Karnes, R. Jeffrey

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 (<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.

Purpose: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) improves prostate cancer (PCa) localization, particularly in biochemical recurrence (BCR). The primary objective was to assess management patterns after PSMA-PET for BCR at 2 academic centers. Methods: This study evaluated clinical management within 6 months after first PSMA-PET for patients with BCR after local therapy. Management categories included no treatment, local therapy, systemic therapy, and metastasis-directed therapy (MDT). We also evaluated clinical management decision variation across strata of PSMA-PET results PSA levels (<2.0, 2.0-4.99, and ≥5.0 ng/mL) at time of imaging. Results: We identified 581 patients who received PSMA-PET from February 2021 to June 2023. PSMA-PET findings were negative in 142 (24%) and demonstrated localized recurrence in 86 (15%), regional nodal disease in 60 (10%), and distant metastasis in 293 (50%). Distant metastasis was identified in 105 (35%) patients with PSA < 2.0, 67 (60%) with PSA 2.0 to 4.99, and 115 (71%) with PSA ≥ 5.0. In patients with negative PSMA-PET, 63 (44%) received treatment. Conversely, 92% with detected metastases were treated (systemic therapy in 189 [64%], MDT in 75 [26%], and local therapy in 7 [2%]). Treatments differed by the PSA level within strata of PSMA-PET findings. Among 293 patients with metastases, MDT was used more commonly in patients with PSA < 2.0 (37%) than PSA 2.0 to 4.99 (30%) or PSA ≥ 5.0 (13%). Conclusions: Most patients undergoing PSMA-PET for BCR had identifiable disease and initiated therapy within 6 months. Identification of distant metastases and treatment choices differed by the PSA level at imaging. Prospective research is needed to determine whether earlier detection and treatment initiation improve clinical outcomes.

ABSTRACTBackgroundCommercial biomarkers and multiparametric MRI (mpMRI) have been utilized to triage men with elevated prostate specific antigen (PSA) and determine patients most likely to harbor clinically‐significant prostate cancer (csPCa). We studied combinations of mpMRI, PSA‐based and novel extracellular vesicle (EV)‐based biomarkers to determine the optimal pre‐biopsy testing to predict csPCa at biopsy.MethodsMen presenting with elevated PSA (≥ 2 ng/mL) were prospectively enrolled and all men underwent clinically indicated mpMRI and blinded study blood draws to determine PSA, prostate health index (PHI) scoring, and EV serum levels. MRI‐fusion transperineal prostate biopsy was performed in all patients. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and receiver operator characteristic (ROC) curves were constructed. Bootstrapping analysis was performed to provide more accurate assessment of predictive abilities.ResultsUltimately, 175 consecutive men were prospectively enrolled. Median age in the study population was 65 years. Combinations of biomarkers and MRI demonstrated better predictive ability for csPCa on biopsy than individual modalities. Predictive ability was greatest for PHI density (PHID)‐mpMRI with an AUC of 0.86 (95% CI: 0.80–0.92) while combinations of PSA density ‐mpMRI (AUC: 0.81; 95% CI: 0.73–0.89) and STEAP1‐mpMRI (AUC: 0.77; 95% CI: 0.70–0.86) demonstrated similar ability to predict csPCa. The study is limited by small, predominantly white patient cohort and requires external validation.ConclusionsInclusion of prostate density with biomarkers increases prognostic ability for detecting csPCa. EV density can refine prediction of csPCa and in combination with PHID‐mpMRI leads to superior specificity, thereby decreasing unnecessary biopsies.

