INTRODUCTION:Prostate cancer is well known to be androgen-dependent, with growth directly relying on the androgen receptor signaling pathway. In fact, androgen deprivation therapy, with or without Docetaxel and/or newer hormonal drugs such as Abiraterone acetate, Enzalutamide, Apalutamide, and Darolutamide, remains the most effective systemic treatment for metastatic disease. Beyond PSA detection, there is a lack of standardized biohumoral markers to understand the biology of metastatic castrate-sensitive prostate cancer (mCSPC), predict response to newer therapies such as immunotherapy, and identify a true oligometastatic state. AREAS COVERED:A comprehensive, non-systematic literature review across Scopus, Google Scholar, Medline, EMBASE, and the Cochrane Library was conducted. New evidence was identified, gathered, and screened for relevance, limited to English-language publications. Information and recommendations on the emerging mCSPC biomarkers, their possible integration, and application for care decisions were evaluated. Our work aimed to summarize the current understanding of molecular characterization of mCSPC and the evidence on the role of emerging molecular biomarkers in guiding personalized treatment for mCSPC. EXPERT OPINION:The integration of data extracted from imaging with the molecular and genetic profiles of a specific tissue, using artificial intelligence, will help assess the genetic and biochemical makeup of living tissue.

PURPOSE:In patients who received breast-conserving surgery for early-stage breast cancer, the present study assessed acute and short-term side effects and oncological outcomes after whole breast irradiation (WBI) with an ultrahypofractionated schedule. METHODS AND MATERIALS:From 2020 to 2025, 2036 patients (median age 70 years; range, 19-93) were recruited from 28 Italian Radiation Oncology Centers. Inclusion criteria included: early-stage breast cancer (either invasive or ductal in situ carcinomas), age ≥ 18 years, breast-conserving surgery and delivery of ultrahypofractionated WBI by means of any radiation therapy (RT) technique. All patients received 26 Gy in 5 consecutive fractions of 5.2 Gy. Depending on risk factors for local relapse, some patients received a sequential or simultaneous integrated boost. Side effects were monitored at diverse time points for ≤2 years. RESULTS:Median follow-up was 12 months (range, 1-55). The incidence of side effects was low, and they were mainly G1. The most frequent acute side effect (37.1%) was erythema, 90.2% were G1. Skin hyperpigmentation, the most frequent short-term late side effect, occurred in 12.2% of patients (95.7% G1) at 6 months, in 5.7% (98.4% G1) at 12 months, 5.7% (96% G1) at 18 months, and 4% (100% G1) at 24 months after the end of RT. In multivariate analysis, significant factors for acute side effects were active smoking and boost administration. Furthermore, age emerged as a protective factor, while a larger breast planning target volume was associated with increased side effects. Significant risk factors for late side effects were active smoking at +6 months and a larger planning target volume boost at +6 and +12 months after the end of RT. CONCLUSIONS:In our large series of patients with early-stage breast cancer, ultrahypofractionated WBI appeared safe and feasible.

Moderately hypofractionated radiotherapy (m-HRT) is a standard of care in the radical treatment of localized prostate cancer (PCa). Still, its role after radical prostatectomy (RP) is yet to be defined. We present long-term outcome and toxicity results of m-HRT in the post-prostatectomy setting. Retrospective analysis of 172 PCa patients treated with daily volumetric image-guided Tomotherapy-based m-HRT between 2013 and 2020. For outcome and toxicity endpoints, we used Kaplan–Meier survival curves and the chi-square test for univariate analysis. The median time from RP to m-HRT was 11 months (interquartile [IQR], 8.3–31.4). The median total dose to the prostate bed was 69.75 Gy (IQR, 65.25–72 Gy) (2.25 Gy per fraction). With a median follow-up of 8.25 years (IQR 7.06–9.17 years), 10-year overall survival (OS), metastasis-free survival (MFS), and biochemical relapse-free survival (b-RFS) were 98.8

