Morris, Michael J.

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

Abstract Purpose: Prostate-specific membrane antigen (PSMA)–directed therapies provide meaningful clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), yet responses remain limited, underscoring the need for additional biomarkers of PSMA expression heterogeneity. In this study, we explored the relationship between PSMA imaging and PSMA expression on circulating tumor cells (CTC) in our early-phase trial using a PSMA-targeted small molecule. Experimental Design: This phase I study investigated EC1169, a small molecule conjugated to a tubulysin analog warhead, and 99mTc–EC0652, a PSMA imaging agent. Part A (dose escalation) identified the recommended phase II dose. Part B (dose expansion) assessed radiographic progression-free survival (rPFS) as its primary endpoint. We enrolled and treated 103 patients with mCRPC. Most part B patients underwent 99mTc–EC0652 PSMA imaging. A CTC assay assessed PSMA-positive CTCs and their association with response and PSMA imaging. Results: 99mTc–EC0652 single-photon emission computed tomography (SPECT) imaging demonstrated increased sensitivity for detecting bone lesions compared with standard scans (computed tomography/bone scans). Using an optimized CTC assay, we observed that patients with a decrease in PSMA+ CTCs at baseline versus C3D1 displayed a longer rPFS (8 vs. 2.9 months; P = 0.04). Importantly, patients with predominantly PSMA-positive disease on 99mTc–EC0652 imaging also harbored PSMA-negative CTCs, with a subset displaying neuroendocrine prostate cancer–like morphology. Conclusions: Although EC1169 showed limited activity, CTC and imaging analyses showed significant heterogeneity in PSMA expression on CTCs in patients with predominantly PSMA-positive lesions on SPECT. Our study highlights the importance of assessing both PSMA-based CTC and imaging assays in future validation trials.

ABSTRACT Enzalutamide and abiraterone are hormonal treatments that improve survival in metastatic castration‐resistant prostate cancer. Identifying genetic variants associated with the clearance of these drugs may aid in improved dosing and outcomes. We performed genetic association studies of enzalutamide and abiraterone oral clearance in the Alliance A031201 clinical trial. Genome‐wide genotyping was performed with the primary analysis limited to European‐descent participants. Pharmacogene metabolic phenotypes were estimated using PyPGx and Stargazer. Associations of metabolic activity groups for CYP3A4 , CYP3A5 , CYP2C19 and SLCO1B1 with enzalutamide clearance ( N = 706) and CYP3A4 , SLCO2B1 and UGT1A4 with abiraterone clearance ( N = 323) were tested by linear regression. Targeted SNP associations were assessed for abiraterone clearance at loci proximal to major metabolizing genes. Full genome‐wide association studies were performed for both sets of clearance values. No significant associations were identified between metabolic phenotypes and enzalutamide or abiraterone oral clearance SNPs in the SULT2A1 5′ flanking region were significantly associated with lower abiraterone clearance, (rs296373, minor allele frequency = 0.15, β = −0.457, p = 3.2E‐06). Liver protein and liver and adrenal gland gene expression QTL databases indicated significantly lower SULT2A1 expression patterns for individuals carrying associated alleles, likely explaining the lower abiraterone oral clearance. CYP2C8*3 was associated with higher enzalutamide clearance ( p = 0.012), but this was not significant after correction for multiple testing. This study is the first to identify the genetic association of SULT2A1, known to be involved in the metabolism of steroids in the liver and adrenal glands, with abiraterone clearance. Genetic variation in SULT2A1 may be useful to inform personalized dosing of abiraterone. ClinicalTrials.gov Identifier: NCT01949337

