PURPOSE:This study investigates a short-course, intensified regimen combining apalutamide, abiraterone acetate, and prednisone (AAP) and stereotactic body radiotherapy (SBRT) to reduce treatment burden and improve disease control in a very high-risk (VHR) population inadequately represented in prior trials. PATIENTS AND METHODS:This multi-institutional, single-arm, phase 2 trial enrolled patients with VHR localized prostate cancer, defined according to the National Comprehensive Cancer Network as histologically confirmed adenocarcinoma with ≥2 high-risk features: Gleason score 8 to 10, prostate-specific antigen (PSA) ≥20, clinical or radiographic ≥T3, or >4 cores containing Gleason score 8 disease. Patients received 6 months of apalutamide, abiraterone acetate, and leuprolide plus prostate/seminal vesicle-directed ultra-fractionated SBRT. The primary endpoint was 3-year biochemical recurrence (BCR) rate by Phoenix criteria, with a prespecified superiority threshold of <10%. Secondary endpoints included PSA ≥0.2 ng/mL, metastasis-free survival (MFS), and time to testosterone recovery >150 ng/dL. RESULTS:Between August 2016 and December 2022, 63 patients were treated. At 3 years, the Phoenix-defined BCR rate was 19%. BCR-free survival was 84.2% [95% confidence interval (CI), 75.6-93.7] with a median follow-up of 41 months (34-43). The 3-year MFS was 93.6% (95% CI, 87.8%-99.8%), with no deaths observed. The median time to testosterone recovery >150 ng/dL was 6 months (range, 3-24 months). No new safety signals emerged, and the only significant quality-of-life (QOL) decline was in the EPIC sexual subdomain at 12 months. CONCLUSIONS:Treatment intensification with apalutamide, AAP, androgen deprivation therapy, and SBRT was well-tolerated with limited impact on QOL. Although BCR rates exceed the superiority threshold, outcomes aligned with historic benchmarks, supporting further evaluation of the regimen in prospective trials.

Prostate cancer with isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2) mutation appears to be a unique molecular subclass, but its associated clinical features have not been previously described. Here, we performed a retrospective analysis of clinical and molecular features of prostate cancer with IDH1 p.R132 or IDH2 p.R172 mutations. A series of 99 IDH1-mutated and 12 IDH2-mutated cases was identified using genomics databases at multiple institutions. An IDH1/2 wild-type control cohort was generated with matched clinical features at diagnosis. IDH-mutated cases frequently presented with localized disease (91%), but exhibited high tumor stage (42% T3) and grade (54% grade group 5). Compared with matched controls, patients with IDH1 mutations exhibited longer overall survival (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.04-0.68; p = 0.01), metastasis-free survival (HR, 0.22; 95% CI, 0.09-0.58; p = 0.002), and progression-free survival on hormonal therapy (HR, 0.35; 95% CI, 0.16-0.76; p = 0.036). IDH1-mutant cases were enriched for concurrent activating mutations of FOXA1 and CTNNB1 and tended to lack TMPRSS2-ERG fusions, SPOP mutations, and RB1 alterations. IDH1 mutations were associated with global transcriptional repression and evidence of metabolic and epigenetic reprogramming. These results depict IDH-mutant prostate cancer as a subtype that can present with high tumor stage and grade, but is associated with favorable outcomes.

