Citations

144 Background: Androgen receptor pathway inhibitors (abiraterone acetate [AAP], apalutamide [APA], enzalutamide [E], darolutamide [DARO] have become the cornerstone for pts with PCa due to survival benefits. Comparative data on fracture risk among ARPi are limited. This study quantified the risk of bone fractures with ARPi plus androgen deprivation therapy (ADT) and compared fracture risk across different ARPi agents. Methods: MEDLINE and EMBASE were searched from inception through September 1 st 2025 to identify positive phase III trials assessing ARPi in addition to ADT in pts with PCa (m0CRPC, mCSPC, mCRPC). Trials were included if they reported bone fractures in either arm. Pairwise, random-effects meta-analysis was conducted using Paul-Mendel approach. Sensitivity analyses using Hartung-Knapp (HK) adjustment was performed to assess robustness of results. To assess the comparative risk of bone fractures among different ARPi agents, mixed treatment comparisons were made using frequentist network meta-analysis. P-scores were computed to assess relative treatment rankings. Treatment effect was expressed as odds ratio (OR) with 95% confidence intervals (CI). Results: This systematic review included 13 phase III trials with 15468 pts (8890 received ARPi+ADT, 6578 received ADT alone). A total of 596 (6.7%) bone fractures were observed with ARPi+ADT compared to 180 (2.74%) with ADT alone. Patients receiving ARPi+ADT were associated with an increased risk of bone fractures compared to those receiving ADT (OR: 2.40; 95% CI: 1.93-2.98). Sensitivity analyses with HK adjustment showed consistent results (2.40; 1.88-3.06). There was no statistically significant effect modification by PCa clinical setting (p: 0.27). Mixed treatment comparisons showed a statistically significant increased risk of bone fractures with AAP+ADT (2.35; 1.29-4.27), APA+ADT (2.04; 1.47-2.86), and E+ADT (3.13; 2.44-4.00) but not with DARO+ADT (1.30; 0.80-2.08) when compared to ADT alone. Among different ARPi agents, E+ADT was associated with an increased risk compared to APA+ADT (1.54; 1.01-2.33) and DARO+ADT (2.44; 1.41-4.17). Ranking analysis showed that E+ADT was ranked as potentially the least safe treatment (P score: 0.05) in terms of relative fracture risk followed by AAP+ADT (P score: 0.30), APA+ADT (P score: 0.43), DARO+ADT (P score: 0.76). Sensitivity analyses limiting to mCSPC trials only showed consistent results. Conclusions: The risk of bone fractures varies among different ARPi agents, with enzalutamide posing the highest relative risk and darolutamide the lowest. These differences may guide treatment selection, particularly in pts with mCSPC and bone metastases. Prospective studies adjusting for covariates are needed to evaluate bone-protective strategies to mitigate fracture risk particularly in mCSPC patients who are considering treatment with ARPi.

142 Background: LuPSMA is a life-prolonging radioligand therapy that is widely considered to have favorable tolerability. SPPADE symptoms (Sleep disturbance, Pain, Physical dysfunction, Anxiety, Depression, low Energy) are common in prostate cancer, yet data on patient-reported outcomes with LuPSMA in real-world settings remain limited. Methods: The E2C2 study (NCT03892967) evaluates the impact of a collaborative care intervention on patient-centered outcomes and healthcare utilization. This analysis includes mCRPC patients who initiated LuPSMA at Mayo Clinic (June 2022-July 2023) and completed at least one symptom survey within 6 weeks before or 2 weeks after the first LuPSMA treatment (baseline survey). SPPADE symptoms were rated on 0-10 scales; scores of 4-6 indicate moderate and 7-10 severe burden. A composite z-score was derived by standardizing each SPPADE domain to the cohort mean and averaging z-scores across domains per patient. Patients were stratified by composite symptom burden using cohort median and upper-tertile cutoffs. Associations with PSA50 response and overall survival (OS, from start of LuPSMA) were assessed using chi-square and Kaplan-Meier methods. In a longitudinal subgroup of patients completing a baseline survey plus at least one additional PRO survey while receiving LuPSMA (≥2 surveys), scores were compared from baseline to best during-treatment using Wilcoxon and Mann-Whitney U tests. Results: Of 373 patients starting LuPSMA, 51 patients met inclusion criteria. Median age was 71 years, 31% had visceral metastases, and median baseline PSA was 