Abiraterone (ABI) and enzalutamide (ENZA) are standard treatments for metastatic castration-resistant prostate cancer (mCRPC). However, their safety and efficacy have not been directly compared in prospective clinical trials. To directly compare their safety and efficacy in prospective clinical trials. A systematic search was performed in PubMed, Embase, and Cochrane Library databases (CRD42024608496) on 24 June 2025. Eligibility criteria included studies on patients with mCRPC treated with ABI or ENZA reporting outcomes such as overall survival (OS), prostate-specific antigen (PSA) response (PSA50/90), progression-free survival (rPFS/bPFS), and rates of grade ≥ 3 adverse events, dose reduction, treatment discontinuation, and major cardiovascular events (MACE). Both first- and second-line mCRPC treatment settings were considered. The inverse variance method was used to calculate pooled hazard ratios (HRs), using the natural logarithm of the HR and its standard error (SE) from the available data. A total of 47 real-world observation studies and data from 71,984 patients were included, with no randomized controlled trials available for direct comparison. ENZA proved more effective in terms of PSA50 (odds ratio (OR): 1.82; 95% confidence interval (CI): 1.38-2.4) and OS (HR: 0.79; 95% CI 0.71-0.87) in the overall cohort as well as in the first-line (PSA50: OR: 1.69; 95% CI 1.23-2.31, OS: HR: 0.85, 95% CI 0.79-0.92) and second-line setting (PSA50 OR: 1.78; 95% CI 1.23-2.58, OS: HR: 0.69; 95% CI 0.60-0.80). However, grade ≥ 3 AEs and treatment discontinuation rates were significantly more frequent with ENZA (OR: 2.17; 95% CI 0.85-5.54 and OR: 1.81; 95% CI 1.45-2.25, respectively), while MACE rates were lower (OR: 0.53; 95% CI 0.33-0.84). ENZA showed greater efficacy, whereas serious AEs were less frequent with ABI. However, this difference may decrease or even disappear upon switching these therapies. Therefore, individual decision-making is encouraged, balancing efficacy and safety. ENZA should be prioritized if OS is the main goal, whereas ABI may be preferred when minimizing AEs is important. ENZA is also associated with a lower risk of MACE.

NUSAP1 mediates enzalutamide resistance in prostate cancer via Wnt/β-catenin signalling-dependent regulation of AR and AR-V7.

Enzalutamide (ENZA) is a second-generation antiandrogen therapy that provides overall survival (OS) benefit for prostate cancer (PC) patients. However, many patients have baseline or develop resistance to ENZA. Currently, no biomarkers are used in clinical decision making to predict the efficacy of ENZA therapy. We aimed to identify cell-free DNA (cfDNA) biomarkers for metastatic castration-resistant prostate cancer (mCRPC) predictive to ENZA response. Comparative whole-exome and transcriptome sequencing was performed on three ENZA-resistant and parental ENZA-sensitive PC cell line pairs. Bioinformatic analysis identified UCA1, ORM1, and androgen receptor (AR) as candidate markers for serum cfDNA testing. Digital droplet PCR was used to analyze UCA1, ORM1 and AR in cfDNA from serum samples of mCRPC patients who underwent ENZA (n = 20), abiraterone (ABI; n = 20) and 40 docetaxel (DOC; n = 40) treatment. UCA1 copy number gain was significantly associated with reduced OS in ENZA-treated patients (p = 0.030). AR gain correlated with poorer OS in ABI-treated patients (p = 0.039), whereas no association was observed in DOC-treated patients. Normal AR and UCA1 levels were associated with significantly better OS in ENZA and ABI-treated patients. These findings suggest that UCA1 gain may predict reduced efficacy of ENZA treatment, while AR gain indicates decreased effectiveness of ABI but not ENZA and DOC therapies. These results may help support therapeutic decisions in the clinical settings.

Castration-resistant prostate cancer (CRPC) is a fatal malignancy often associated with alterations in cell cycle regulation, particularly within the Cyclin/CDK/RB axis. Despite ongoing clinical trials assessing CDK4/6 inhibitors in prostate cancer, clinical evidence remains limited. Although the androgen receptor (AR) inhibitor enzalutamide (ENZ) initially demonstrates therapeutic efficacy, resistance develops over time, and monotherapy offers limited antitumor benefits, highlighting the need for effective combination therapies. In this study, pharmacological profiling, genetic dependency analysis, RNA sequencing, and functional validation were conducted across various in vitro and in vivo preclinical CRPC models. The combination of ENZ and the CDK4/6 inhibitor dalpiciclib (DAL) exhibited potent antitumor activity in CRPC cell lines, a cell-derived xenograft (CDX) model, and a lymphatic metastatic model. Moreover, ENZ plus DAL inhibited cell cycle progression, migration, and DNA replication, while promoting apoptosis in CRPC cells. Mechanistically, ENZ blocked AR-mediated transcriptional activation of MCM4, a critical component of the DNA helicase complex, thereby enhancing the effect of CDK4/6 inhibition on DNA replication and inducing a pronounced synergistic antitumor response. These results suggest that the ENZ-DAL combination is a promising therapeutic approach that warrants further clinical evaluation in CRPC patients.

