Citations

Abstract Objectives Sarcomatoid urothelial carcinoma (sUC) is associated with poor clinical outcomes. Herein, we evaluated clinicopathologic features (including PD-L1 expression) for institutional cases. Methods Sixty-five patients with sUC treated by radical cystectomy were matched for age, sex, and pathologic stage to 190 patients with pure urothelial carcinoma (UC). Outcomes were evaluated using the Kaplan-Meier method. Immunohistochemistry (IHC) results for tumor-specific PD-L1 expression in sUC were quantified using H-scores (range, 0-300). Cases with constitutive PD-L1 expression (cPD-L1; H-score ≥240) were evaluated for amplification events using fluorescence in situ hybridization (n = 28), mate-pair sequencing (Mpseq; n = 6), RNA sequencing (n = 5), and targeted next-generation sequencing (n = 8). PD-L1 regulatory pathways were evaluated using gene set enrichment analysis in the Cancer Hallmark dataset. Results Most patients with sUC had advanced disease (≥pT2, 62/65, 95%), without significant differences in overall and cancer-specific survival, when matched to pure UC. Median PD-L1 H-scores using different clones were 100 (SP142), 120 (SP263), and 195 (22C3). cPD-L1 was seen in 43% (28/65) of cases of sUC that were enriched for TP53, TERT, and CDKN2A/B alterations. PD-L1 amplification was identified in 7 (of 28, 25%) of these cases. Bionformatics analysis consistently identified IL6-JAK-STAT3 and interferon α/γ signaling in sUC with cPD-L1 expression. Conclusions Our results suggest that cPD-L1 expression in most sUC occurs secondary to IL6-JAK-STAT3 and interferon α/γ signaling. This provides a biologic rationale for evaluating response to immunotherapy in this patient population.

Non-muscle-invasive bladder cancer (NMIBC) comprises approximately 75% of new bladder cancer cases and generally carries a favorable prognosis, yet high rates of recurrence and progression necessitate close surveillance with frequent cystoscopies and repeated transurethral resections. Upfront treatment for high-risk disease is typically Bacillus Calmette-Guérin (BCG), although combinations with immune checkpoint inhibitors have reported results. Patients with BCG-unresponsive, intolerant, or refractory disease represent a subset of patients with high risk of progression, with early radical cystectomy being the standard approach for this setting. Global BCG shortages and the substantial impact of cystectomy on quality of life underscore the need for therapeutic alternatives. Over the past decade, investigational trials in immunotherapy have expanded treatment options for BCG-unresponsive NMIBC with CIS, leading to FDA approval of intravesical nadofaragene firadenovec, nogapendekin alfa-inbakicept, and systemic pembrolizumab. This narrative review summarizes developments in intravesical and systemic immunotherapies for NMIBC, highlights ongoing trials, and addresses controversies in trial design, treatment sequencing, comparative efficacy, and safety.

Importance Patients with recurrent prostate cancer after previous radiotherapy typically have poor survival. Those with recurrences prostate confined might be suitable for salvage focal therapy (sFT) or salvage radical prostatectomy (sRP). sFT may offer good cancer control with comparatively less toxic effects, but outcomes beyond 5 years have not been reported, and no study has compared sFT to sRP. Objective To compare cancer control and perioperative complications among patients after sFT vs sRP. Design, Setting, and Participants In this international, multicenter cohort study of matched comparison data, patients undergoing sFT were derived from the prospective UK HIFU (high-intensity focused ultrasound) Evaluation and Treatment and International Cryotherapy Evaluation registries (9 centers; 2006-2024) and the prospective UK Focal Recurrent Assessment and Salvage Treatment cohort study (6 centers; 2014-2018). Patients undergoing sRP were derived from an international retrospective registry (12 centers in 8 countries; 2000-2021). Patients with biopsy-confirmed, localized recurrent prostate cancer postradiotherapy, either external beam radiotherapy, brachytherapy, or both, were included. Data were analyzed from March to July 2025. Exposures sFT using HIFU or cryotherapy vs sRP. Main Outcomes and Measures The primary outcome was cancer-specific survival up to 10 years. Secondary outcomes were overall survival, any perioperative complications (Clavien-Dindo grades 1-5), and major perioperative complications (Clavien-Dindo grades 3-5). Comparisons were made on matched patients following 1:1 cardinality matching within individual multiply-imputed datasets. Matching variables used were radiotherapeutic treatment, years between primary and salvage treatments, European Association of Urology recurrence risk group, and presalvage age, prostate-specific antigen, prostate volume, grade group, T stage, and androgen-deprivation therapy use. Results A total of 923 patients were eligible for matching (419 undergoing sFT and 504 undergoing sRP). Of the patients undergoing sFT, 325 (77.6%) underwent HIFU and the remainder cryotherapy, with 241 (57.5%) treated with quadrant ablation. Of patients treated with sRP, 376 (74.6%) underwent open surgery and the remainder robot-assisted surgery. For sFT vs sRP, 10-year cancer-specific survival was 92% (95% CI, 86%-98%) vs 99% (95% CI, 97%-100%), with no statistically significant difference (restricted mean time lost, −0.09 years; 95% CI, −0.22 to 0.03 years; P = .15; subdistribution hazard ratio, 0.45; 95% CI, 0.05-4.00; P = .47). There was no statistically significant difference in 10-year overall survival (restricted mean survival time, −0.13 years; 95% CI, −0.86 to 0.60 years; P = .72). Undergoing sRP was associated with statistically significant higher odds of any complication (adjusted odds ratio, 24.20; 95% CI, 12.94-45.27; P < .001) and major complication (adjusted odds ratio, 9.31; 95% CI, 3.42-25.36; P < .001). Conclusions and Relevance In this cohort study, sFT and sRP were effective for treating localized radiorecurrent prostate cancer, while sFT was associated with fewer perioperative complications. sFT may provide a favorable therapeutic ratio for many patients with localized radiorecurrent prostate cancer.