BACKGROUND:The ARTO trial showed improved early clinical outcomes by adding metastasis-directed therapy (MDT), through stereotactic body radiotherapy (SBRT), to abiraterone acetate and ADT in oligometastatic castrate-resistant prostate cancer. The aim of this analysis is to explore the long-term impact of MDT on overall survival. METHODS:ARTO was a multicentre, phase 2, randomised trial conducted in 16 academic and community centres across Italy. All patients included were aged 18 years or older and had a diagnosis of prostate adenocarcinoma with metastatic castrate-resistant prostate cancer, no more than three metastatic sites, and no previous systemic therapy for metastatic castrate-resistant prostate cancer status. Patients were randomly assigned (1:1, using random permuted blocks; stratified by treating centre, Eastern Cooperative Oncology Group performance status, and number of metastases) in an open-label design to androgen deprivation therapy plus oral abiraterone acetate 1000 mg daily with or without SBRT to all sites of metastatic disease (one to five fractions providing a biologically effective dose ≥100 Gy). The primary endpoint was 6-month biochemical response (PSA decrease of ≥50% compared with baseline) and has been reported previously. After meeting its primary endpoint, the power calculation was updated post-hoc to assess overall survival, finalised before data unmasking. We present an unplanned long-term follow-up focusing on overall survival. All analyses were performed on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov (NCT03449719) and is now closed. FINDINGS:Between Jan 2, 2019, and Sept 7, 2022, 157 patients were randomly assigned to the control (n=82) and experimental (n=75) groups. No data about race or ethnicity were collected. After a median follow up of 53 months (IQR 43-60), median overall survival was 50 months (95% CI 36-not reached [NR]) in the control group versus NR (55-NR) in the experimental group (HR 0·55, 95% CI 0·33-0·92, p=0·021). Most common grade 3-4 adverse events recorded were infectious complications (five in the control group vs zero in the experimental group) and cardiovascular disorders (three in the control group vs three in the experimental group). One treatment-related death occurred in the control group due to myocardial failure. INTERPRETATION:The ARTO trial showed significant benefit in overall survival with the addition of MDT to systemic therapy versus systemic therapy alone. FUNDING:Fondazione Radioterapia Oncologica.

Prostate Cancer (PCa) is the second leading cause of cancer death in the elderly (≥75 years). There is currently little data on hypofractionated radiotherapy in older patients affected by localized PCa. We present the long-term results of hypofractionated radiotherapy in elderly patients with localized PCa from the IPOPROMISE database. retrospective analysis of 719 PCa elderly (≥75 years) patients treated with daily volumetric image-guided hypofractionated radiotherapy between 2007 and 2020. For survival endpoints, we used Kaplan-Meier survival curves and univariate and multivariable Cox’s proportional hazards regression models. Median age at PCa diagnosis was 78.4 years (interquartile [IQR], 76.8–80.3 years), 74