11164 Background: Several therapies are approved for metastatic hormone sensitive prostate cancer (mHSPC), with differing efficacy and costs. While many cost-effectiveness analyses (CEAs) rely on randomized trial data, such analyses lack generalizability to real-world practice. We evaluated the real-world cost effectiveness (CE) of adding androgen receptor pathway inhibitors (ARPIs) to androgen deprivation therapy (ADT) for first-line (1L) mHSPC using the IRONMAN registry (NCT03151629). Methods: We conducted a US public payer perspective CEA using individual patient-level IRONMAN data. Eligible patients (pts) received 1L ADT alone, ADT + enzalutamide (ENZ), or ADT + apalutamide (APA) with ≥1 follow-up visit. A 3-state Markov model with 1-month cycles and a 10-year horizon was used. Progression-free survival (PFS) was proxied by time-to-next-treatment (TTNT); overall survival (OS) was time from 1L initiation to death or last follow-up. Costs and outcomes were discounted at 3% per year. Outcomes were measured in life-years gained (LYG) and incremental cost-effectiveness ratios (ICER) were reported. Uncertainty was assessed via one-way sensitivity analysis and probabilistic sensitivity analysis. A scenario analysis evaluated hypothetical ENZ price reductions aligned with planned Inflation Reduction Act negotiations. Results: 1187 pts with mHSPC met inclusion (ADT: n=405, ENZ: n=412, APA: n=370; Table 1). In the base case, both ARPI strategies improved OS versus ADT alone, though only APA provided a statistically significant reduction in risk (ENZ: HR 0.78, 95% CI 0.58-1.03, p=0.08; APA: HR 0.50, 95% CI 0.36-0.70, p<0.001). Using TTNT as a proxy for PFS, ADT alone had a reduced risk compared to either ARPI (ENZ: HR 1.97, 95% CI 1.39-2.77, p<0.001; APA: HR 1.51, 95% CI 1.05-2.18, p=0.028); underreporting of subsequent therapies in the ADT alone group may have contributed to this finding. Median follow-up was 26.7 months; median TTNT and OS were not reached. Neither ARPI strategy was CE at conventional US thresholds (ENZ: ICER = $444,947/LYG; APA: ICER = $669,530/LYG), and ENZ would require a 79% price discount to meet CE thresholds. Sensitivity analyses supported the base case results. Conclusions: Adding ENZ or APA to ADT for 1L mHSPC improved OS but was not found to be to be cost-effective at current US prices over a 10-year horizon. Substantial ENZ price reductions would be required to reach commonly used CE thresholds. Baseline characteristics. ADT(N = 405) ENZ(N = 412) APA(N = 370) Median age at study entry (IQR) 71 (64, 78) 71 (65, 76) 71 (65, 76) PSA at study entry (ng/mL) Median (IQR) 9 (1, 53) 4 (1, 21) 3 (0, 13) Range 0, 5430 0, 3560 0, 5530 Missing (%) 137 (34) 62 (15) 56 (15) Duration of follow-up (months) Median (IQR) 24 (10, 41) 28 (17, 41) 28 (17, 40) Range 3, 80 3, 67 2, 64