42.1 ng/mL. Overall, 85% of patients reported at least one moderate symptom and 46% at least one severe symptom. The most common moderate-to-severe symptoms were low energy (58%), pain (52%), and sleep disturbance (49%). Using an upper-tertile cutoff of the composite SPPADE score, 17 patients had high and 34 had low/moderate symptom burden prior to LuPSMA. PSA50 response was achieved in 17.6% of patients with high vs 47.1% with low/moderate composite symptom scores (p = 0.08). Median OS was 9.2 vs 16.7 months for high vs low symptom groups (p = 0.15, median split). The longitudinal subgroup included 24 patients with serial ePRO assessments while on LuPSMA. Composite SPPADE scores improved from baseline to the best during-treatment assessment in both PSA50 responders (n=10) and non-responders (n=14), with median composite z-score Δ of 0.35 vs 0.20, respectively (p = 0.68). Conclusions: Among patients with mCRPC receiving LuPSMA, baseline SPPADE symptom burden was high. Though not statistically significant in this underpowered cohort, PSA response and OS were numerically inferior in those with higher baseline burden. These findings suggest that ePRO-captured symptom burden may provide prognostic and patient-centered insights beyond traditional clinical variables. Clinical trial information: NCT03892967 .

127 Background: Bone metastases affect up to 90 % of patients with metastatic hormone-resistant prostate cancer (mHRPC) and cause substantial morbidity from skeletal-related events (SREs) such as fracture, spinal-cord compression, and palliative interventions. Bone-modifying agents (BMAs) including bisphosphonates and denosumab reduce SRE risk and are NCCN-recommended, however, real-world use remains inconsistent. Methods: Patients with mHRPC treated from January 2017-September 2024 across Mayo Clinic sites were identified using SQL-based EHR queries confirmed by manual chart review. Bone Metastases were detected through keyword searchers of radiology reports and confirmed through manual chart review. SRE-prevention dosing was defined as zoledronic acid 4mg IV or denosumab 120mg SC; osteoporosis dosing was excluded. SREs were identified using diagnosis codes and text-pattern searches for radiotherapy, surgery, fracture, and spinal-cord compression. Descriptive statistics summarized BMA utilization and SRE incidence. Categorical variables were compared using Chi-square tests, and a risk ratio (RR) with 95% confidence intervals was calculated to evaluate association between early BMA initiation and SRE risk. Results: Among 778 patients with mHRPC, 685 (88 %) had bone metastases (mean age 70.5 years). Of these, 169 (24.7 %) had an SRE, and 261 (38.1 %) received BMAs at SRE-prevention doses (denosumab n = 157 [60 %]; zoledronic acid n = 104 [40 %]). Based on a chi-square test, combined SRE incidence did not differ significantly (No BMA 23 %, denosumab 23 %, zoledronic 33 %; p = 0.069). Bone pain at baseline was more common in patients who later received a BMA (136 [68 %]) than in those who did not (82 [41 %]; p < 0.001). Among 200 randomly sampled non-BMA patients, 83 had no recorded BMA discussion (66 also lacked bone pain), 38 lacked dental clearance, 32 had uncompleted plans and 18 declined therapy. Early BMA initiation (before first bone metastases) was associated with fewer SREs (16 % vs 29 %; RR 0.56, 95 % CI 0.33–0.96). Conclusions: Less than half of bone-metastatic mHRPC patients received BMAs. Non-initiation was often linked to modifiable factors such as delayed dental clearance or lack of treatment discussions, highlighting the need for system-level strategies to improve timely bone-directed care. SREs were common, affecting one quarter of patients. Small sample size precluded meaningful comparison of the impact of BMAs on SRE incidence however early BMA initiation may lower SREs. Incidence of SREs stratified by no BMA vs BMA treatment. SRE No BMA BMA Overall Pathological Fracture 6.4% (27/424) 4.9% (13/261) 5.8% (40/685) Radiotherapy to Bone 13.9% (59/424) 18.8% (49/261) 15.7% (108/685) Spinal Cord Compression 0.7% (3/424) 3.1% (8/261) 1.6% (11/685) Surgery to Bone 2.1% (9/424) 0.3% (1/261) 1.5% (10/685) Combined 23% (98/424) 27.2% (71/261) 24.7% (169/685)

