INTRODUCTION: The incidence of synchronous metastatic hormone-sensitive prostate cancer (mHSPC) is rising with the increasing use of next-generation imaging. Local radiotherapy (RT) was shown to improve survival in patients with mHSPC; however, new data require a re-assessment of the indication and value of local RT in mHSPC. METHODS: In this prospectively registered systematic review and meta-analysis (CRD42025648251), we searched MEDLINE, Scopus, CENTRAL, and Google Scholar in March 2025 for phase 3 RCTs evaluating the addition of RT to systemic therapy to improve OS in mHSPC patients. Hazard ratios (HRs) were pooled using random-effects meta-analysis. Risk of Bias was assessed with Cochrane's RoB 2 tool. RESULTS: Out of the 10,615 individual records, we identified three RCTs: HORRAD (n = 432), STAMPEDE (n = 2,061), and PEACE-1 (n = 1,173). The systemic treatment included androgen deprivation therapy (ADT) in HORRAD, ADT ± Docetaxel in STAMPEDE, and ADT ± Docetaxel ± Abiraterone in PEACE-1 trial. Local RT was not associated with significantly improved OS in all patients (HR = 0.92; 95 % confidence interval [CI] 0.85-1.00; p = 0.06), or in those with low metastatic burden (HR = 0.74; 95 %CI 0.51-1.06; p = 0.1); however, exploratory analyses showed a significant improvement in androgen deprivation resistance-free survival (HR = 0.76; 95 %CI 0.70-0.82; p < 0.001). Local RT was associated with significant reduction in local prostate cancer related events in the HORRAD (18 % vs. 30 %) and PEACE-1 (12 % vs. 22 %) trials, but not in the STAMPEDE trial (49 % vs. 51 %). CONCLUSION: Local RT does not improve OS in unselected patients treated with modern systemic therapies for mHSPC. However, it delays ADT resistance and reduces local adverse events, with relatively tolerable toxicity. Future studies should refine selection criteria, ideally using PSMA-PET imaging, dynamic response markers, and/or genomic profiling, to identify mHSPC patients most likely to benefit from local RT.

• Keywords
• Adverse events, Local treatment, Metastatic hormone sensitive prostate cancer, Overall survival, Primary tumor/prostate/local treatment, Radiotherapy,
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: To validate the clinical utility of a previously identified circulating tumor DNA methylation marker (meth-ctDNA) panel for disease detection and survival outcomes, meth-ctDNA markers were compared to PSA levels and PSMA PET/CT findings in men with different stages of prostate cancer (PCa). METHODS: 122 PCa patients who underwent [⁶⁸Ga]Ga-PSMA-11 PET/CT and plasma sampling (03/2019-08/2021) were analyzed. cfDNA was extracted, and a panel of 8 individual meth-ctDNA markers was queried. PET scans were qualitatively and quantitatively assessed. PSA and meth-ctDNA markers were compared to PET findings, and their relative prognostic value was evaluated. RESULTS: PSA discriminated best between negative and tumor-indicative PET scans in all (AUC 0.77) and hormone-sensitive (hsPC) patients (0.737). In castration-resistant PCa (CRPC), the meth-ctDNA marker KLF8 performed best (AUC 0.824). CHST11 differentiated best between non- and metastatic scans (AUC 0.705) overall, KLF8 best in hsPC and CRPC (AUC 0.662, 0.85). Several meth-ctDNA markers correlated low to moderate with the tumor volume in all (5/8) and CRPC patients (6/8), while PSA levels correlated moderately to strongly with the tumor volume in all groups (all p < 0.001). CRPC overall survival was independently associated with LDAH and PSA (p = 0.0168, p < 0.001). CONCLUSION: The studied meth-ctDNA markers are promising for the minimally-invasive detection and prognostication of CRPC but do not allow for clinical characterization of hsPC. Prospective studies are warranted for their use in therapy response and outcome prediction in CRPC and potential incremental value for PCa monitoring in PSA-low settings.

• Keywords
• DNA methylation, Epigenetics, PET/CT, PSMA, Prostate cancer, cfDNA,
• MeSH
• Circulating Tumor DNA * blood   genetics   MeSH
• Gallium Isotopes MeSH
• Middle Aged MeSH
• Humans MeSH
• DNA Methylation * MeSH
• Biomarkers, Tumor * genetics   blood   MeSH
• Prostatic Neoplasms * genetics   diagnostic imaging   blood   MeSH
• Positron Emission Tomography Computed Tomography * methods   MeSH
• Prognosis MeSH
• Prostate-Specific Antigen blood   MeSH
• Cross-Sectional Studies MeSH
• Gallium Radioisotopes MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Circulating Tumor DNA * MeSH
• gallium 68 PSMA-11 MeSH Browser
• Gallium Isotopes MeSH
• Biomarkers, Tumor * MeSH
• Prostate-Specific Antigen MeSH
• PSMA-11 MeSH Browser
• Gallium Radioisotopes MeSH

Purpose: The addition of androgen receptor pathway inhibitors (ARPIs) to androgen deprivation therapy (ADT), with or without docetaxel (Doc), is currently recommended for metastatic, hormone-sensitive prostate cancer (mHSPC). Recently, the ARANOTE trial evaluated the efficacy and safety of Darolutamide + ADT in this setting. We aimed to update a network meta-analysis (NMA) of these combination therapies. Methods: We conducted a systematic search for RCTs on systemic therapies for mHSPC using MEDLINE, Embase, and the Web of Science Core Collection in September 2024. An NMA utilizing random-effects models was performed to compare progression-free survival (PFS), overall survival (OS), and adverse event (AE) incidence (PROSPERO: CRD42024591458). Results: A total of 12 RCTs (n = 11,954) were included in our NMAs. Triplet therapies were associated with significant improvements in PFS compared to ARPI-based doublet therapies (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.59-0.93; p = 0.01), but the difference did not reach the conventional levels of statistical significance for OS (HR: 0.82; 95% CI: 0.67-1.01; p = 0.059). In a subset analysis, compared to ARPI-based doublet therapies, triplet therapies showed a significant improvement in PFS in patients with high-volume disease (HR: 0.64; 95% CI: 0.47-0.88; p < 0.01), whereas no significant improvement was observed in those with low-volume disease (HR: 0.86; 95% CI: 0.45-1.67; p = 0.7). No significant difference in grade ≥ 3 AEs was observed between triplet therapies and ARPI-based doublet therapies. The main limitations include patient heterogeneity and limited follow-up in some studies. Conclusions: Triplet therapies can improve the oncologic outcomes of patients with mHSPC compared to ARPI-based doublet therapies, without significantly increasing severe AEs. These findings warrant further confirmation in a head-to-head trial powered for overall survival.

• Keywords
• ARPI, adverse event, docetaxel, mHSPC, network meta-analysis, overall survival, progression-free survival, systematic review, triplet therapy,
• Publication type
• Journal Article MeSH
• Review MeSH