5081 Background: Treatment intensification improves survival in hormone-sensitive prostate cancer (HSPC). However, direct comparisons between triplet therapies consisting of androgen-deprivation therapy, docetaxel, and an androgen receptor pathway inhibitor (ADT+Docetaxel+ARPI) and ARPI doublets are limited. In addition, available evidence remains fragmented between high-risk non-metastatic (nmHSPC) and metastatic (mHSPC) disease states. We conducted a network meta-analysis (NMA) to rank treatment regimens and inform clinical decision-making. Methods: We analyzed 13 phase III RCTs including approximately 13,000 patients with high-risk HSPC, encompassing metastatic and high-risk non-metastatic disease. Treatment strategies included ADT alone, docetaxel (DOC), abiraterone (ABI), enzalutamide (ENZ), apalutamide (APA), darolutamide (DARO), and triplet combinations. A frequentist random-effects NMA was performed with overall survival (OS) as the primary endpoint. Secondary efficacy endpoints included progression-free survival (PFS) and time to castration resistance (TTCR). Safety was assessed using treatment-emergent grade ≥3 AEs, assuming network transitivity. Results: For the primary endpoint (OS), triplet therapies ranked highest, including ADT+DOC+DARO (HR 0.55 [95% CI 0.43–0.69]) and ADT+DOC+ABI (HR 0.60 [95% CI 0.45–0.81]) compared with ADT alone. ARPI doublets also demonstrated robust OS benefits, including ABI (HR 0.63 [0.58–0.69]), APA (HR 0.67 [0.51–0.89]) and ENZ (HR 0.69 [0.51–0.94]). No statistically significant OS difference was observed between triplets and ARPI doublets, although triplets numerically favored higher efficacy. For PFS (I² = 86.5%), triplet therapies remained superior, with ADT+DOC+DARO showing the greatest benefit (HR 0.24 [0.13–0.45]), followed by the ENZ doublet (HR 0.40 [0.27–0.60]). Secondary endpoints (TTCR, PSA-PFS) consistently favored ARPI-based regimens. Regarding safety, triplet therapies significantly increased the odds of Grade ≥3 AEs versus ADT (OR ~2.6–3.7), driven primarily by docetaxel-associated fatigue and ABI-related hypertension. Conversely, APA, ENZ, and DARO doublets demonstrated favorable safety profiles, with no significant increase in overall Grade ≥3 AEs compared with ADT alone (ORs 1.02–1.06). Benefits were consistent across nmHSPC and mHSPC subgroups (p for interaction = 0.66). Conclusions: Triplet therapy represents the efficacy standard for fit patients with high-volume mHSPC. However, ARPI doublets offer a compelling alternative with comparable survival benefits and a superior safety profile, making them the preferred choice for high-risk nmHSPC and patients prioritizing tolerability. Clinical selection should stratify based on disease volume and fitness for docetaxel-associated toxicity.

The poly (ADP-ribose) polymerase inhibitor talazoparib, in combination with the androgen receptor pathway inhibitor enzalutamide, has demonstrated improved survival outcomes compared with enzalutamide monotherapy in homologous recombination repair mutations (HRRm)-positive metastatic castration-resistant prostate cancers (mCRPC) in the TALAPRO-2 trial. However, potential cost-effectiveness of the combination regimen remains limited. Our objective was to evaluate lifetime cost-effectiveness of talazoparib plus enzalutamide (TALA + ENZA) versus enzalutamide (ENZA) alone from a U.S. payer perspective. A partitioned survival model with progression-free survival and overall survival inputs were derived from the TALAPRO-2. Costs for drugs, adverse events, disease management, and end-of-life care were included. Health outcomes included life-years (LYs) and quality-adjusted life-years (QALYs). Incremental cost-effectiveness ratios (ICERs) were calculated for TALA + ENZA versus ENZA. Deterministic and probabilistic sensitivity analyses assessed parameter uncertainty, and scenario analyses explored drug price reductions and shorter time horizons. In the base case, TALA + ENZA yielded 4.84 total LYs and 3.25 QALYs, compared with 3.27 LYs and 1.95 QALYs for ENZA alone, resulting in incremental gains of 1.57 LYs and 1.30 QALYs. Total costs were $1,544,791 for TALA + ENZA and $378,932 for ENZA, yielding an ICER of $896,159 per QALY gained. Sensitivity analyses identified utility and drug cost inputs as the most influential parameters. Probabilistic analysis showed a 50% probability of cost-effectiveness at a willingness-to-pay (WTP) threshold of approximately $1.0 million/QALY gained. For HRRm-positive mCRPC, TALA + ENZA provided survival and QALY gains compared with ENZA alone but at higher cost, resulting in an ICER exceeding typical U.S. WTP thresholds.

The ENABLE study, an investigator-initiated, multicenter, randomized controlled trial, demonstrated comparable survival benefits between enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) for castration-resistant prostate cancer (CRPC). Because randomized controlled trials typically exclude patients with a history of other cancers (HOCs), we evaluated the efficacy of these agents in this population. This sub-analysis was conducted as a post hoc analysis using data from the ENABLE study. Endpoints included time to PSA progression, radiographic progression-free survival, overall survival (OS), prostate cancer-specific survival, and safety. Outcomes were compared between patients with and without a HOC+ versus HOC- and between treatment arms within each group. The HOC+ group included 35 patients (13 ENZ, 22 ABI), whereas the HOC- group included 149 patients (79 ENZ, 70 ABI). The most frequent malignancy was gastric cancer (n = 10, 29%). HOC+ patients had significantly worse OS than HOC- patients (median 24.7 vs. 37.4 months; HR 1.96; 95% CI 1.02-3.77; p = 0.0426), while other survival endpoints did not differ between the groups. Within the HOC+ group, OS was significantly worse with ENZ than with ABI (median 16.0 vs. 30.5 months; HR 3.27; 95% CI 1.08-9.89; p = 0.0354), whereas no significant differences were observed between the arms in the HOC- group. Although OS was poorer in HOC+ patients, other outcomes were similar, supporting the feasibility of ENZ and ABI regardless of cancer history. The longer OS with ABI in HOC+ patients represents a hypothesis-generating observation and should be interpreted with particular caution.