TPS5127 Background: Androgen deprivation therapy (ADT) ± androgen receptor pathway inhibitor therapy is a primary treatment for metastatic hormone-sensitive prostate cancer, but is noncurative and has significant toxicities when used long-term. In patients with OMPC for whom delaying ADT is appropriate, metastasis-directed therapy such as stereotactic body radiation therapy (SBRT) has been shown to provide local disease control. However, many patients do not experience a complete prostate-specific antigen (PSA) response and develop poly-metastatic disease. [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) is a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with demonstrated efficacy and a manageable safety profile in patients with PSMA-positive metastatic castration-resistant prostate cancer in the VISION and PSMAfore trials. PSMA-DC (NCT05939414) is an ongoing, international, randomized phase 3 trial to evaluate the efficacy of 177 Lu-PSMA-617 versus observation after SBRT in delaying castration and disease progression in patients with PSMA-positive OMPC. Methods: Eligible patients have histologically confirmed prostate cancer, biochemical recurrence post-definitive treatment, OMPC with ≤ 5 PSMA-positive metastatic lesions including ≥ 1 distant metastasis on PSMA PET/CT scans (all must be amenable to SBRT), PSA doubling time < 10 months and non-castration testosterone levels (> 100 ng/dL). Exclusion criteria include distant metastasis by conventional imaging (CI; CT/MRI and bone scans) at screening, prior ADT (except adjuvant ADT completed > 12 months before randomization), or other systemic therapy for metastatic prostate cancer. Patients (N = ~450) will be randomized 2:1 to 177 Lu-PSMA-617 or observation and will receive SBRT to all metastatic lesions within 14 days, completed within 3 weeks. Patients will then receive either intravenous 177 Lu-PSMA-617 (7.4 GBq/6 weeks; 4 cycles), starting 7–21 days after SBRT, or undergo observation only. Additional SBRT for new lesions is allowed. ADT is allowed after a metastasis-free survival (MFS) event by CI confirmed by blinded independent review committee (BIRC). Safety follow-up will occur 42 days after the last 177 Lu-PSMA-617 dose and at the week 24 visit for the observational arm. Long-term follow-up for the 177 Lu-PSMA-617 arm will include safety assessments every ~32 weeks. The primary endpoint is MFS by CI as assessed by BIRC using RECIST v1.1, or death. To provide 90% power to detect a hazard ratio of 0.6, 187 MFS events are required. The key secondary endpoint is time to next hormonal therapy. Additional secondary endpoints include time to PSA progression, radiographic progression-free survival, symptomatic progression, patient-reported health-related quality of life, overall survival and safety. Shore et al. PSMA-delay castration (DC): an open-label, multicenter, randomized phase 3 study of [ 177 Lu]Lu-PSMA-617 versus observation in patients with metachronous PSMA-positive oligometastatic prostate cancer (OMPC). J Urol 2025;213 (5S2_suppl):e28. https://www.auajournals.org/doi/10.1097/01.JU.0001110444.53548.eb . Reused with permission; ©American Urological Association, 2025. This abstract previously presented at 2025 AUA Annual Meeting. Clinical trial information: NCT05939414 .

TPS5118 Background: The median overall survival of patients with mCRPC remains under 2 years even with newer therapies. Xaluritamig, an XmAb 2+1 T-cell engager that targets the six-transmembrane epithelial antigen of prostate 1 (STEAP1), facilitates lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. In a first-in-human study, xaluritamig demonstrated encouraging efficacy and a manageable safety profile for patients with mCRPC refractory to standard of care therapies (Kelly WK, et al. Cancer Discov. 2024;14(1):76-89). Methods: XALute is a randomized, multicenter, open-label, phase 3 study to evaluate the efficacy and safety of xaluritamig vs cabazitaxel or second ARDT in men with mCRPC previously treated with taxane chemotherapy. Enrollment in the control arm treatments will be split evenly between cabazitaxel and second ARDT. Stratification factors include LDH ≤ or > 260 IU/L, liver metastases (Y/N), prior prostate-specific membrane antigen radioligand therapy (PSMA-RLT) (Y/N) and the intention to treat with cabazitaxel or ARDT switch. Approximately 675 patients will be enrolled. Participants will be randomly assigned in a 2:1 ratio to xaluritamig monotherapy or standard care. Participants will receive treatment until radiographic disease progression per Prostate Cancer Clinical Trials Working Group 3 (PCWG3), unacceptable toxicity, initiation of other anticancer therapy, withdrawal of consent, death, or end of study as determined by the sponsor. The primary efficacy endpoint is overall survival. The key secondary efficacy endpoint is radiographic progression-free survival per PCWG3 by blinded independent central review. Key inclusion criteria are pathological/cytological confirmation of prostate adenocarcinoma; mCRPC with at least one metastatic lesion; evidence of progressive disease; prior treatment with at least one ARDT; one taxane therapy in the mCRPC setting, and ongoing androgen deprivation with serum testosterone levels (<50 ng/dL or <1.7 nmol/L). Prior treatment with PSMA-RLT, poly ADP-ribosylation inhibitors, and immune checkpoint inhibitors are permitted. Exclusion criteria include prior STEAP1-targeted therapy, any anticancer therapy within 4 weeks prior to first dose of study treatment (not including androgen deprivation therapy), prior PSMA-RLT within 2 months of first dose of study treatment unless less than 2 cycles received, and prior radionuclide therapy (radium-223) within 2 months of first dose of study treatment To mitigate risk of cytokine release syndrome, xaluritamig will be administered with step dosing. Cabazitaxel or second ARDT will be administered according to regional prescribing information. Funded by Amgen Inc. Clinical trial information: NCT06691984 .

