PURPOSE:Oligometastatic prostate cancer (oligoPCa) represents a clinical state of limited metastatic spread in which metastasis-directed therapy (MDT) may offer meaningful disease control either alone or with systemic therapy. As imaging, systemic therapy, and biologic characterization evolve, management strategies for both synchronous and metachronous presentations continue to undergo significant refinement. RECENT FINDINGS:Randomized trials such as STOMP and ORIOLE have demonstrated improved progression-free and androgen deprivation therapy (ADT)-free survival with MDT in metachronous oligometastatic disease. More recent studies, including EXTEND and RADIOSA, suggest that combining MDT with short-course systemic therapy may further enhance disease control, while ongoing trials continue to evaluate MDT in synchronous disease. In parallel, the systemic therapy landscape has expanded with early adoption of second-generation androgen receptor pathway inhibitors (ARPIs), PARP inhibitors for selected biomarker-defined populations, and radioligand therapies such as lutetium-177. Emerging evidence also suggests that molecular imaging with PSMA PET, genomic classifiers (e.g., Decipher), multimodal digital pathology tools (e.g., ArteraAI), and machine learning-based predictive models may help identify patients most likely to benefit from MDT. Additionally, novel immuno-oncology and bispecific antibody-based strategies are under active investigation. SUMMARY:The integration of MDT with modern systemic and biologically informed strategies holds promise for personalized management of oligoPCa. Future efforts should prioritize biomarker- driven patient selection and rational treatment sequencing to optimize long-term outcomes.

Patient clinical data, ctDNA sample parameters, and ctDNA fraction and ploidy inferred by IchorCNA and ACE

Supplementary Figure S20. Correlation between ctDNA fraction changes and EDI during ASI

Supplementary Figure S11. Tumor subclone changes in longitudinal ctDNA samples: P126, P127, P131, P132, P138, and P142

Aggressive-variant prostate cancers (AVPCs) respond poorly to anti-androgen therapy but show sensitivity to taxane-platinum chemotherapy, though outcomes remain poor. We conducted a phase 2 trial testing induction cabazitaxel plus carboplatin (CabCarb) followed by olaparib maintenance versus observation in men with AVPC. The primary endpoint of improved progression-free survival (PFS) was not met, likely due to the study being underpowered after 38.5% of patients experienced early progression (ChemoPD) prior to randomization. No genomic alterations predicted ChemoPD; however, transcriptomic analysis revealed the enrichment of metabolic pathways, including arginine metabolism, in ChemoPD tumors. These findings were supported by metabolomics data from preclinical models. In AVPC models, arginine depletion with ADI-PEG20 enhanced CabCarb efficacy in vitro and in vivo. Together, these results provide insight into the heterogeneity of AVPCs and establish a rationale for novel combination treatment strategies to overcome chemotherapy resistance.

Supplementary Figure S7. Prognostic significance of clinical features and genomic aberrations at baseline timepoints, before therapies