TPS412 Background: PARP inhibitors (PARPi) are approved for the treatment of patients with metastatic castration-resistant prostate cancer. Saruparib is a new generation PARPi that selectively inhibits and traps PARP1. In the Phase I/IIa PETRA study (NCT04644068), activity with saruparib monotherapy (PSA 50 , objective response) has been observed in patients with advanced/metastatic prostate cancer. The Phase I/II PETRANHA study (NCT05367440) has demonstrated that saruparib can be safely combined with androgen receptor pathway inhibitors to treat patients with metastatic prostate cancer. The Phase III EvoPAR-Prostate02 study (NCT06952803) is evaluating the efficacy and safety of adjuvant saruparib versus placebo in patients with early-stage, high-risk prostate cancer with BRCA1 / BRCA2 gene mutation (BRCAm) who have received definitive radiotherapy (RT) and are receiving a standard concomitant androgen deprivation therapy (ADT) regimen. Methods: EvoPAR-Prostate02 is a two-cohort, randomized, double-blind, placebo-controlled study. Eligibility criteria include age ≥18 years, diagnosis of high-risk or very high-risk localized/locally advanced prostate adenocarcinoma or high-risk biochemical recurrence following radical prostatectomy, with a confirmed BRCAm by central tumor tissue testing. Patients must have completed primary or salvage RT with curative intent, with no evidence of disease or disease detected only in the pelvis at time of study entry, and must still be receiving ADT. Key exclusion criteria include persistent cytopenias, conditions with predisposition to bleeding, and history of myelodysplastic syndrome/acute myeloid leukemia. In both Cohort A (ADT alone) and Cohort B (ADT plus abiraterone/prednisone), randomization is 1:1 to saruparib or placebo. Treatment with saruparib/placebo continues for 24 months or until unacceptable toxicity, confirmed disease progression by blinded independent central review (BICR), or patient-initiated withdrawal. ADT and abiraterone treatment duration is limited to 24 months, inclusive of pre-study regimen. The primary endpoint is metastasis-free survival (MFS), confirmed by standard clinical imaging (computed tomography/magnetic resonance imaging and bone scan, or prostate-specific membrane antigen-positron emission tomography [PSMA PET]), as assessed by BICR. Overall survival (OS) is a key secondary endpoint. Statistical analyses of MFS and OS will be conducted within each cohort using a stratified log-rank test. Approximately 700 patients will be randomized. Recruitment began in July 2025 and is ongoing. Clinical trial information: NCT06952803 .

TPS5146 Background: The androgen receptor (AR) is a key driver of prostate cancer progression. AR pathway inhibitors (ARPIs) are standard of care for metastatic prostate cancer, but acquired resistance is inevitable and often involves reactivation of AR signaling via AR gene alterations such as amplifications or ligand binding domain mutations. The need remains for alternative strategies to target the AR. AZD9750 is a novel oral proteolysis-targeting chimera that potently degrades wild-type, mutant, and amplified forms of the AR. Preclinical data also showed significant antitumor benefit with AZD9750 as monotherapy and combined with the PARP1 selective inhibitor saruparib (AZD5305). ANDROMEDA (NCT07336446) is a first-in-human, phase I/II, open-label, multicenter study investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AZD9750 as monotherapy and combined with saruparib in patients (pts) with metastatic castration-resistant prostate cancer. Methods: This study follows a modular design in which pts receive AZD9750 as monotherapy (Module 1) or combined with saruparib (Module 2; Table). Each module has 2 parts: monotherapy dose escalation or combination dose finding (Part A) and dose optimization and expansion (Part B). Eligible pts are ≥18 years of age with histologically or cytologically confirmed adenocarcinoma of the prostate and documented metastatic disease with serum testosterone level ≤50 ng/dL, evidence of disease progression, and ECOG performance status of 0 or 1. Pts should have previously received ARPIs and taxane-based chemotherapy, with the exception of no prior taxane-based chemotherapy in Module 1 Part B3. Primary endpoints include occurrence of dose-limiting toxicities (Part A only), incidence of adverse events (AEs) and AEs leading to treatment discontinuation (Parts A and B), and preliminary efficacy (ie, ≥50% decrease in prostate-specific antigen [PSA]; Part B only). Secondary endpoints include preliminary efficacy (ie, ≥50% and ≥90% decrease in PSA, objective response rates and progression-free survival per RECIST v1.1 and PCWG3 criteria, change in target lesion size per RECIST v1.1 criteria, time to PSA response, and time to PSA progression per PCWG3 criteria) and pharmacokinetic parameters (Parts A and B). This study is currently recruiting for monotherapy dose escalation. Clinical trial information: NCT07336446 . Study part Module 1: AZD9750 monotherapy Module 2: AZD9750 plus saruparib Part A A1. Dose escalationA2. Backfill cohorts Combination dose finding a Part B B1. Dose optimization a B2. Dose expansion b B3. Dose expansion b Combination dose expansion c a Recommended doses determined in Module 1 Part A; b To be opened once recommended phase II dose identified in Module 1 Part B1; c To be opened once combination dose identified in Module 2 Part A.