TPS4616 Background: Osseous metastases (OM) occur in approximately 30% patients with advanced RCC. Despite therapeutic advances, OM are associated with poor survival and risk of symptomatic skeletal events (SSEs). Cabozantinib targets multiple tyrosine kinases, including vascular endothelial growth factor (VEGF) receptors and MET (Mesenchymal-Epithelial Transition factor), which are overexpressed in OM, contributing to cabozantinib’s enhanced bone activity. Radium-223, an alpha-emitting bone-seeking radioisotope, prolongs survival in men with metastatic castration-resistant prostate cancer to the bone. Building on this therapeutic approach targeting OM, our pilot study of radium-223 with VEGF inhibition in RCC with OM has also shown safety, improvement in circulating bone turnover markers, and early efficacy (McKay et al, CCR 2018). To address the unmet need to improve SSE rates and outcomes in RCC and OM, we designed a study investigating cabozantinib with or without radium-223 in patients with RCC with OM (NCT04071223). Methods: This is an open-label, multicenter randomized phase-2 study. Key inclusion criteria include metastatic RCC of any histology with ≥1 OM, at least 1 OM without prior radiation, any number of prior therapies, and Karnofsky performance status ≥ 60%. Use of a bone protecting agent is required unless contraindicated. Patients are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) radium-223. The starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade ≥3 toxicity. Radium-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The starting dose for cabozantinib in Arm B is 60 mg daily. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, time to first SSE, objective response rate, time to subsequent anti-cancer therapies, quality of life (QoL) measures, and correlative analyses including liquid biopsy and tumor tissue analysis. The study is designed to have 85% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided α = 0.05 significance. To ensure 124 evaluable patients, target accrual is 134 (67 per arm). The group-sequential design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events have been observed. The safety run-in, performed in the first 12 patients randomized to combination therapy, did not demonstrate dose limiting toxicities. Final data analysis will occur when 99 events have been observed. The study was activated in July 2020 and accrual is ongoing throughout the National Clinical Trials Network (NCTN). Continued site participation and enrollment are essential to evaluate this therapeutic strategy. Clinical trial information: NCT04071223 .

