Background: Homologous recombination repair (HRR) testing is increasingly relevant in prostate cancer because it identifies patients who may benefit from biomarker-guided treatment strategies, including poly(ADP-ribose) polymerase inhibitors (PARPi). However, real-world implementation of HRR testing remains variable across countries and clinical settings, and the extent to which current testing pathways capture actionable alterations is not well defined. Methods: ARON-3 is a multinational, multicentre, retrospective real-world study of patients with prostate cancer. In this subanalysis, we assessed genomic testing uptake within the overall ARON-3 cohort and characterised HRR testing pathways and detected pathogenic alterations among patients with available genomic results. Genomic testing included germline, somatic tumour, and/or circulating tumour DNA (ctDNA) assays performed in routine practice across participating centres. Multivariable logistic regression was used to identify clinicopathologic factors associated with undergoing genomic HRR testing. Results: Among 2,192 patients included in ARON-3, genomic testing results were available for 719 (33%). Among tested patients, 660 (92%) underwent germline testing and 610 (85%) somatic testing; 549 (77%) underwent both, whereas 109 (15%) had germline-only and 61 (8%) somatic-only testing. In multivariable analysis, metastatic castration-resistant prostate cancer, high-volume disease, and Gleason score > 8 were independently associated with higher odds of testing, while age >= 70 years was associated with lower odds of testing. Overall, 238 tested patients (33%) harboured pathogenic HRR alterations, corresponding to 11% of the entire ARON-3 cohort. Somatic pathogenic alterations were more frequent than germline alterations. BRCA2 was the most frequently altered gene, while non-BRCA1/2 alterations were also detected, particularly in centres using broader multigene panels. Most centres relied on BRCA1/2-focused assays, and the use of liquid biopsy remained limited. Conclusions: This multinational real-world analysis demonstrates substantial heterogeneity in HRR testing uptake and testing pathways across participating ARON-3 centres. Testing was more commonly performed in patients with more advanced disease features, suggesting that clinically relevant subgroups may still be differentially selected for genomic assessment. Broader and more standardised implementation of comprehensive HRR profiling may improve the identification of actionable alterations and strengthen precision medicine in prostate cancer.
ABSTRACT Background Acromegaly is characterized by organomegaly driven by chronic GH/IGF‐1 excess, and the prostate gland may be affected as part of this generalized organ enlargement. Although prostatic enlargement has been documented in previous studies, whether it is accompanied by symptomatic or functional impairment and its potential impact on quality of life remain unclear. This study aimed to evaluate prostate‐related changes in male patients with active and remitting acromegaly compared to healthy controls, and to assess their association with lower urinary tract symptoms, mood, and quality of life. Methods This cross‐sectional study included 57 male patients with acromegaly (25 active, 32 in remission) and 24 healthy male controls of comparable age and BMI. All participants underwent transabdominal prostate ultrasonography, uroflowmetry, and completed the IPSS, SF‐36, PHQ‐9, GAD‐7, and FSS questionnaires. The AcroQoL was administered to the acromegaly group. Correlations between IGF‐1 levels and prostate parameters were analyzed using Spearman's correlation. Results Patients with acromegaly had a larger median prostate volume (30 vs. 20 mL, p = 0.03), more frequently had a prostate volume exceeding 30 mL (47% vs. 11%, p = 0.004), and more frequently had prostatic calcification (31% vs. 5%, p = 0.03) than controls, despite lower testosterone levels. Within the acromegaly group, a prostate volume exceeding 30 mL was more frequent in active disease than in remission (64% vs. 33%, p = 0.02), whereas median prostate volume did not differ significantly (31 vs. 24.5 mL, p = 0.1). IGF‐1 was correlated with free PSA (rho = 0.29, p = 0.03) but not with total prostate volume (rho = 0.09, p = 0.53). Calcification rates did not differ by remission status. No significant differences were observed in IPSS scores, uroflowmetry parameters, SF‐36, PHQ‐9, GAD‐7, or AcroQoL between groups. Conclusion Male patients with acromegaly have larger prostate volumes and more frequent prostatic calcification than controls; prostatic enlargement was more frequent in active disease, whereas calcification did not differ by remission status. These structural alterations were not accompanied by differences in lower urinary tract symptoms, uroflowmetry parameters, or quality of life, suggesting that dedicated urologic surveillance may not be warranted in asymptomatic middle‐aged patients.