Abstract Background: Castration-resistant prostate cancer (CRPC) bone metastases lack curative therapies. Fibroblast growth factor receptor (FGFR) signaling is implicated in bone physiology, cancer stemness and therapy resistance. Previously, we demonstrated Dovitinib, a multi-tyrosine kinase inhibitor that targets FGFR, disrupts tumor-bone crosstalk. Here we evaluate Erdafitinib, a selective pan-FGFR inhibitor approved for metastatic urothelial carcinomas, for bone metastatic prostate cancer (PCa). Methods: Spheroid formation (area, circularity, solidity, Feret’s diameter) and cell viability were assessed in PCa (PC3, 22Rv1, C42b, DU145), osteoblast progenitor (MC3T3), FGFR1-overexpressing-PC3 and shFGFR1-MC3T3 cell lines treated with Erdafitinib. Tumor-free mice and mice intrafemorally grafted with PCa patient-derived xenografts (MDA-PCa-PDX) were treated (12.5mg/kg, BID 21 days). Tumor and non-tumor bearing femurs were analyzed via μCT and bone histomorphometry; tumors were monitored by MRI. A pilot clinical study evaluated Erdafitinib for CRPC bone metastases (NCT04754425). Results: Erdafitinib significantly disrupted PCa spheroids stem-like morphology. C42b were highly resistant, 22Rv1 and DU145 moderately responsive, and PC3 more sensitive (IC50 585.5nM), losing responsiveness with FGFR1-isoforms overexpression (α, 2508nM; β, 4896nM). MC3T3, pre-osteoblastic line, exhibited the highest sensitivity (49.75nM), independently of FGFR1 modulation. In tumor-free mice, Erdafitinib decreased bone volume, increased bone surface and modified trabecular architecture (number, thickness, separation, shape). In PDX-bearing mice, bone mineral density and volume were reduced in contralateral tumor-free and FGFR1-low tumor-bearing femurs. A 40% tumor volume reduction was observed in FGFR1-high tumors, without significant osseus changes. In our clinical study, 20% of patients responded to Erdafitinib with reductions in alkaline phosphatase levels but unchanged PSA, confirming bone-microenvironment targeting. Conclusion: Erdafitinib impacts PCa stem-like features and viability, with variable response. Importantly, it may disrupt the tumor-bone interplay by modulating both tumor stemness and the bone compartment, potentially posing a modified environment that may be less amenable for metastasis. Future directions will define responsive PCa patients and evaluate combinatorial strategies. Citation Format: Agustina Sabater, Pablo Sanchis, Jun Yang, Peter D.A. Shepherd, Jiabin Dong, Elba Vazquez, Christopher Logothetis, Paul G. Corn, Geraldine Gueron, Estefania Labanca. FGFR Inhibitor, Erdafitinib, Reshapes Prostate Cancer Skeletal Metastases via Modulation of Cancer-Stemness and Tumor-Bone Interface [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P31.

Supplementary Figure S23. Correlation between ctDNA fraction changes and EDI during chemotherapy

Supplementary Figure S2. Landscape of genomic aberrations in longitudinal plasma samples

Supplementary Figure S19. Survival analysis of genomic alterations that related to ASI resistance or shorter PFS of ASI in cBioPortal

Supplementary Figure S3. Significant copy number variations in the ctDNA samples

Abstract 6 UT MD Anderson Cancer Ctr., Houston, TX.Prostate cancer (PCa) progression remains a major clinical challenge with limited therapeutic options, and the complexity of metabolic pathways fueling advanced PCa rests poorly understood. We have identified a shift from glycolysis to ketone body (KB) metabolism in castration-resistant PCa (CRPC), with an upregulation of ketolytic/ketogenic enzymes. From these, ACAT1 is a potential therapeutic candidate, as its expression is elevated in aggressive PCa and associates with unfavorable clinical outcomes. Here, we investigated the contribution of the bone niche -the dominant PCa metastatic site- to KB metabolism during PCa progression and evaluated ACAT1 inhibition as a treatment strategy for advanced disease. Co-culture experiments between PCa cells and bone progenitors (MC3T3, Raw264.7) were used to evaluate bone-driven metabolic adaptations. To validate in vivo the effect of the bone niche, we implanted MDA PCa patient-derived xenograft (PDX) 183 either intrafemorally (i.f.) or subcutaneously (s.c.) in sham or castrated CB17 SCID mice. We assessed cell viability in PCa cells lines and in PDX-derived organoids (PDX.DO), treated with increasing concentrations of ACAT1 inhibitor, arecoline hydrobromide (AH). ACAT1 and phospho-ACAT1 levels were measured by Western blot and immunofluorescence. Intracellular KB and ATP content were quantified by luciferase-based assays. Lipid uptake and accumulation were quantified by flow cytometry using Bodipy probes. In vivo, mice bearing MDA PCa PDXs 183, 203 and 173 were treated with AH (50 mg/kg/day i.p., 21 days). Tumor volume, KB content, and ACAT1 modulation were evaluated. We observed transcriptional activation of lipid and KB metabolism in PC3 cells from PCa-bone co-cultures, and consistently, in i.f. PDXs compared to matched s.c. tumors, alongside a significant increase in ACAT1 expression levels. Castration dynamically modulated ACAT1 levels in MDA PCa 183 tumors growing i.f., with initial downregulation followed by restoration over time, underscoring KB metabolism as a mechanism of resistance within the bone niche. Functional studies showed that AH treatment reduced cell viability in PC3, C42B, and 22Rv1 cells, as well as PDX.DO, decreased ACAT1 and phospho-ACAT1 expression, lowered KB levels, and altered lipid dynamics by increasing lipid accumulation, uptake, and decreasing ATP content (P<0.05). In vivo, AH treatment in MDA PCa 183 tumors led to a significant reduction in tumor volume and intratumoral KB content (P<0.05). Moreover, in the CRPC model MDA PCa 203 -derived from a longitudinal sample of the same patient as 183-, and in the aggressive hormone-naïve model MDA PCa 173, AH treatment significantly reduced both tumor volume and KB content (P<0.05). In conclusion, our findings reveal KB metabolism as a critical vulnerability in PCa progression, with ACAT1 emerging as a druggable target whose inhibition disrupts tumor growth and metabolic fitness. Citation Format: Pablo Sanchis, Agustina Ayelen Sabater, Jiabin Dong, Peter Shepherd, Nicolás Anselmino, Paul G. Corn, Elba Vazquez, Christopher J. Logothetis, Daniel Frigo, Geraldine Gueron, Estefania Labanca. Exploiting ketone body metabolism as a therapeutic vulnerability in prostate cancer [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 4740.