202 Background: While several PARP inhibitors are approved in combination with hormonal therapies for metastatic castrate resistant prostate cancer (CRPC), their use in castrate sensitive prostate cancer (CSPC) is understudied. We previously reported that olaparib monotherapy (without ADT) shows significant clinical activity in BRCA2 -altered patients with biochemically recurrent (BCR) prostate cancer. Here, we explored prognostic and predictive PARP-related mRNA biomarkers derived from primary prostate tumors. Methods: We characterized the expression of 16 PARP transcripts using a cohort of 52,266 radical prostatectomy (RP) specimens (2016-2024) undergoing Decipher prostate genomic classifier testing (Veracyte Inc). Transcriptome-wide mRNA expression data as well as baseline clinical/pathologic factors were retrieved from the Decipher GRID database (NCT02609269). Associations between high PARP expression (top 25%), baseline factors, and gene signatures were examined using logistic regression. We assessed the association between PARP expression and distant metastases in 3 retrospective cohorts (n= 545, 855, and 325). Finally, we evaluated PARP expression in our prior phase II trial (NCT03047135, n=39) of olaparib monotherapy in the setting of BCR following RP. Results: Higher mRNA levels of PARP1 , 2 , 8 and 14 showed strong associations (all P <0.001) with known adverse prognostic factors such as very-high Decipher score (>0.85), high Gleason grade (GG5) and non-organ confined disease (EPE, SVI and LNI), while higher PARP6 and 7 expression were associated with more favorable disease characteristics. High PARP1 expression was positively correlated with DNA-repair deficiency (r=0.77) and tumor immune microenvironment (r=0.62) signatures. In 3 independent retrospective cohorts of intermediate-high risk PCa patients, higher PARP1 expression was strongly associated with development of distant metastases after RP (HR 1.70, 1.81, and 1.67 respectively; all P <0.05). Finally, in our phase II trial of patients with BCR who received olaparib monotherapy, PARP1 (but not PARP2 ) expression from RP was 1.5-fold higher in samples with BRCA2 mutations (median 0.416 vs 0.276, P =0.01) and was associated with overall improved PSA progression-free survival (continuous variable, HR 0.55, P =0.01) and longer time to next systemic treatment (continuous variable, HR 0.66, P =0.02). Conclusions: High PARP1 mRNA expression, measured at RP, is associated with aggressive disease biology and greater risk of metastasis. However, high PARP1 (but not PARP2 ) levels are associated with improved response to PARP inhibition in the setting of BCR prostate cancer. Future trials testing PARP (including PARP1-selective) inhibitors in the CSPC space should consider measuring PARP1 mRNA levels in addition to BRCA1/2 mutation status. Clinical trial information: NCT02609269 , NCT03047135 .

382 Background: The natural history of biochemical recurrence (BCR) after radical prostatectomy (RP) is heterogeneous, with most patients not progressing to metastasis. Determining the impact and optimal timing of salvage radiation therapy (SRT) remains challenging, particularly in the absence of prospective randomized trials with a surveillance control arm. Our objective isto quantify the oncologic benefit of SRT among men with BCR after RP. Methods: Patients who underwent RP at Mayo Clinic between 1990 and 2017 and developed BCR (PSA≥0.20ng/mL) were included. Patients treated with SRT were compared to those managed with surveillance using risk-set matching with time-dependent propensity scores, accounting for covariates at BCR and post-BCR. The primary outcome was metastases, analyzed via Kaplan-Meier and Cox proportional hazard models. The number needed to treat (NNT) with SRT to prevent progression was calculated using regression outputs at 5 and 15 years post-BCR. Interaction analyses identified factors modifying SRT’s effect on metastasis. Results: Of 6,881 patients with BCR, 2,109 received SRT. At a median follow-up of 10.2 years, 1,147 patients with BCR developed metastases. After 1:1 matching, SRT was associated with lower metastasis risk than surveillance at 5 years (12.7% vs 19.3%, p<0.0001) and 15 years (28.6% vs. 31.5%, p<0.001). SRT was independently associated with decreased metastasis risk (HR 0.75, 95%CI 0.63–0.90, p=0.002) on multivariable analysis, translating to NNT of 23 and 15 at 5 and 15 years, respectively (Table). Additionally, we noted a significant interaction between PSA at SRT and the association of SRT with metastasis (p-interaction=0.02), such that the reduction in metastatic progression with SRT vs. surveillance was restricted to the cohort of patients who received SRT for PSA>0.40ng/mL (HR 0.66, 95%CI 0.54–0.80, p<0.001). Conclusions: Most patients with BCR post-RP do not develop metastases. Indeed, the NNT with SRT to reduce metastasis versus surveillance indicates a generally indolent disease course. Further, the lack of a significant association of SRT with reduction of metastases in patients with a PSA≤0.40ng/mL underscores the importance of careful patient selection when considering early SRT. Our data establish the rationale for a randomized trial comparing early SRT versus surveillance for appropriately selected patients with BCR after RP. Hazard ratios of SRT after matching by propensity scores, and number needed to treat for systemic progression, prostate cancer specific mortality and overall mortality. DiseaseOutcome Hazard Ratio(95% CI) P value Number Needed to Treat* (95% CI) 5 years 15 years Systemic progression 0.75(0.63 – 0.90) 0.002 23(17 – 41) 15(11 – 27) Prostate cancer mortality 0.81 (0.64 – 1.03) 0.086 103(62 – 494) 26(15 – 124) Overall mortality 0.79 (0.70 – 0.89) 0.0001 38(29 – 62) 12(9 – 20) *Number needed to treat (NNT) calculated using regression based absolute differences in event free survival between salvage radiation therapy (SRT) and observation.