Demographics and baseline disease characteristics for patients with ATM alterations by central testing who started on ceralasertib 160 mg twice daily.

PURPOSE:Ceralasertib is an oral ataxia telangiectasia and Rad3-related (ATR) inhibitor with preclinical activity in ataxia-telangiectasia mutated (ATM)-altered cancers. The phase IIa PLANETTE study evaluated ceralasertib in previously treated advanced solid tumors (cohort A) or metastatic castration-resistant prostate cancer (cohort B) with ATM alterations (ATM mutations and/or ATM protein deficiency). PATIENTS AND METHODS:Patients received ceralasertib 160 mg twice daily on days 1 to 14 of a 28-day cycle. Efficacy was evaluated in patients with centrally confirmed ATM alterations. The primary endpoint was objective response rate (ORR; cohort A) or composite response rate (CRR: radiographic response, prostate-specific antigen response, or circulating tumor cell conversion; cohort B). Secondary endpoints included progression-free survival (PFS) and safety. RESULTS:Cohorts A and B included 30 and 15 patients, respectively. ORR (cohort A) was 7.1% [80% confidence interval (CI), 1.9-17.9; n = 2/28]: one complete response ongoing at 14.1 months (breast cancer) and one partial response ongoing at 7.4 months (endometrial cancer). CRR (cohort B) was 7.7% (80% CI, 0.8-28.6; n = 1/13). In patients with centrally confirmed ATM protein loss, the ORR was 18.2% (80% CI, 4.9-41.5; n = 2/11) and CRR was 0% (80% CI, 0-28; n = 0/7). The median PFS was 3.7 months in each cohort (cohort A, 80% CI, 1.9-5.6; cohort B, 80% CI, 1.9-not calculable). Grade ≥3 adverse events (AE) occurred in 50% of cohort A and 53.3% of cohort B patients. The most common AEs overall were asthenia/fatigue, nausea, and anemia. CONCLUSIONS:Ceralasertib monotherapy was tolerated; however, responses were limited. Alternative patient selection and combination treatments are being explored. SIGNIFICANCE:In the phase IIa PLANETTE study in advanced/metastatic ATM-altered cancers, ceralasertib 160 mg twice daily (days 1-14, 28-day cycle) was tolerated; objective responses were limited, corroborating previous findings with ATR inhibitors in ATM-deficient tumors. Optimizing biomarker-based patient selection beyond ATM deficiency represents a key aspect of future ATR inhibitor development.

Abstract Chromosomal instability (CIN) signatures are DNA copy number-based genomic biomarkers with emerging evidence for predicting treatment sensitivity across multiple drugs and cancer types. Modern computational approaches enable the quantification of CIN signatures from clinically validated targeted DNA sequencing panels such as MSK-IMPACT. In this study, we derived copy number profiles from 63,630 tumor-normal MSK-IMPACT pairs using FACETS and computed pan-cancer CIN signatures across 73 cancer types. Analyses were restricted to pre-treatment samples, and CIN signature exposures were used to build three therapy-specific biomarkers: (i) a new biomarker of sensitivity for PARP inhibitors (PARPi) trained on progression-free survival (PFS) data from BRCA wild-type (BRCAwt) high-grade serous ovarian cancer (HGSOC) (ii) a new biomarker of sensitivity to platinum-based chemotherapies trained on disease-free survival (DFS) data from locally advanced rectal cancer (LARC) and (iii) an existing biomarker for resistance to anthracycline-based chemotherapies, now derived from targeted sequencing data for the first time. Each biomarker was validated in at least one independent MSK-IMPACT cohort of a different cancer type, using PFS calculated from treatment initiation and assessed at 12 months. The PARPi biomarker performed similarly to the Myriad MyChoice Genomic Instability Score (GIS) in identifying BRCAwt HGSOC patients with longer PFS after treatment (CIN signatures: n=84, HR=0.38, p=0.005; GIS: n=84, HR=0.41, p=0.004) and fully identified responders in an independent BRCAwt prostate adenocarcinoma (PRAD) cohort (Sensitivity 100%, Specificity 60%, AUC=0.73). The platinum biomarker predicted longer PFS in primary head and neck squamous cell carcinoma (HNSCC) (n=82, HR=0.43, p=0.007). The anthracycline biomarker predicted shorter PFS in hormone-receptor positive HER2 negative (HR+/HER2-) breast cancer - both primary (n=191, HR=1.72, p=0.015) and metastatic (n=216, HR=1.72, p=0.003) - and in primary soft-tissue sarcoma (n=251, HR = 1.81, p=0.006). These results highlight the feasibility and clinical potential of CIN signatures at a pan-cancer level, illustrating how the frequently overlooked complexity of genome-wide copy number alterations contained in routine targeted panels can be transformed into interpretable biomarkers to guide therapy selection. This proof-of-concept establishes that CIN signatures can be extracted from regulatory-approved assays such as MSK-IMPACT, although further validation is needed to facilitate clinical adoption. Citation Format: David Gómez-Sánchez, Adam Price, Max Schmidt, Sharafudeen Abubakar, Farheen Shah, Christina Lee, Chin-Tung Chen, Barbara Hernando, Daniel Muldoon, Areej Alsaafin, Evan Seffar, George Li, Subhiksha Nandakumar, Wassim Abida, Stephen Graves, Mackenzie Sullivan, Rachel N. Grisham, Britta Weigelt, Luc GT Morris, Nadeem Riaz, Pedram Razavi, Allison L. Richards, Mark Donoghue, Walid Khaled Chatila, Chaitanya Bandlamudi, Nikolaus Schultz, Michael F. Berger, Sohrab Shah, Geoff Macintyre, Julio Garcia-Aguilar, Francisco Sanchez-Vega. CIN signatures as biomarkers of drug sensitivity: Real-world evidence from DNA targeted sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1024.