TPS898 Background: Enfortumab vedotin with pembrolizumab (EV/Pembro) is now first-line therapy for locally advanced or metastatic urothelial carcinoma (la/mUC) following the EV-302/KEYNOTE-A39 trial, which demonstrated a 67.7% response rate and prolonged survival. However, ~35% of cancers exhibited primary resistance and most responders relapse within one year, with post-EV/Pembro therapies achieving < 15% response and median survival < 3 years. We previously showed that therapeutic plasma exchange (TPE) removed soluble PD-L1 and other immune checkpoint inhibitor (ICI) blocking soluble factors from the blood and that this overcame ICI resistance. Combining TPE with EV/Pembro rechallenge may overcome acquired resistance and restore antitumor immunity. Methods: RECIPE-B1 [NCT07087860] is an open-label, randomized phase II trial enrolling 50 patients (1:1) with EV/Pembro-refractory la/mUC and ECOG 0–2. Arm A receives TPE on days 1–3 followed by EV 1.25 mg/kg IV plus pembrolizumab 200 mg IV on day 3 of each 21-day cycle for the first three cycles, then continues EV/Pembro alone from cycle 4. Arm B receives investigator’s-choice next-line standard of care (SOC) per NCCN guidelines. Tumor assessments occur at the end of cycle 4 (±28 days) and every 12 weeks thereafter; safety is monitored each cycle (CTCAE v5.0). The primary endpoint is objective response rate (ORR) by RECIST 1.1, comparing TPE + EV/pembro versus SOC. Secondary endpoints include progression-free survival, overall survival, duration of response, quality of life (EORTC QLQ-CIPN20), and safety. Correlative studies evaluate circulating and urinary tumor DNA and exosomal biomarkers (including exosomal Nectin-4) as predictors of response and resistance. The trial is open at Mayo Clinic; as of September 2025, 2 of 50 patients have been enrolled, with planned accrual of ~2 patients/month and central coordination at Mayo Clinic and affiliates. Clinical trial information: NCT07087860 .

TPS892 Background: Enfortumab Vedotin (EV) plus pembrolizumab (Pembro) is now first-line therapy for advanced urothelial carcinoma (UC), yielding ~30% complete response (CR) rates; nevertheless, most patients (pts) progress within 1 year and median overall survival (OS) remains < 3 years. In muscle invasive bladder cancer, local consolidation after systemic therapy improves outcomes, suggesting that residual, treatment-refractory intravesical disease drives relapse. We hypothesize that cytoreductive cystectomy/nephroureterectomy (CC/U)—with metastasis-directed therapy (MDT) as needed—can consolidate responses to EV/Pembro and extend benefit in regionally advanced or metastatic UC. CAST-AI prospectively evaluates this multimodal strategy and integrates correlative studies of exosomal Nectin-4 and circulating tumor DNA (ctDNA) from blood and urine as predictive/MRD biomarkers. Methods: CAST-AI is a phase II, decentralized single-arm trial enrolling pts with histologically confirmed UC of the bladder or upper urinary tract with ≥N1 and/or M1 disease and ECOG PS 0–2 who are potential surgical candidates (planned n = 75). Treatment: EV 1.25 mg/kg IV D1 & D8 + Pembro 200 mg IV D1 q21d, ≥4 cycles; MDT permitted any time pre-surgery. Response assessments occur q9 weeks (±4) to 18 months, then q12 weeks (±4). Surgical eligibility requires: (A) fitness for surgery; (B) complete or partial response (CR/PR) or, for select low-burden/unmeasurable disease, urologist-adjudicated candidacy; (C) all distant sites addressed; and (D) procedure in pt’s best interest. Post-CC/U maintenance EV/Pembro is encouraged per clinical discretion and guided by definitive surgical pathology results, which provide true pathologic staging often unattainable through imaging after systemic therapy. Primary endpoint: 12-month progression-free survival (PFS). Secondary endpoints: Objective response rate (ORR), CR rate, down-staging at CC/U, PFS, OS, and safety (using CTCAE). Exploratory endpoints: longitudinal exosomal Nectin-4 and ctDNA dynamics as MRD and early relapse indicators; tissue–blood–urine Nectin-4 concordance; pt-reported tolerability (using CIPN20). Key exclusions: > 20% variant histology or disallowed subtypes (e.g., micropapillary, plasmacytoid, sarcomatoid, neuroendocrine); prior chemotherapy for UC; contraindications to surgery/EV/ICI; or active uncontrolled comorbidities/infections. Status: Enrollment is open and ongoing, with 25 of 75 pts enrolled as of September 2025. The trial uses a decentralized model, allowing pts to receive EV/Pembro at their local facility, with central coordination, biospecimen shipping, and surgical evaluation at Mayo Clinic or affiliated sites. ClinicalTrials.gov: NCT06764095. Clinical trial information: NCT06764095 .