ABSTRACT Background Circulating steroid trajectories after robot‐assisted radical prostatectomy are poorly characterized from the day‐of‐surgery baseline, and relevant biology extends beyond testosterone and dihydrotestosterone to adrenal‐derived 11‐oxygenated androgens and steroid conjugate turnover. This study aimed to characterize 3‐ and 6‐month plasma steroid differences from a day‐of‐surgery baseline and evaluate baseline steroid biomarkers for adverse pathology, upgrading, and early detectable prostate‐specific antigen (PSA). Methods This prospective, single‐center cohort included 173 men undergoing robot‐assisted radical prostatectomy. Fasting plasma was sampled before premedication on the morning of surgery and at 3 and 6 months. A 34‐analyte steroid panel, including conjugated analytes, was quantified using liquid chromatography–tandem mass spectrometry. Longitudinal differences were analyzed using mixed‐effects models. Baseline screening used logistic regression with false discovery rate correction and adjusted models for retained signals. Results For most analytes, 168–170 baseline samples and 131/108 samples at 3/6 months were available. Relative to baseline, 11‐ketotestosterone increased at 3 and 6 months (fold changes 1.36 [95% CI 1.24–1.49] and 1.25 [1.13–1.38]), corticosterone decreased (0.61 [0.52–0.70] and 0.59 [0.51–0.69]), cortisol decreased (0.91 [0.84–1.00] and 0.86 [0.78–0.94]), and conjugated corticosterone/corticosterone increased (1.96 [1.57–2.45] and 2.41 [1.90–3.06]), all p < 0.04. At 6 months, neither testosterone (fold change 0.88; 95% CI 0.75–1.03) nor dihydrotestosterone (0.90; 0.79–1.04) differed significantly from the day‐of‐surgery baseline. The conjugated/unconjugated estrone ratio (E1C/E1) was the only retained baseline adverse‐pathology signal, with inverse adjusted associations for pT3a/b disease (OR 0.61; 95% CI 0.41–0.90; p = 0.013) and composite adverse pathology (OR 0.53; 95% CI 0.36–0.78; p = 0.001). No biomarker remained significant for upgrading or detectable PSA. Conclusions Relative to the day‐of‐surgery baseline, longitudinal differences involve corticosteroid‐related and 11‐oxygenated analytes, but their mechanisms remain unresolved. These data define postoperative steroid trajectories from a day‐of‐surgery baseline without establishing prostatectomy‐specific endocrine effects. Baseline E1C/E1 warrants external validation as a hypothesis‐generating marker of adverse pathology.
Background We sought to characterize an LHB-associated tumor transcriptomic state across public prostate cancer datasets. Tumor LHB expression and the correlation-derived signature were treated as molecular measurements only; serum luteinizing hormone and testosterone were not available or analyzed.Methods In 501 TCGA-PRAD tumors, the 25 genes most positively and 25 most negatively correlated with LHB defined a direction-weighted signature. The frozen score was projected without refitting into GSE54460, GSE116918, and two GSE21034 platform views. Cohort-specific grade, biochemical recurrence, and compact expression programs were evaluated. Program genes did not overlap the signature, and LHB was excluded from steroidogenesis. In GSE176031, upper and lower signature-score quartiles were compared within each of 53 samples.Results The score was higher in high-grade TCGA-PRAD tumors (mean difference, 0.327; P = 7.12 & times; 10-9) and had positive but heterogeneous grade differences in the external datasets. Across all five bulk views, the score correlated negatively with androgen receptor signaling (r = -0.365 to -0.627) and positively with cell cycle (r = 0.283-0.692) and epithelial-mesenchymal transition (r = 0.217-0.734). Direct LHB transcripts were detected in 30 of 53,765 cells. Sample-level single-cell contrasts showed lower androgen receptor signaling and higher cell-cycle and epithelial-mesenchymal-transition scores in signature-high epithelial states; the LHB-excluded steroidogenesis contrast was near zero.Conclusions The LHB-correlation-derived signature identifies an AR-low, proliferative, mesenchymal-associated expression state across datasets. It does not measure circulating hormones, establish LHB-dependent biology, or support clinical use. Paired molecular and functional studies are required.
Background Androgen receptor pathway inhibitors (ARPIs) such as abiraterone and enzalutamide are common therapies in the management of metastatic castration-resistant prostate cancer (mCRPC). However, the comparative effectiveness of these oral ARPIs in frail and comorbid patient populations remains uncertain. This study aims to determine whether one ARPI is associated with longer overall survival (OS) than the other, expanding upon prior work through inclusion of a contemporary patient cohort and examination of how comorbidities influence OS.Methods Using data from the nationwide Veterans Affairs (VA) healthcare system, we identified 8859 veterans with mCRPC treated with either abiraterone or enzalutamide between September 2014 and September 2022. Patients with prior docetaxel exposure were excluded, and frailty was defined using the VA Frailty Index (VA-FI). Analyses were weighted for clinical covariates, including age, race, and BMI, using IPTW. Kaplan-Meier analysis was used to compare OS between treatment groups.Results Among frail patients with mCRPC, enzalutamide treatment was associated with longer OS compared to abiraterone (22.8 vs. 20.9 months, p = 0.001). Similarly, enzalutamide was associated with longer OS than abiraterone among patients with cardiovascular disease or diabetes (26.3 vs. 23.9 months, p = 0.023) and among patients without cardiovascular disease or diabetes (30.0 vs. 28.0 months, p = 0.019).Conclusions Enzalutamide was associated with improved OS compared to abiraterone in frail patients with mCRPC, regardless of comorbid cardiovascular disease or diabetes. These findings highlight the importance of considering specialized patient populations, including frailty and comorbidity profiles, in ARPI selection and clinical care.