Representativeness of Study Participants

MRI scan showing target lesion reduction in the responder with endometrial cancer receiving ceralasertib 160 mg BID in Cohort A

PURPOSE:Poly(ADP-ribose) polymerase inhibitors (PARPis) are effective for the treatment of metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations, but predictive biomarkers beyond individual gene alterations remain poorly defined. We aimed to identify genomic features associated with response to PARP inhibition in real-world data. MATERIALS AND METHODS:This is a single-center retrospective study of patients with mCRPC who received PARPi therapy. All patients underwent tumor genomic profiling using a single panel sequencing assay. Responses were defined as prostate-specific antigen (PSA50) (≥50% PSA decline from baseline) and objective radiographic response by RECIST 1.1. We explored the association of genomic features with response to therapy. RESULTS:Among 120 patients with mCRPC who received a PARPi, 54% had BRCA2/1 alterations and 16% had no HRR gene alterations. Other alterations include ATM (10%), CDK12 (10%), BARD1 (2%), CHEK2 (7%), and PALB2 (2%). Overall, 37% had PSA50 responses (95% CI, 27 to 47) and 43% had RECIST responses (95% CI, 27 to 61). Patients with BRCA2 alterations had the highest response rates (52% PSA50, 72% RECIST), and biallelic BRCA2 loss was associated with better outcomes. Panel-based mutational signatures (SigMA, SBS3 from DeepSig) were associated with BRCA-mutated status and overall response to PARPi. Six patients without known HRR gene alterations had responses; one was later found to harbor BRCA2 loss. Limitations include the small study size, retrospective design, and use of panel-based sequencing. CONCLUSION:Most PARPi responders had alterations in HRR genes, particularly BRCA2, although some responders lacked known biomarkers associated with PARPi response. Our findings in this real-world data set support HRR gene testing for PARPi use in mCRPC and highlight the need for novel genome-wide biomarkers for patient selection.