TPS283 Background: Emerging evidence suggests that metastasis-directed therapy (MDT) with stereotactic body radiotherapy (SBRT) can delay systemic therapy in oligometastatic castration-sensitive prostate cancer (omCSPC). However, the optimal timing of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitor (ARPI) initiation in this setting remains undefined. While deferred ADT following MDT may preserve quality of life, early short-course ADT/ARPI may eradicate micrometastatic disease and extend progression-free survival. Extracellular vesicles (EVs) carrying PSMA-positive prostate cancer (PC) signals and circulating tumor DNA (ctDNA) may serve as real-time biomarkers of MRD and treatment response. Methods: DIVINE [NCT06378866] is an open-label, phase II, randomized trial enrolling men with omCSPC defined by 1–5 metastases (≥1 extrapelvic) on conventional imaging (CT/MRI and bone scan) and testosterone >100 ng/dL. PSMA PET may be obtained for correlative purposes but does not determine eligibility. Participants (N = 220) are randomized 1:1 to: Arm A (Early systemic): SBRT plus 6 months of ADT + ARPI. Arm B (Deferred systemic): SBRT alone with observation, reserving systemic therapy until radiographic progression not amenable to further SBRT (mrPD). SBRT is delivered per institutional standard; repeat SBRT is allowed until lesions become non-addressable. The primary endpoint, modified radiographic progression-free survival (mrPFS), is the time from randomization to death or radiographic progression not amenable to further MDT, defined by PCWG3 (bone) and modified RECIST 1.1 (soft tissue) criteria on conventional imaging. Soft-tissue progression requires ≥ 20% increase in measurable disease or a new lesion; bone progression requires ≥ 2 new confirmed lesions. Secondary endpoints include OS, biochemical PFS, time to local and distant progression, and grade 3–5 adverse events during systemic therapy. Exploratory endpoints evaluate EV and ctDNA kinetics as MRD markers, correlation of PSMA-positive EV burden with outcomes, and duration of response after short-course ADT/ARPI. Correlative analyses will longitudinally quantify PSMA-positive EVs and ctDNA at baseline, on treatment, and at progression to define MRD dynamics and resistance patterns. The trial uses Pocock–Simon dynamic allocation by EV strata and metastatic burden to ensure balance across arms. The trial is open and actively enrolling across all Mayo Clinic sites; as of October 2025, 35 of the planned 220 patients have been accrued. Clinical trial information: NCT06378866 .