PURPOSE Despite evidence of diagnostic accuracy but unclear long-term clinical benefit, national utilization patterns of prostate-specific membrane antigen positron emission tomography (PSMA-PET) are undefined. METHODS We conducted a serial cross-sectional study to evaluate the use of PET imaging among commercial insurance beneficiaries with prostate cancer using administrative claims from deidentified Blue Cross Blue Shield Axis database. Eligible patients included prevalent and incident prostate cancer cases. We calculated the proportions undergoing PET imaging in semiannual periods from January 1, 2016, through December 31, 2024. We examined the association between regional-level contextual sociodemographic and health care characteristics, and regional use of PSMA-PET imaging in 2024. RESULTS A total of 514,750 male beneficiaries age 40-89 years with prostate cancer were identified between 2016 and 2024. The proportion of individuals with prostate cancer undergoing PET imaging increased from 4.5 [95% CI, 4.1 to 4.9] per 1,000 in the first half of 2016 to 77.6 (95% CI, 76.2 to 79.1) per 1,000 in the second half of 2024, P < .001. Increases in PET were driven by uptake of PSMA-PET following approval in 2021, which increased from 0.8 (95% CI, 0.6 to 0.9) per 1,000 in the second half of 2021 to 77.0 (95% CI, 75.5 to 78.5) per 1,000 in the second half of 2024, P < .001. PSMA-PET use in 2024 was higher in regions with greater education (99.3 v 114.6 per 1,000 in lowest [Q1] v highest [Q4] educated) and income (95.4 v 112.3 per 1,000 in Q1 v Q4 income) measures, P < .001. CONCLUSION PSMA-PET was rapidly incorporated into clinical practice among commercial insurance beneficiaries with prostate cancer with higher adoption in geographic regions with higher income and education.