5057 Background: RB function is often attenuated in tumors through hyperphosphorylation; thus, RB activity can be “re-awakened” in RB+ tumors by suppressing key kinases that phosphorylate RB (CDK4/6). We report a phase Ib/II trial to determine the safety, tolerability and antitumor activity rib with enza in patients (pts) with mCRPC (NCT02555189). Methods: RiboX was a multicenter, phase Ib/II, open label trial which enrolled taxane-naïve pts with progression to mCRPC and retained RB expression. For phase Ib, a traditional 3x3 dose-escalation was used to establish the RP2D for the phase II portion. Pts received rib at 200, 400 or 600mg once daily (QD) Days (D) 1-21 in combination with fixed dose enza (160mg QD D1-28). In phase II, pts were randomized 1:1 to enza monotherapy (Arm A) or enza + rib (Arm B). The study was later modified to a single arm Simon two-stage design using the RP2D of 600mg rib with 160mg enza. The primary phase II endpoint was the proportion of pts a PSA50 response at 12 weeks. The null hypothesis was that the PSA50 response was ≤78% and 31 responses were required to reject the null hypothesis. Secondary endpoints were rPFS, PSA PFS, OS and safety. Results: 12 pts were enrolled in the phase Ib portion across three dose levels upon confirmation of RB expression on tumor biopsy. No DLTs were observed in dose-escalation and the RP2D was established at rib 600mg QD D 1-21 + enza 160mg QD D 1-28. The phase II portion included 12 pts treated with enza mono; 28 phase II pts and 6 phase 1b pts yielded 34 pts treated with combination at RP2D. The PSA50 response at 12 weeks was 75% (95% CI, 43-95) for enza mono and 82% (95% CI, 65-93) for the combination, failing to reject the null hypothesis. Median rPFS for evaluable pts was 10.9 mo (95% CI, 2.5-45.9) for enza mono (n = 12) and 27.0 mo (95% CI, 11.3-37.0) for combination (n = 30). PSA PFS was 10.1 months (95% CI, 1.8-33.1) for enza mono (n = 12) and 14.8 mo (95% CI, 6.7-35.9) for combination (n = 34). OS was 31.2 mo (95% CI, 15.0-NA) for enza mono (n = 12) and 58.1 mo (95% CI, 33.4-NA) for combination (n = 34). Four pts treated with combination were included for PSA PFS but did not have data for rPFS. Among pts treated at RP2D in the combination arm, the most common TEAE’s included fatigue 59%, nausea 26.9%, neutropenia 26.7% (grade 3, 12%), diarrhea 20.9%, dizziness 14.7%, arrhythmia 2.9%, seizure 2.9%. Conclusions: The combination of enza + rib was well tolerated; however, no significant difference in PSA50 response was observed, and the primary endpoint was not met. A disease-stabilizing effect was observed in a subset of patients treated with the enza + rib combination, with evidence of prolonged survival. Further investigation into this disease-stabilizing effect and refinement of patient selection criteria beyond RB expression may be warranted. Funding: Novartis Pharmaceuticals and DOD (W81XWH-22-2-0020). Clinical trial information: NCT02555189 .

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.

Baseline disease characteristics for patients with ATM alterations by central testing who started on ceralasertib 160 mg BID in Cohort B

Adverse events observed in ≥2 patients who started on ceralasertib 240 mg BID in Cohort

TPS5152 Background: Although radical prostatectomy (RP) is a curative approach for patients (pts) with high-risk localized prostate cancer (PC), recurrence rates remain high. Neoadjuvant studies of androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI) suggest improvement in local disease control at the time of RP and may be associated with better long-term outcomes (McKay et al. PC Prostatic Dis. 2018; McKay et al. ASCO 2023: #5095). An ongoing phase 3 study is evaluating ADT plus apalutamide for 6 months prior to RP in pts with high-risk or locally advanced PC; co-primary endpoints are pathologic complete response (pCR) and metastasis-free survival (NCT03767244). BMS-986365 is an orally administered ligand-directed degrader targeting the androgen receptor (AR) via a first-in-class dual mechanism of 1) AR degradation and 2) AR antagonism. A phase 1 study showed that BMS-986365 was well tolerated with a manageable safety profile, with antitumor activity in pts with metastatic castration-resistant PC (mCRPC) regardless of AR gene alterations (Rathkopf et al. Ann Oncol. 2025), leading to an ongoing phase 3 study in mCRPC (rechARge: NCT06764485). Due to its dual mechanism and promising data in mCRPC, we hypothesize that neoadjuvant treatment with ADT plus BMS-986365 prior to RP will result in robust pathologic response rates. Methods: This is a single center, phase 2, single-arm trial testing the combination of ADT plus BMS-986365 for 6 months prior to RP in pts with high-risk localized PC. Eligible pts include those who are candidates for RP and meet ≥ 1 high-risk criteria: PSA ≥ 20 ng/mL, Gleason ≥ 8, or clinical stage ≥ cT3a (N1M0 disease allowed). Pts will receive degarelix SC once monthly (first dose 240mg, maintenance dose 80mg) and BMS-986365 at a dose of 300mg PO twice daily (liquid-filled capsule formulation) for 6 months; RP will occur 2 weeks after the last dose of BMS-986365. The dose of BMS-986365 was selected based on the phase 1 data and equivalent doses utilized in the ongoing phase 3 rechARge study. The primary endpoint is the rate of pCR and/or minimal residual disease (MRD, defined as tumor ≤ 5mm) at the time of RP. A two-stage design will evaluate if pCR and/or MRD rate exceeds 0.20, which is the rate observed in historical studies of ADT and ARPI prior to RP (McKay et al. J Urol. 2021) 10 pts will be enrolled in Stage 1; if ≥ 3/10 pts achieve a pCR and/or MRD, an additional 20 pts will be enrolled in Stage 2. If ≥ 10/30 pts achieve a pCR and/or MRD, the treatment will be declared sufficiently active (alpha = 0.05, power 0.80). Secondary endpoints include safety and time to biochemical recurrence. As part of exploratory analyses, cfDNA, pre-/post-treatment (prostatectomy) tissue, and pre-/post-treatment multiparametric MRI will be collected. The study opened to accrual in January 2026. Clinical trial information: NCT07335796 .