4516 Background: Ipilimumab/nivolumab (ipi/nivo) is a standard of care first-line treatment (tx) for patients (pts) with mccRCC; however, ideal timing of subsequent immunotherapy txs are not well defined. We performed an analysis of patients initially treated with ipi/nivo and subsequent cohort assignments on PDIGREE (A031704). Methods: The PDIGREE trial treated pts with IMDC intermediate/poor risk mccRCC with first-line ipi/nivo (Step 1) at NCTN sites (categorized as academic (A), academic regional (R), and community (C)). Subsequent management was based on iRECIST responses at 12 weeks: pts with complete response (CR) received 1-year nivo maintenance; pts with progressive disease (PD) received cabozantinib (cabo) monotherapy, pts with non-CR/non-PD were randomized to nivo with or without cabo (for primary endpoint of overall survival [OS], target sample size was 1175). Enrollment was held when the randomized sample target was reached. Pts with unresolved toxicity at week 22 were managed off protocol. Step 1 pt demographics, assignments into Step 2, and adverse event (AE) data are presented. Descriptive statistics were used, and cohorts were compared using a chi-square test. These data were released with DSMB approval and do not inform the primary OS endpoint (1EP). Results: From May 2019 to May 2024, 1111 pts were enrolled and treated with ipi/nivo. Pt characteristics included median age 64.0 years (range 29.0-86.0); 819 (73.7%) males; White (85.1%), Hispanic (10.4%), Black (4.2%), and American Indian/Native Hawaiian (1.3%); 849 (76.8%) intermediate risk/257 (23.2%) poor risk; 458 (41.2%) at Academic, 113 (10.2%) at Regional, and 540 (48.6%) at Community centers; and 603 (54.3%) with de novo metastases. 364 pts (33%) stopped tx in Step 1: 160 (44%) for AEs, 46 (13%) for PD/clinical PD/suspected PD, 42 (12%) withdrawals, 39 (11%) alternative txs, 37 (10%) deaths on the study, 12 (3%) other complicating disease, 8 (2%) MD decision and 19 (5%) other reasons. Of the 37 deaths, 15 (1.4%) grade 5 SAEs were reported, 6 of which were due to PD. Of 747 (67%) pts registered to Step 2 at 3 months, 9 (1.2%) achieved CR, and 141 (18.9%) pts were assigned to the PD cohort. 597 pts (80%) were randomized for the 1EP, notable with fewer pts with poor risk [(21 vs 27%, p = 0.01] and bone metastases [24.5% vs 34.2%, p = 0.0007] compared to Step 1 pts who discontinued tx. Gr 3/4 tx-related AEs in 314/1093 (29%) evaluable pts included diarrhea/colitis (8%), transaminase elevation (3%), rash (2%), adrenal insufficiency (2%), fatigue (2%), and hypophysitis (1%). Conclusions: The PDIGREE trial enrolled a representative US-based population with mccRCC. Step 1 pt characteristics and associated outcomes with induction ipi/nivo reveal new insights into the tolerability and tx response of 1L ipi/nivo. Clinical trial information: NCT03793166 .

309 Background: Standard of care (SOC) treatment options for HR-PCa include RT with long-term androgen deprivation (LT-ADT) or RP with selective use of post-operative RT +/- androgen deprivation therapy (ADT). The optimal treatment approach has been assessed in retrospective population-based and multi-center comparisons, which have yielded mixed results with substantial bias. Therefore, we conducted an emulated randomized comparison of RT vs RP in HR-PCa leveraging patients enrolled in RCTs. Methods: We searched Medline for RCTs in HR-PCa with a SOC arm of an RT- or RP-based regimen. Inclusion required similar experimental treatment and contemporaneous enrollment in the same country to reduce bias. This identified 2 trials, NRG/RTOG 0521 (RT+LT-ADT +/- 6 cycles docetaxel [doce]), and CALGB 90203 (RP +/- neoadjuvant 6 cycles doce and ADT). Due to inherent difference in the biochemical recurrence criteria after RT vs RP, we chose inverse probability of treatment weighted (IPTW) cumulative incidence of distant metastasis (DM) as the primary endpoint, considering deaths as competing events. Death after DM was measured to create a harmonized metric of deaths likely attributed to PCa. To assess potential residual selection bias, death without DM to capture non-cancer associated deaths was analyzed. Results: Overall, 1290 patients (RT n=557, RP n=733) were included, with similar median follow-up of 6.4 years. Prior to IPTW, RP patients were significantly younger with lower baseline PSA compared to RT patients. Adjuvant (18%) and salvage therapy (44%) was used in RP cohort. Cumulative incidence of DM was significantly lower in patients who underwent RT compared to RP (8-year DM: 16% vs 23%; p=0.01; subdistribution hazard ratio [sHR] 0.48 [95%CI 0.34-0.69], p<0.001). 8-year rates of death after DM were 10% vs 8% (p=0.72) in the RP and RT patients, respectively. RT patients had significantly greater risk of death without DM (HR 2.09 [1.01-4.34], p=0.048) with early differences measured. On a cross-arm comparison, 8-year cumulative incidence of DM when comparing SOC RT+LT-ADT group versus the doce+ADT+RP group was 18% vs 21%, respectively (sHR 0.75 [0.45-1.24], p=0.26). Conclusions: HR-PCa patients enrolled on RCTs had significantly lower incidence of DM with an RT-based strategy compared to an RP-based approach. Longer follow-up is needed to assess deaths attributed to PCa. Despite the strengths of the comparison (use of cooperative group RCT data, contemporaneous enrollment in the same country, patients fit enough for chemotherapy, and IPTW adjustments) there appears to be residual unmeasured bias, as expected, based on greater early deaths without DM in the RT arm. Utilization of post-operative radiotherapy and ADT+Doce may mitigate differences between RP and SOC RT+LT-ADT.