Abstract Background Prostate cancer is a heterogeneous disease comprising diverse cell types within the tumor microenvironment that support cancer cell survival. Using single cell and spatial transcriptomics, we previously identified subpopulations of treatment-persistent cancer cells exhibiting regenerative properties and a distinct molecular signature. Herein, we aimed to characterize the locked ‘Persist’ signature (PS) and its association with outcomes in a large cohort of non-metastatic prostate cancer tumors. Methods Patients with non-metastatic prostate cancer that underwent Decipher prostate genomic classifier and whole-transcriptome profiling on biopsy (BX, n=146,941) and radical prostatectomy (RP, n=55,329) specimens between October 2016 and February 2024 were included (Veracyte Inc., San Diego, CA, USA). Baseline clinical and pathological data from deidentified patients as well as signature scores were retrieved from the Decipher Genomic Resource for Intelligent Discovery (GRID) registry (Clinical Trials identifier: NCT02609269). The PS score based on the expression of 17 genes was calculated for all samples. Results PS was significantly associated with adverse clinical and pathological variables. In biopsy sample, PS was higher in cases with worse T3/4 clinical stage, Grade group (GG4-5), and high/very high NCCN risk (p&lt;0.001 for all). In RP sample, PS was significantly higher in patients with GG4-5, extraprostatic extension, seminal vesicle invasion and lymph node involvement (p&lt;0.001 for all). PS was also higher in patients with very high Decipher (&gt;0.85) in both BX and RP (p&lt;0.001 for both). When evaluating the prognosis of PS in multiple retrospective cohorts, PS in biopsy was prognostic of adverse pathology features at RP. PS was also prognostic of distance metastasis (DM) in multiple RP cohorts with long-term follow up (META855). In the ARNEO trial testing apalutamide in addition to ADT as neo-adjuvant treatment prior RP, PS was prognostic of early recurrence. In the Stampede trial, PS was prognostic of progression free survival, PCSM and OS in both non-metastatic and metastatic disease. When associating PS with other GRID signatures, PS was higher in samples with homologous recombination deficiency, TP53 mutations, Luminal B and luminal proliferating subtypes. On the other hand, PS was lower in samples with low androgen receptor-activity, RB-loss and neuroendocrine-like tumors. Finally, PS was positively correlated with radiation sensitivity signatures. Conclusions Persist is a novel molecular signature associated with more aggressive tumor characteristics. Future studies aim to further examine beyond this signature potential to identify patients at risk of aggressive prostate cancer, and understand what the optimal treatments for those with treatment-persistent prostate cancer cells are. Citation Format: Francesco Ballesio, Sinja Taavitsainen, Mohammed Alshalalfa, Antti Kiviaho, Mazlina Ismail, Reetta Nätkin, Alexander Giesen, Thomas Munro, James A. Proudfoot, Hyunnam Ryu, Elai Davicioni, Matthew C. Cooperberg, R. Jeffrey. Karnes, Ruochen Jiang, Steven Joniau, Gerhardt Attard, Frank Claessens, Matti Nykter, Alfonso Urbanucci. Persist: a molecular signature for prostate cancer patients with preexisting treatment-persistent cells associated with aggressive disease [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B079.

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions for patients with prostate cancer across the disease spectrum. The Guidelines sections included in this article focus on metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). For patients with mCSPC, disease characteristics, such as whether metastases arose synchronously or metachronously and the degree of metastatic burden, impact therapy decisions, including how much treatment intensification is appropriate and when prostate-directed and/or metastasis-directed therapy should be considered. In the mCRPC setting, androgen deprivation therapy is continued with the sequential or concurrent addition of certain androgen receptor pathway inhibitors, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, biomarkers, the extent and location of metastases, symptoms, and potential side effects.

Importance Prostate-specific membrane antigen positron emission tomography (PSMA-PET), a form of molecular imaging, increases detection of advanced and metastatic prostate cancer, but its potential to increase treatment costs due to increased detection is poorly defined. Objective To estimate lifetime health and cost outcomes and evaluate the cost-effectiveness associated with implementing PSMA-PET in the clinical evaluation of a patient with a biochemical recurrence (BCR) of prostate cancer, with evaluation of sources of uncertainty in the underlying evidence and assessment of the need and focus of additional data collection. Design, Setting, and Participants This economic evaluation developed a decision-analytic model consisting of a decision tree and a Markov model informed by published literature and a study of patients with BCR prostate cancer undergoing PSMA-PET after definitive surgery or radiation therapy at 2 high-volume US academic centers. The analysis was performed between August 1, 2024, and May 1, 2025. Interventions Patients underwent (1) PSMA-PET, (2) PSMA-PET imaging as a reflex test if computed tomography plus bone scan (CTBS) was negative or equivocal (CTBS + PSMA-PET), and (3) CTBS alone. Main Outcomes and Measures Lifetime quality-adjusted life-years (QALYs) and costs, incremental cost-effectiveness ratio (ICER), and value of information estimates were assessed, with 95% uncertainty intervals (UIs). We assumed a willingness-to-pay threshold of $150 000 per QALY. Results The model simulated 1000 patients with BCR (median age, 66 years) and estimated that up-front PSMA-PET is expected to have the highest mean QALYs (7.12 QALYs [95% UI, 6.71-7.51 QALYs]) compared with 6.55 QALYs (95% UI, 6.08-7.03 QALYs) for CTBS; it was also estimated to have higher mean costs ($451 000 [95% UI, $336 000-$577 000]) compared with $351 000 (95% UI, $263 000-$455 000]) for CTBS; consequently, PSMA-PET had mean increments of $99 000 (95% UI, $55 000-153,000) in costs and 0.58 QALYs (95% UI, 0.35-0.82 QALYs) compared with CTBS, leading to an ICER of $172 000 per QALY, which exceeded the assumed $150 000/QALY willingness-to-pay threshold. In patients with lower prostate-specific antigen levels (&amp;lt;2 ng/mL), PSMA had mean increments of $61 000 (95% UI, $21 000-$104 000) in costs and 0.54 QALYs (95% UI, 0.34-0.77 QALYs) compared with CTBS, leading to an ICER of $113 000/QALY, suggesting it had the potential to be cost-effective. Because of high decisional uncertainty, additional information regarding outcomes and diagnostic characteristics may be associated with reduced uncertainty and a gain of 15 747 QALYs. Conclusions and Relevance This study found that PSMA-PET may be associated with improved disease detection but may not be cost-effective due to high treatment costs offsetting moderate improvements in QALYs. Further research is needed to identify patient subsets and clinical scenarios in which molecular imaging provides the greatest value.