397 Background: ARTO (NCT03449719) was a multicenter randomized phase II trial exploring the benefit of concomitant Abiraterone acetate and stereotactic body radiotherapy (SBRT) administration in oligometastatic castrate resistant prostate cancer patients (omCRPC). Both biochemical response and biochemical progression free survival (bPFS) were improved by the addition of SBRT in the experimental arm if compared to abiraterone alone. Here is presented a secondary analysis focusing on prognostic impact of BRCA alterations in enrolled patients. Methods: Patients affected by omCRPC (< 3 non-visceral metastatic lesions) were randomized 1:1 to receive either Abiraterone alone (ARM A) or associated with concomitant SBRT on all sites of disease (ARM B). Subgroup analysis focusing on BRCA positive, negative or BRCA untested patients were conducted. Results: Overall population consisted of 157 patients, 89 patients were tested for BRCA 1 and BRCA 2 alterations, of whom 80 and 9 patients resulted negative and positive, respectively. Sixty eight patients were untested. In the BRCA negative population, bPFS events were registered in 43 patients (72.1 and 32.4% of population included in ARM A and B, respectively). Six bPFS events were registered in BRCA positive population (80 and 50% of patients included in ARM A and B, respectively). In the BRCA untested population, 26 bPFS events were detected (52.9 and 23.5% of patients included in ARM A and B, respectively). No significant difference in terms of bPFS was detected between BRCA positive and negative patients (HR 0.93, p=0.86). Conversely, BRCA untested patients had a significant lower risk of biochemical progression (HR 0.58, p=0.02). Benefit of SBRT in the experimental arm was confirmed both in the BRCA negative and BRCA untested populations in terms of bPFS, with HR of 0.37 (95% CI 0.19-0.73) and 0.50 (95% CI 0.14-0.76), respectively. In BRCA positive patients, results were inconclusive due to limited sample size (HR 0.5, 95% CI 0.09-2.89). Conclusions: In a well selected cohort of omCRPC included in a prospective trial, benefit of SBRT was confirmed in BRCA negative and untested patients. Larger cohorts of BRCA positive omCRPC patients undergoing SBRT are needed to confirm these results in this scenario. Clinical trial information: NCT03449719 . Biochemical progression free survival (BPFS) results in the two trial arms according to BRCA status. BRCA negative BRCA positive(vs negative) BRCA untested(vs negative) N Events N Events HR (95%CI), p N Events HR (95%CI), p BPFS 80 43 9 6 0,93(0,39-2,19)p=0,863 68 26 0,58(0,35-0,94)p=0,028 arm A 43 31 5 4 0,86(0,30-2,44)p=0,773 34 18 1,07(0,24-4,85)p=0,926 arm B 37 12 4 2 0,64(0,36-1,15)p=0,135 34 8 0,56(0,23-1,38)p=0,207

INTRODUCTION:In polymetastatic cancer, radiotherapy (RT) serves as a palliative and symptom-directed approach. Based on modern RT, ablative irradiation has acquired a central role as a metastasis-directed therapy (MDT). MDT is under investigation as a treatment option in patients with widespread metastatic disease. AREAS COVERED:We aimed to describe the emerging field of radiotherapy-based MDT in polymetastatic disease. EXPERT OPINION:New innovative approaches in radiation oncology allow for the precise and safe delivery of ablative doses to multiple disease sites throughout the body in the same treatment session and the tracking of tumors in real time without interruptions during systemic therapy. This treatment strategy could work synergistically with systemic therapy in two ways: [a] ablating high-risk or symptomatic metastases in polymetastatic patients may prevent further disease spread and reduce the overall tumor burden, even while systemic therapy continues to manage micrometastatic disease elsewhere; [b] delivering high doses of radiation to the tumor site leads to microenvironment modifications, inducing immunogenic cell death, releasing tumor antigens, and enhancing immune surveillance and systemic therapy efficacy. Several clinical trials are ongoing to improve tailored treatment strategies in the polymetastatic setting, which is one of the goals of precision medicine.

ARTO trial was a phase II randomized trial suggesting the benefit of a concomitant treatment strategy including Abiraterone acetate plus predisone (AAP) and stereotactic body radiotherapy (SBRT) in oligometastatic castrate resistant prostate cancer (omCRPC). The object of the current analysis is to explore whether the benefit provided by SBRT to AAP is maintained at later stages of disease after oligoprogression Patients enrolled in ARTO trial in whom a first progression event was reported were divided in two groups according to the treatment approach received, regardless of the initial randomization. After first progression event, Patients in Group A received SBRT on oligoprogressive disease, while patients in group B received second line systemic treatment. Palliative RT was not considered for the purpose of this analysis. Progression-Free survival (PFS) 1 and 2 were defined as time between AAP start and first progression event and time between first and second progression event, death or last follow up, (whichever came first), respectively. Cox regression analysis was performed to compare PFS1 + PFS2 in patients in group A vs Group B. Kaplan–Meier analysis was performed to compare overall survival between the two groups Median PFS1 + PFS2 was 45.9 months vs. not reached in group A (n = 43) vs Group B (n = 20), respectively (HR 0.63, 95