214 Background: 177 Lu-PSMA-617 (LuPSMA) has revolutionized care for patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC), but only half achieves PSA decline ≥50%. Biomarkers are urgently needed to improve pt selection. EVs and ctDNA released by cancer cells into the blood are emerging biomarkers to estimate overall tumor burden and capture tumor heterogeneity in mCRPC. Here, we analyzed pre-treatment plasma levels of tumor EVs and ctDNA in a pilot cohort of 35 pts with mCRPC treated with LuPSMA. Methods: Blood samples were collected pre-cycle 1 of LuPSMA at Tulane Cancer Center between 12/2018-1/2025. Plasma-derived small and large EVs were incubated with fluorescently conjugated antibodies and enumerated using nanoscale flow cytometry. ctDNA fraction was estimated from plasma cfDNA methylation WGS (∼10×) with ichorCNA. We also analyzed EVs from blood samples of male healthy donors (HD) and pts with localized prostate cancer (LPC) collected 1 day to 8 months after radical prostatectomy (post-RP) from 6/2020-8/2024 at Mayo Clinic as controls. Results: Median age at collection for 10 HD was 55 yrs and for 36 pts with LPC post-RP was 65 yrs. Median PSMA+ EV level was 2.0 x 10 6 /mL for post-RP and 1.4 x 10 6 /mL for HD. For 35 pts with mCRPC, 25 pts had complete data for analysis. Median PSMA+ EV level was 1.4 x 10 7 /mL, significantly higher than post-RP (p<0.001) and HD (p<0.001). At LuPSMA start, median age was 69 yrs (range 54-83), PSA was 82 ng/mL (range 0.8-503), median time from CRPC diagnosis to start was 50 months (range 6.9-285), median time from plasma collection to treatment initiation was 0.5 months (range 0-7.3). Median number of prior lines of life-extending therapy was 4 (range 1-11), including 100% androgen receptor pathway inhibitor and 75% docetaxel. Pts received median 4 cycles of LuPSMA. Median ctDNA fraction was 14.0% (range 0-51.1). Median time to reach nadir PSA for pts with any decline was 2.6 months. 15 pts (60%) achieved PSA40 (defined ≥40% decline in PSA from start to nadir) (range -99% to -42%) compared to 10 pts (40%) who did not (range -16% to rise), which predicted better median overall survival (OS) after LuPSMA start (40.7 v 6.0 months; HR 0.23, 95% CI, 0.07-0.71; p=0.0001). Pts were classified as LuPSMA responders using PSA40. Responders had a lower ratio of large to small PSMA+ EVs (0.30 v 0.53, p=0.0042) with an area under the receiver operating characteristic curve (AUC) of 0.83 (95% CI, 0.68-0.99), and a lower median ctDNA fraction (6.1% v 26.2%, p=0.0044) with an AUC of 0.83 (95% CI, 0.68-1.00). Incorporating both PSMA+ EV and ctDNA fraction together predicted PSA40 response with an AUC of 0.93 (95% CI, 0.84-1.00, p=0.0003). Conclusions: Using pre-LuPSMA plasma samples from a heavily pre-treated historical cohort, we integrated non-invasive liquid biopsy methods to successfully predict response to LuPSMA using PSA decline. Prospective validation is underway.

Abstract Background Clival metastases are a rare and clinically aggressive manifestation of advanced prostate cancer, associated with cranial nerve palsy and poor survival. The molecular features of prostate cancers giving rise to clivus metastases remain unknown. Patients and methods We performed a multi-center retrospective study across six institutions, identifying prostate cancer patients with radiographically confirmed clival metastases and available next-generation sequencing (NGS) data. Baseline characteristics and clinical outcomes were collected. Genomic alterations from tissue- and/or blood-based assays were aggregated at the patient level and compared with a publicly available metastatic castration-resistant prostate cancer (mCRPC) cohort (SU2C/PCF). Results Fifty-nine patients with clival metastases contributed 87 molecular assays. More than half of patients had Gleason grade group 5 cancer and presented with de novo metastatic (M1) disease. The median interval from initial prostate cancer diagnosis to clival metastasis was 71.4 months (95% CI, 42.0-101.7), while median overall survival following clival involvement was only 15.3 months (95% CI, 6.9-22.8). Compared with the SU2C/PCF mCRPC cohort, clival metastases showed significant enrichment of BRAF and CHEK2 alterations as well as homologous recombination repair (HRR) with relative depletion of AR-related, PI3K pathway, and G2–M pathway alterations. Conclusion Prostate cancers giving rise to clival metastases exhibit a distinct molecular profile enriched for DNA damage–repair and RAF kinase alterations, suggesting unique metastatic biology and potential therapeutic vulnerabilities.