Objective To investigate the diagnostic performance of perilesional biopsies (PLBx) compared to other biopsy strategies, assessing the impact of the Prostate Imaging‐Reporting and Data System (PI‐RADS) score and biopsy history in patients with a visible lesion at multiparametric magnetic resonance imaging of the prostate (mpMRI), as the European Association of Urology guidelines recommend combining MRI‐targeted biopsies (TBx) with PLBx as an alternative to systematic biopsies (SBx) even though evidence is limited. Patients and Methods We relied on a cohort of 2852 patients with PI‐RADS ≥3 lesions undergoing TBx + SBx at three tertiary referral centres. The primary outcome was detection of clinically significant PCa (csPCa) (International Society of Urological Pathology Grade Group [ISUP GG] ≥2) of TBx + PLBx vs TBx + SBx. Results were stratified by PI‐RADS score and biopsy history. The PLBx cores were defined as samples taken from prostate sectors adjacent to the mpMRI lesion. We finally assessed insignificant PCa (insPCa, i.e., ISUP GG 1) detection across biopsy strategies. Differences were assessed using the chi‐square test. Results Detection of csPCa was 48%. Overall, TBx + SBx had a higher csPCa detection rate than TBx + PLBx (50% vs 45%, P = 0.03), particularly in PI‐RADS 3 lesions (26% vs 21%, P = 0.02) and active surveillance (AS) patients (46% vs 40%, P = 0.04). No significant differences were found in PI‐RADS 4 (53% vs 50%, P > 0.1) or PI‐RADS 5 (76% vs 75%, P > 0.1). In the biopsy naïve and previous negative biopsy groups, csPCa detection was similar between strategies ( P > 0.1). Conclusions Overall, TBx + SBx offers the highest detection of csPCa. Even though TBx + PLBx may be considered in PI‐RADS 4–5 lesions to reduce insPCa detection, TBx + SBx remains the preferred strategy for PI‐RADS 3 and AS patients.

ABSTRACT Purpose The natural history of biochemical recurrence (BCR) after radical prostatectomy (RP) remains understudied, with limited long‐term data from large cohorts inclusive of both salvage radiotherapy (SRT)‐treated and untreated patients. Herein, we sought to evaluate the outcomes of patients with BCR and the impact of SRT on disease progression. Materials and Methods Patients undergoing RP who developed BCR (PSA ≥ 0.20 ng/mL) were included. Patients with BCR treated with SRT were compared to untreated patients using risk‐set matching with time‐dependent propensity scores. The primary outcome was metastases, analyzed using Kaplan–Meier and Cox models. The number needed to treat (NNT) with SRT to prevent progression was derived at 5 and 15 years. Results Among 6881 patients with BCR, 2109 received SRT. At a median follow‐up of 10.2 years, 1147 patients developed metastases. The median PSA at the time of SRT was 0.50 ng/mL. After 1:1 propensity score matching (2109 patients per cohort), SRT significantly reduced the risk of metastases at 5 (12.7% vs. 19.3%, p < 0.0001) and 15 years (28.6% vs. 31.5%, p < 0.001). On multivariable analysis, SRT independently reduced metastasis risk (HR 0.75, 95% CI 0.63–0.90, p = 0.002), translating to NNT of 23 and 15 at 5 and 15 years, respectively. Interaction analyses between SRT and nodal status ( p = 0.04) showed greater metastasis risk reduction in pN+ (HR 0.41, 95% CI 0.22–0.77, p = 0.005) compared to pN− disease (HR 0.81, 95% CI 0.67–0.97, p = 0.02). Conclusions Most patients with BCR post‐RP do not progress to metastasis. For those who do progress, SRT inarguably improves the oncologic outcomes in the BCR setting. However, careful patient selection and shared decision making should be encouraged in order to limit overtreatment and side effects.