INTRODUCTION:de novo low-volume metastatic hormone-sensitive prostate cancer (mHSPC) patients are characterized by a limited number of metastases at diagnosis. Intensifying the current diagnostic and therapeutic approach including multimodality therapy seems to be key in the clinical management of such patients. AREAS COVERED:We comprehensively review the current staging and treatment options for de novo low-volume mHSPC. EXPERT OPINION:PSMA-PET should be used in staging high-risk prostate cancer to detect metastatic disease and better stratify patients for individualized treatment. In the era of Androgen Receptor Pathway Inhibitors (ARPIs), Androgen Deprivation Therapy (ADT) alone should be considered an undertreatment for the majority of the patients. Based on current data in the literature, the most effective therapeutic strategy seems to be the combination of intensified systemic treatment (including ADT + ARPI) and radiotherapy for the primary tumor. The role of cytoreductive radical prostatectomy is currently being investigated as well as metastasis-directed therapy to metastatic sites.

Background:Still controversial is the optimal radiotherapy (RT) schedule for high-risk patients after mastectomy or breast conserving surgery (BCS). An alternative to conventional RT schedules is hypo-fractionation (HF) (40.5 Gy or 42.67 Gy in 15-16 fractions). The present observational, retrospective study assessed acute and late toxicities after hypo-fractionation targeting the chest wall/breast and regional lymph nodes, compared with a cohort that had received conventional fractionation. The aim was to establish the safety of hypo-fractionation in wide-field irradiation. Materials and methods:This study enrolled 80 patients (median age 63 years; range 34-83) who underwent either BCS (9) or mastectomy (71) as well as axillary lymph node dissection. The RT schedule was 40.05 Gy in 15 fractions over 3 weeks. A simultaneous integrated boost (SIB) (49.5 Gy in 15 fractions) was delivered to the tumour bed in 9 patients who received whole breast irradiation (WBI). Acute and late toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE v4.02) and compared with outcomes in 51 patients after conventionally fractionated RT to the chest wall/breast and regional nodes. Median follow-up was 16 months (range 2.7-33.8 months). Results:All patients completed RT with no toxicity-related interruption. No patient developed any cardiac or pulmonary toxicity or ≥ grade 3 acute skin and oesophageal toxicity. Late G1 skin toxicity occurred in 9/75 patients who were eligible for analysis. No patient developed ≥ G2 late toxicity. The incidences of acute toxicity, skin rash and dysphagia were significantly lower after HF (p < 0.001 and 0.040, respectively). No significant differences emerged in late edema and skin toxicity. Conclusions:The efficacy and safety of hypofractionated regimens were confirmed in real-life settings. Present evidence supports the use of HFRT as standard treatment, providing patients with the advantages of shorter treatment times and reduced healthcare costs.

High-risk prostate cancer (PC) accounts for 50–75% of 10-year relapse after primary treatment. Routine clinicopathological parameters for PC patient stratification have proven insufficient to inform clinical decisions in this setting. Tumor genomic profiling allowed overcoming the limits of diagnostic accuracy in the field of PC, integrated with radiomic features, automated platforms, evaluation of patient-related factors (age, performance status, comorbidity) and tumor-related factors (risk class, volume, T stage). In this scenario, the use of biomarkers to guide decision-making in localized, high-risk PC is evolving actively and rapidly. Additional tests for prostate-specific antigen have demonstrated superior sensitivity and specificity for detecting clinically significant PC, as well as commercially available genomic classifiers improving the risk prediction of disease recurrence/progression/metastasis, in combination with common clinical variables. This narrative review aimed to summarize the state of the art on the utility and evolution of old and emerging biomarkers in the diagnosis and prognosis of localized, high-risk PC, and the potential for their application in clinical practice. We focused on the theoretical molecular foundation of prostate carcinogenesis and explored the impact of genomic profiling, next-generation sequencing, and artificial intelligence in the extrapolation of customized features able to predict disease aggressiveness and possibly drive personalized therapeutic decisions.

