE v5.0, biochemical progression-free survival (bPFS), distant metastasis-free survival (dmFS), local and regional control, overall survival (OS), cost-utility analysis based on EQ-5D-5 L compared with RT and transportation costs during treatment, and the lymphocyte nadir relative to baseline. This is one of the first multicenter randomized phase II/III trials designed to demonstrate that SBRT does not increase patient-reported gastrointestinal (GI) or genitourinary (GU) symptoms compared with standard-of-care (SOC) fractionations at the 2-year time point. ClinicalTrials.gov ID NCT06523634. Date of registration: May 28, 2024.

TPS412 Background: PARP inhibitors (PARPi) are approved for the treatment of patients with metastatic castration-resistant prostate cancer. Saruparib is a new generation PARPi that selectively inhibits and traps PARP1. In the Phase I/IIa PETRA study (NCT04644068), activity with saruparib monotherapy (PSA 50 , objective response) has been observed in patients with advanced/metastatic prostate cancer. The Phase I/II PETRANHA study (NCT05367440) has demonstrated that saruparib can be safely combined with androgen receptor pathway inhibitors to treat patients with metastatic prostate cancer. The Phase III EvoPAR-Prostate02 study (NCT06952803) is evaluating the efficacy and safety of adjuvant saruparib versus placebo in patients with early-stage, high-risk prostate cancer with BRCA1 / BRCA2 gene mutation (BRCAm) who have received definitive radiotherapy (RT) and are receiving a standard concomitant androgen deprivation therapy (ADT) regimen. Methods: EvoPAR-Prostate02 is a two-cohort, randomized, double-blind, placebo-controlled study. Eligibility criteria include age ≥18 years, diagnosis of high-risk or very high-risk localized/locally advanced prostate adenocarcinoma or high-risk biochemical recurrence following radical prostatectomy, with a confirmed BRCAm by central tumor tissue testing. Patients must have completed primary or salvage RT with curative intent, with no evidence of disease or disease detected only in the pelvis at time of study entry, and must still be receiving ADT. Key exclusion criteria include persistent cytopenias, conditions with predisposition to bleeding, and history of myelodysplastic syndrome/acute myeloid leukemia. In both Cohort A (ADT alone) and Cohort B (ADT plus abiraterone/prednisone), randomization is 1:1 to saruparib or placebo. Treatment with saruparib/placebo continues for 24 months or until unacceptable toxicity, confirmed disease progression by blinded independent central review (BICR), or patient-initiated withdrawal. ADT and abiraterone treatment duration is limited to 24 months, inclusive of pre-study regimen. The primary endpoint is metastasis-free survival (MFS), confirmed by standard clinical imaging (computed tomography/magnetic resonance imaging and bone scan, or prostate-specific membrane antigen-positron emission tomography [PSMA PET]), as assessed by BICR. Overall survival (OS) is a key secondary endpoint. Statistical analyses of MFS and OS will be conducted within each cohort using a stratified log-rank test. Approximately 700 patients will be randomized. Recruitment began in July 2025 and is ongoing. Clinical trial information: NCT06952803 .

CDK12 mutations occur in 2-7% of metastatic prostate cancers (mPCa) and are considered to be exclusively somatic. Here, we identified five patients with mPCa (ages 44-62) harboring germline CDK12 truncating variants among 4,535 tested (0.1%). All had CDK12-driven cancers defined by an additional somatic CDK12 variant and the CDK12-specific hallmark genomic instability signature characterized by hundreds of tandem duplications. Two patients had multiple independent CDK12-driven tumors with distinct secondary somatic CDK12 variants. Germline CDK12 truncating variants were enriched in mPCa compared to gnomAD V4.1.0 controls (n=807,162; odds ratio 11.4, 95% CI 3.6-27.8) and V2.1.1 non-cancer controls (n=134,187; odds ratio 29.6; 95% CI 6.8-28.6). Family history revealed multiple related individuals with prostate or ovarian cancer, and germline variant inheritance was confirmed in the two tested pedigrees. Our data suggest that germline CDK12 truncating variants are a rare driver of lethal mPCa.

Metastasis-directed therapy (MDT) is an emerging treatment option for metachronous oligometastatic castration-sensitive prostate cancer (omCSPC) and can delay time to progression and the need to initiate androgen deprivation therapy (ADT). However, optimal ways to synergize MDT and ADT are not known, and better personalization of MDT is needed. We examined the role of combined ADT and MDT and the ability of genomic alterations to provide prognostic and predictive information regarding response to MDT. We found that high-risk (HiRi) mutations in TP53, BRCA1/2, ATM, and Rb1 are poor prognostic markers in omCSPC. In addition, patients harboring HiRi mutations experienced greater benefit from addition of ADT to MDT, indicating that these alterations are predictive biomarkers for treatment intensification. Our results suggest that genetic biomarkers might aid in treatment personalization for patients with omCSPC.