410 Background: Inflammasomes are multiprotein complexes that regulate inflammation-associated signaling pathways. Although inflammation plays a crucial role in cancer cell proliferation, the specific role of inflammasomes in prostate cancer (PCa) remains underexplored. This study aims to elucidate the expression of inflammasome-related genes in PCa and assess their association with clinical outcomes. Methods: De-identified transcriptome data from a cohort of 52,266 radical prostatectomy (RP) samples tested (2016-2024) with the Decipher prostate genomic classifier (Veracyte, San Diego, CA) were retrieved from the GRID registry (NCT02609269). Expression analysis focused on 33 genes involved in inflammatory pathways. Outcomes analysis was conducted on a retrospective cohort of 855 patients treated with RP (META855), using Cox regression analysis, adjusting for baseline pathological characteristics. Results: Analysis of baseline gene expression in the GRID RP cohort revealed that most genes exhibit low baseline expression, whereas HSP90AB1, APP, TXN, and TXNIP demonstrate strong expression signals. Higher expression of most genes was associated with higher rate of Gleason grade group 4 or 5 in the GRID RP cohort. On survival analysis of the META855 cohort, higher expression (top 25%) of AIM2 and HSP90AB1 were associated with worse metastasis-free survival (p<0.05 for both). Conversely, both high and low expression levels of NLRP3 were associated with better metastasis-free survival outcomes following RP compared to average expression (p<0.05). On multivariable Cox regression analysis, adjusting for grade group, seminal vesicle involvement, lymph node involvement, and margin status, higher expression of AIM1 (HR 1.75) and HSP90AB1 (HR 1.60) were significantly associated with shorter time to metastasis following RP (p<0.05 for both). Conclusions: There is a molecular heterogeneity within pro-inflammatory genes among patients with PCa.Our findings showed thathigher expression of HSP90AB1 is linked to poorer oncological outcomes, whereas both high and low expression levels of NLRP3 are associated with better outcomes following RP.Further refinement is required to build a robust signature, along with external validation of these findings in other cohorts.

Abstract Metastasis accounts for the overwhelming majority of cancer deaths. In prostate cancer and many other solid tumors, progression to metastasis is associated with drastically reduced survival outcomes, yet the mechanisms behind this progression remain largely unknown. ATPase family AAA domain containing 2 (ATAD2) is an epigenetic reader of acetylated histones that is overexpressed in multiple cancer types and usually associated with poor patient outcomes. However, the functional role of ATAD2 in cancer progression and metastasis has been relatively understudied. Here, we employ genetically engineered mouse models of prostate cancer bone metastasis, as well as multiple independent human cohorts, to show that ATAD2 is highly enriched in bone metastasis compared with primary tumors and significantly associated with the development of metastasis. We show that ATAD2 expression is associated with MYC pathway activation in patient datasets and that, at least in a subset of tumors, MYC and ATAD2 can regulate each other’s expression. Using functional studies on mouse bone metastatic cell lines and innovative organ-on-a-chip bone invasion assays, we establish a functional role for ATAD2 inhibition in reducing prostate cancer metastasis and growth in bone. Implications: Our study highlights ATAD2 as a driver of prostate cancer progression and metastasis and suggests it may constitute a promising novel therapeutic target.