16 Background: In PSMAfore (NCT04689828), [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) prolonged rPFS versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive adults with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) progressing once on an ARPI. Baseline circulating tumor DNA (ctDNA) fraction was associated with rPFS at the second interim analysis (IA) of OS (ASCO 24). Here, we assessed the association of baseline and cycle 2 day 1 (C2D1) ctDNA fraction, and early ctDNA and prostate-specific antigen (PSA) dynamics, with rPFS and OS at the third IA of OS. Methods: Patients were randomized 1:1 to 177 Lu-PSMA-617 (7.4 GBq Q6W; x6) or ARPI change. Endpoints included rPFS (primary) and OS (key secondary). Plasma ctDNA fraction was analyzed at baseline and at C2D1 using an in-house custom panel. Cox regression (adjusted for 3 risk classes based on clustering of 17 baseline clinical features) and random forest (adjusted for 15 baseline clinical features) modeling were used to assess the association of ctDNA fraction and PSA with clinical outcomes at the Feb-27-2024 data cutoff. Results: Patients with plasma samples at baseline and C2D1 were included ( 177 Lu-PSMA-617, n/N = 82/234; ARPI change, n/N = 91/234). Cox regression models adjusted for clinical features in the 177 Lu-PSMA-617 arm showed that higher ctDNA fraction was associated with shorter rPFS and OS (Table). These associations were stronger for C2D1 than baseline, both when comparing individual models and within a model including both timepoints (Table). In random forest models including clinical features and C2D1 ctDNA fraction, the total area under curves were not improved by addition of baseline ctDNA fraction (rPFS, 0.87; OS, 0.86). In the overall population, fractional decreases from baseline to C2D1 in ctDNA ( p = 0.0015) and PSA ( p < 0.0001) were strongly associated with longer rPFS, and were weakly correlated with one another (correlation coefficient, 0.26). In the 177 Lu-PSMA-617 arm, fractional decrease in ctDNA ( p = 0.002) was more strongly correlated with OS than was decrease in PSA ( p = 0.12). Conclusions: This exploratory analysis suggested that C2D1 ctDNA fraction was more strongly associated than baseline ctDNA fraction with rPFS and OS. Early ctDNA fraction dynamics contributed additional information in the prediction of rPFS and OS beyond PSA dynamics alone. Clinical trial information: NCT04689828 . Cox regression models. a rPFS OS Baseline model, HR (95% CI); p 6.0 (1.6–23.0); 0.0095 12.0 (3.0–48.7); 0.00052 C-index ± SE 0.69 ± 0.04 0.75 ± 0.04 C2D1 model, HR (95% CI); p 47.7 (10.1–226.0); < 0.0001 82.7 (16.4–417.0); < 0.0001 C-index ± SE 0.72 ± 0.03 0.77 ± 0.03 Baseline + C2D1 model Baseline, HR (95% CI); p 3.1 (0.7–14.0); 0.14 2.1 (0.4–12.7); 0.41 C2D1, HR (95% CI); p 35.9 (7.2–180.0); < 0.0001 52.5 (7.6–362.0); < 0.0001 C-index ± SE 0.72 ± 0.03 0.79 ± 0.03 a HRs correspond to 1 unit change in ctDNA fraction.