Background:Risk stratification for prostate cancer (PCa) progression or aggressiveness is often based on clinicopathologic features, some of which may be influenced by genetic factors. We developed a novel, germline polygenic risk score (PRSagg) to predict likelihood of developing aggressive PCa. Methods:PRSagg was developed using data from 38,688 patients with PCa (case-only analysis) from the Million Veteran Program (MVP) through a genome-wide search for variants associated with PCa grade group at diagnosis. We tested associations of PRSagg with grade group using the entire MVP dataset using the .632 bootstrap method. In an MVP cohort with localized PCa that was initially monitored without treatment, we tested PRSagg for association with unfavorable outcomes (subsequent development of grade group 4-5, metastasis, and/or biochemical recurrence after definitive treatment). We performed external validation in data from patients in the PRACTICAL Consortium (n=45,214) and from participants in the ProtecT randomized trial who underwent active monitoring (n=316). Odds ratios (ORs) were calculated per standard deviation (SD) increase with 95% confidence intervals, while adjusting for age, genetic ancestry, a previously developed polygenic score for risk of PCa (PHS601), and a polygenic score for benign elevated prostate-specific antigen (PRSPSA). For the outcome of metastasis, we additionally adjusted for PSA at diagnosis. Results:In the MVP training dataset, PRSagg (172 variants) was associated with higher grade group at diagnosis (OR = 1.53 [1.51-1.56]) and with increased risk of unfavorable outcomes during monitoring (OR = 1.13 [1.09-1.18]). These findings were confirmed in the external datasets. PRSagg was associated with greater odds of higher grade group at diagnosis (OR = 1.09 [1.061.11]). Among ProtecT participants undergoing active monitoring, PRSagg was associated with higher risk of metastasis (OR = 2.15 [1.02-3.88]). Among MVP participants with high polygenic risk of developing any PCa, the risk of aggressive disease was highest in men with high PRSagg and low genetic risk of PSA elevation. Conclusions:Among men who develop PCa, a weighted sum of common germline variants (PRSagg) is independently associated with PCa aggressiveness. These findings may inform future study of germline influence on tumor evolution and risk-stratified intensity of active surveillance.

Oligometastatic cancer is characterised by a low volume of metastases to a small number of anatomical sites. However, evaluating the impact of metastases-directed therapies (MDTs) on overall survival or quality of life is often challenging. Current clinical trials use a wide range of primary endpoints that might not be validated or suited to MDT. To address this issue, we did a systematic review of international trial registries, alongside a Delphi consensus process involving 30 experts and five patient representatives. The aim was to identify preferred primary endpoints for MDT trials in oligometastatic disease, regardless of tumour type. Overall survival and progression-free survival were the most frequently used endpoints across the 121 comparative trials reviewed. Over four Delphi consensus rounds, overall survival had the highest level of agreement, although its limitations as a sole endpoint were emphasised. In addition to the widely used progression-free survival endpoint, polymetastatic progression-free survival and start-or-switch of systemic therapy-free survival also reached consensus, particularly for trials integrating systemic therapies. Both polymetastatic progression-free survival and systemic therapy-free survival permit repeat MDT without classifying it as treatment failure. Patient representatives highlighted the importance of time-to-deterioration of quality of life. This consensus supports overall survival as a primary endpoint and, in addition to progression-free survival, recommends polymetastatic progression-free survival and systemic therapy-free survival, especially in combination with systemic therapies. Adopting these endpoints will make MDT trials more relevant, comparable, and patient-centred, thereby empowering future clinical and policy decisions.

Climate change, pollution, and resource depletion pose significant challenges to modern society, including the healthcare sector. While the delivery of health services inherently entails energy and resource utilization, the health care sector has a relevant role to play for sustainable development, since it is estimated to account for approximately 4.7% of total greenhouse gas emissions in the EU whilst also contributing to natural resource depletion, toxic chemical release, and the generation of non-compostable waste. In response, the European Society for Radiotherapy and Oncology (ESTRO) established the Green Task Force in 2022 to support the development of a strategic framework, which integrates environmental sustainability into ESTRO’s activities.This position paper presents ESTRO’s principles for environmental sustainability, which focus on four key areas: (1) raising awareness and sharing best practices, (2) monitoring the environmental impact of ESTRO’s activities, (3) evaluating interventions to reduce carbon emissions and improve the environmental sustainability of ESTRO activities, and (4) embedding sustainability into governance and professional activities. Examples of strategies which can reduce climate impact of ESTRO activities include advocating for environmentally conscious radiotherapy practices, considering venues that facilitate shorter travelling for participants in ESTRO conferences and educational activities, promoting digital participation, facilitating sustainable travel options and promoting healthy lifestyle.By emphasizing sustainability, ESTRO aims to lead the radiation oncology community toward a more environmentally responsible future, balancing scientific progress with climate-conscious practices. This initiative aligns with global sustainability goals and underscores the role of oncology professionals in addressing the climate crisis.