Cox proportional hazards model of genomic aberrations and progression free survival of ASI

Supplementary Figure S1. cfDNA molecular features

Supplementary Figure S14. Tumor subclone changes in longitudinal ctDNA samples: P217, P220, P229, P244, P251, and P259

Supplementary Figure S10. Tumor subclone changes in longitudinal ctDNA samples: P36, P75, P115, P118, P124, and P125

Supplementary Figure S17. Clonal substructure, evolutionary dynamics, and genomic features in relation to clinical parameters

Supplementary Figure S6. Mutation signature and CNV signature changes in relation to treatments

PURPOSE We tested the hypothesis that adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy improves progression-free survival (PFS) among patients with oligometastatic disease. METHODS EXTEND was a multicenter randomized phase II trial. Patients with 1-5 metastases were randomly assigned to MDT + SOC versus SOC in one of the six baskets (breast, pancreas, kidney, two prostate baskets, and an other basket) with basket-specific stratification and powering. PFS, the primary end point, was prespecified in the per-protocol set within each basket, across all baskets, and across all baskets excluding the prostate baskets. Exploratory end points included circulating tumor DNA (ctDNA) and immune profiling. RESULTS From 2018 through 2023, 521 patients were screened, 350 were randomly assigned, and 334 were analyzed per protocol (MDT + SOC, n = 166; SOC, n = 168). Radiotherapy was used as MDT for 98% of metastases (370/379). Overall, after a median follow-up of 53 months, PFS was improved with MDT + SOC (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.72], P < .001). Similarly, PFS was improved when excluding the prostate baskets (HR, 0.60 [95% CI, 0.40 to 0.89]). Within each basket, PFS superiority was identified for the pancreas, prostate, and other baskets, whereas the breast and kidney baskets were inconclusive. At enrollment, detectable ctDNA correlated with shorter PFS and survival; by contrast, ctDNA clearance 3 months postenrollment correlated with improved survival. MDT + SOC-induced systemic immune activation was most pronounced among baskets demonstrating PFS superiority. CONCLUSION The phase II EXTEND trial supports the addition of MDT to SOC for oligometastatic disease. Histology-specific efficacy signals were identified for phase III testing. Translational insights suggest the potential for optimizing the definition of oligometastasis using ctDNA and point to systemic immune responses as a possible mechanism of benefit from MDT.