160 Background: Apalutamide+androgen deprivation therapy (ADT) showed to significantly improve overall survival in low and high volume metastatic hormone sensitive prostate cancer (mHSPC) if compared to ADT alone. However, a randomized phase II trial (ARTO, NCT03449719) suggested that stereotactic body radiotherapy (SBRT) improved clinical outcomes when administered concomitantly with abiraterone acetate in metastatic castration resistance prostate cancer (mCRPC). Nonetheless, evidence related to use of SBRT in addition to androgen receptor pathway inhibitors (ARPIs) in oligometastatic HSPC is currently lacking. PERSIAN trial is aimed to test the hypothesis that metastases directed SBRT will improve outcomes in selected subgroups of patients with oligometastatic mHSPC treated with apalutamide + ADT. Methods: PERSIAN NCT05717660 is a phase II randomized trial enrolling patients affected by metachronous oligometastatic HSPC. Patients with de novo metastatic disease or with > 5 distant metastases are excluded from the trial. All patients are randomized to standard of care with apalutamide+ADT (ARM A: Control) or the same systemic treatment combined with SBRT on all sites of metastatic disease evidenced on conventional imaging (ARM B: Treatment). Here is presented the first interim analysis focused on rate of complete biochemical response (PSA < 0.2 ng/ml) after 3 months since apalutamide + ADT start. Results: Up to date, 174 patients have been enrolled (96.6% of the target sample size), 87 of these reached a minimum follow up of 3 months. Rate of patients with a complete biochemical response was 91.1% vs 92.9% in the control vs treatment arm, respectively (OR 1.27, 95% CI 0.27-6.03, p=0.765). Patients with PSMA positive lesions undetected on conventional imaging vs patients in whom number of target lesions was consistent on conventional and PSMA imaging had similar results (OR 0.74, 95%CI 0.08-6.94, p=0.791). Presence of bone metastatic lesions did not influence rate of complete biochemical response (OR 1.39, 95%CI 0.29-6.67, p-value 0.678). When adjusted for number of lesions, a significant benefit in favour of experimental arm was detected for patients with <3 metastatic sites (OR 5.88, 95%CI 1.13-33.3, p=0.03). Conclusions: Rate of early complete biochemical response showed a non significant trend in favour of experimental arm, with a 27% odds increase in the overall population for patients undergoing SBRT. Clinical benefit of SBRT is significantly improved in patients with lower burden of disease (<3 metastatic lesions). Trial accrual will be completed within the end of 2024, early results about complete biochemical response at 6 months in the complete cohort will be available in the second half of 2025. Clinical trial information: NCT03449719 .

Background and objective: For inoperable patients, stereotactic body radiation therapy (SBRT) is a noninvasive treatment approach for primary renal cell carcinoma (RCC). We aimed to evaluate local control (LC) of primary RCC treated with SBRT. Methods: This multicenter retrospective study involved 16 centers in Australia, France, Italy, and the Netherlands. The primary endpoint was the LC probability, and the secondary endpoints were progression-free survival, overall survival (OS), cumulative incidence of cancer-related deaths, toxicities, and renal function evolution after SBRT. Key findings and limitations: A total of 144 patients, treated between 2008 and 2020, with a median follow-up of 43 mo (interquartile range [IQR], 24.0-81.2), were included. The median age was 76 yr (IQR, 67.0-82.0) and the median tumor size was 4.4 cm (IQR, 3.3-5.6). The median baseline estimated glomerular filtration rate (eGFR) was 60 ml/ min/1.73 m2 . Of the patients, 40% had mild to moderate eGFR (30-60 ml/min). The two main treatment regimens were 42 Gy in three fractions and 26 Gy in one fraction. The LC probability was 98% at 1 yr (95% confidence interval [CI], 94-99) and 96% (95% CI, 92-99) at 5 yr. The median OS was 58 mo and the cumulative incidence of cancer-related deaths was 8% (95% CI, 3-15) at 5 yr. Seventy-one patients (49%) experienced at least one toxicity, including grade 1 in the majority (32%), grade 2 (14%), and grade 3 (1%). Two patients (1%) underwent dialysis (grade 4). The median eGFR loss was-7 ml/min (IQR, -17; 0) at the last follow-up. Conclusions and clinical implications: This large series of primary RCC treated with SBRT demonstrates exce llent LC and renal function preservation, and is associated with an acceptable toxicity profile. SBRT is an alternative treatment for inoperable patients. (c) 2025 Euro pean Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.