Prostate Biomarkers trial in metastatic hormone-sensitive prostate cancer (mHSPC) tests whether circulating tumor deoxyribonucleic acid (ctDNA) can personalize first-line treatment for mHSPC by safely de-escalating therapy in patients with undetectable ctDNA and by intensifying biomarker-matched treatment in ctDNA-detectable disease, aiming to preserve outcomes while reducing toxicity and improving quality of life.

PURPOSE:Although radiotherapy is a cornerstone of multidisciplinary cancer care, radiation oncology research represents only a small proportion of the oncology research portfolio. Several factors intrinsic to radiotherapy, such as the incremental nature of technological advances, the reliance on long-term clinical endpoints, or the substantial upfront investments required to investigate innovative radiotherapy technologies, pose challenges to conducting randomized controlled trials. Alternative, blended approaches to evidence generation are therefore required to assess the breadth of radiotherapy innovations. METHODS:The European Society for Radiotherapy and Oncology and the European Organisation for Research and Treatment of Cancer launched E2-RADIatE (EORTC-ESTRO RADiotherapy Infrastructure for Europe; EORTC 1811 - NCT03818503) in 2019. This pragmatic, observational, prospective multi-cohort study uses a centralised database to collect real-world data on cancer patients, their radiotherapy treatments, and outcomes across Europe. It aims to generate evidence and new hypotheses to assess radiotherapy innovations. RESULTS:After five years, two cohorts (OligoCare and ReCare) are actively recruiting patients. The platform has enabled the generation of new research hypotheses and the testing of innovative methodological strategies with the opening of the first international oncology Trial Within Cohorts (TWiCs). Engagement of the international radiotherapy community has been central to the development and sustainability of the infrastructure, while several barriers and limitations inherent to this type of real-world research have also been identified. CONCLUSION:The five-year experience of E2-RADIatE demonstrates the feasibility and added value of a large-scale, prospective, real-world, multi-cohort infrastructure to support evidence generation in radiotherapy, while highlighting regulatory and methodological challenges that must be addressed to maximise impact.

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. 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). 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 40·7 months (IQR 25·6-53·7). MDT was associated with improved progression-free survival (trial-level hazard ratio [HR] 0·44, [95% CI 0·35-0·56], p<0·0001; patient-level HR 0·45 [0·35-0·57], p<0·0001), radiographic progression-free survival (trial-level HR 0·60 [0·42-0·85], p=0·0039; patient-level HR 0·59 [0·46-0·76], p<0·0001), and castration resistance-free survival (trial-level HR 0·58 [95% CI 0·37-0·92], p=0·019; patient-level HR 0·58 [95% CI 0·37-0·91], p=0·017). The association between MDT and overall survival showed an HR of 0·63 (95% CI 0·39-1·00, p=0·051) in trial-level analyses and 0·64 (95% CI 0·40-1·01, p=0·057) in patient-level analyses. 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. FUNDING:Philanthropic gift and National Cancer Institute.

Background and purpose:Traditional dose-volume histogram (DVH) metrics used in radiotherapy plan evaluation lack spatial information and are sensitive to organ volume variations. This study investigated the use of Dose Gradient Curves (DGCs) as a robust, volume-independent alternative for assessing organ sparing in prostate stereotactic body radiation therapy (SBRT). Materials and methods:Treatment plans of 154 prostate cancer patients were retrospectively analysed. A benchmark set of 20 high-quality plans was established, and average DVH (aDVH) and DGC (aDGC) curves were derived for the bladder and anorectum. Plan quality of the remaining 134 plans was assessed using aDVH, aDGC, and expert-reviewed ground truth. A ΔAUC-based classifier was developed to automatically detect suboptimal organ sparing. The robustness of benchmark set size was evaluated by comparing subsets of five plans with extreme organ volumes. Results:The inclusion of dose-gradient information improved accuracy and precision compared to DVH-based methods. For the bladder, DGC analysis achieved 99% accuracy and precision, compared to 87% and 94% for DVH. For the anorectum, DGC yielded 97% accuracy and 100% precision. The ΔAUC classifier achieved F1 scores of 97.1% (bladder) and 89.7% (anorectum). Reducing the benchmark set to five plans did not significantly affect DGC-based evaluations, unlike DVH-based assessments. Conclusions:DGC-based plan evaluation offers a reliable and volume-independent method for assessing organ sparing in prostate SBRT. It enabled automated detection of suboptimal plans and remained robust even with reduced benchmark sizes. Further investigation prior to clinical implementation is required.