209 Background: Prostate cancer (PC) progression is driven by aberrant activity of the androgen receptor (AR) or its associated ligands - androgens. Dysregulation of genes that regulate androgen production, uptake, and conversion (APUC) may impact the efficacy of hormone therapies for PC. In our recent study of primary (n=2593) or metastatic PC (n=4490) biopsies, 6 APUC genes ( HSD3B1 , HSD3B2 , CYP11A1 , CYP11B1 , CYP17A1 , CYP3A43 ) showed strong clustering in prostate adenocarcinoma. Tumors with high APUC expression (APUC-6 high) had low AR alterations/signaling activity and showed prolonged overall survival. Here we examined the genomic, transcriptomic, and immune cell-fraction compositions in APUC-6 high versus AR-high tumors. Given improved outcomes in APUC-6 high tumors, we hypothesize reduced features of tumor aggressiveness or a favorable immune milieu in these specimens. Methods: Metastatic PC samples in the SU2C/PCF dataset (n=208) were annotated as APUC-6 high or AR-high based on gene expression quartiles, with the upper quartile defining “high” status. Additional stratification was performed to ensure that no samples classified as both APUC-6 high and AR-high were included in either group. This stratified two groups of tumors (n= 41, each). Transcriptomic, genomic, and clinical features between the two groups were compared. Gene Set Enrichment Analysis was used to identify upregulated gene-expression hallmark pathways, and CIBERSORT was used to infer fractions of 22 immune cell types. Results: APUC-6 high tumors exhibited fewer AR genomic alterations, AR gene expression, and AR-V7 detection. APUC-6 high and AR-high groups harbored significant differences in mutation alteration frequencies of 4 genes: AR, EDN2, EDA2R, and OPHN1 (q < 0.05). There were no differences in the frequency of poor-prognosis mutations such as in TP53, PTEN, or RB1. APUC-6 high tumors were enriched in several hallmark inflammatory pathways and epithelial to mesenchymal transition (EMT) (NES>1.5, FDR<0.05). APUC-6 high tumors contained a higher fraction of naïve CD4 T-cells (224-fold, q = 0.0226), and also exhibited numerically higher levels of activated natural killer cells and neutrophils (1.35-fold and 2.11-fold, q = 0.081, 0.051, respectively), relative to AR-high tumors. Conclusions: APUC-6 high tumors, characterized by a favorable prognosis, are associated with upregulation of inflammatory pathways and EMT, and a distinct immune cell repertoire despite no difference in aberrations of canonical drivers of aggressiveness, such as TP53, PTEN , or RB1 status. The more inflamed tumor microenvironment observed in APUC-6 high tumors warrants further exploration of distinct clinical approaches to this distinct phenotype. Validation of these findings in larger cohorts is ongoing.