Structurally similar, functionally different: Impact of coformer positional isomerism on co-amorphous enzalutamide.

Resistance to second-generation antiandrogens like enzalutamide (ENZ) in castration-resistant prostate cancer (CRPC) is a major clinical challenge, yet the role in the tumor microenvironment remains poorly understood. This study identifies a unique AR-positive tumor-associated macrophages (AR+ TAMs) subpopulation, enriched in ENZ-resistant patients and correlated with poor prognosis, which acquires functional AR protein not through endogenous expression but via ANXA2-dependent phagocytosis of tumor cells. The internalized AR protein translocates to the macrophage nucleus, directly binds the IL-6 promoter to enhance its transcription and secretion. Macrophage-derived IL-6 subsequently activates the JAK2/STAT3 pathway in cancer cells, suppressing ENZ-induced apoptosis and conferring therapeutic resistance. Genetic or pharmacological blockade of IL-6 signaling restored ENZ sensitivity in vitro and in vivo, and combining an anti-IL-6 antibody with ENZ synergistically overcomes resistance in patient-derived xenograft and orthotopic models. These findings reveal a novel phagocytosis-mediated, paracrine mechanism of ENZ resistance orchestrated by AR+ TAMs, challenging the tumor-centric view of therapy failure and providing a strong rationale for co-targeting the IL-6 pathway to improve outcomes of AR-directed therapy in CRPC.

Objectives: Limited intracellular exposure can reduce the in vitro activity of pazopanib (PAZ) and enzalutamide (ENZ). This study developed bovine serum albumin (BSA) particles co-encapsulating PAZ and ENZ (PE-BSA) and evaluated physicochemical properties, release kinetics, 4T1 cellular uptake, and in vitro cytotoxicity versus free drugs and single-drug particles. Methods: Drug-loaded BSA particles were prepared using a crosslinking-based method. Particle size (PS), polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE) were determined. In vitro release was assessed over 48 h and fitted to kinetic models. 4T1 uptake was quantified after 2 and 4 h by intracellular drug levels. Cytotoxicity was measured by MTT at 24 and 72 h (1-100 µg/mL). Moreover, cell death analyses were conducted. Stability studies at +4 °C and serum were also carried out. Results: PE-BSA was nanoscale and monodisperse (PS 128.7 ± 2.6 nm; PDI 0.026 ± 0.01) with ZP -31.65 ± 1.13 mV and high EE (PAZ 98.59 ± 1.78%; ENZ 69.79 ± 0.02%). At 24/48 h, cumulative release from PE-BSA was 11.96/12.31% for PAZ and 52.26/85.95% for ENZ. The release kinetics were best described by the Korsmeyer-Peppas model for PAZ (r2 = 0.9578) and the Higuchi model for ENZ (r2 = 0.9605), indicating diffusion-controlled release. PE-BSA increased 4T1 uptake versus free drugs (2 h: 10.02% PAZ and 21.9% ENZ; 1.77-fold and 4.15-fold), with sustained enhancement at 4 h (2.2- and 4.69-fold, respectively). After 24 h, PE-BSA induced a markedly higher apoptotic response in 4T1 cells (32.5% early apoptosis and 0.8% late apoptosis/early necrosis) compared with free-PAZ (6.6% early apoptosis) and P-BSA (7.3% early apoptosis). Particles were stable. Conclusions: PE-BSA produced BSA particles with diffusion-governed release and enhanced 4T1 internalization, supporting albumin particles as a delivery platform to increase intracellular exposure of PAZ/ENZ in vitro.

Although enzalutamide (ENZA) has improved the overall survival of patients with metastatic prostate cancer, ENZA resistance (ENZA-resistant) inevitably develops, largely limiting its efficacy. Alternative oncogenic pathways may bypass androgen receptor (AR) signaling to promote ENZA-resistant. Glutamyl-tRNA synthetase 2 (EARS2) is involved in mitochondrial biogenesis and is associated with cancer, but its action mechanism in prostate cancer (PCa) is not well defined. EARS2 expression was detected in primary PCa and castrate-resistant prostate cancer samples, ENZA-resistant cell lines, and ENZA-resistant xenograft models, and the prognostic relationship of EARS2 in patients with PCa was analyzed. In AR-sensitive LNCaP cells, changes in EARS2 expression were explored before and after stimulation with dihydrotestosterone (DHT) or bicalutamide. AR was knocked down in AR-positive LNCaP and C4-2B cells to explore the relationship between EARS2 and AR. The effect of EARS2 on PCa cells was further explored. ENZA-resistant xenograft model was built to explore the effect of EARS2 on tumorigenesis in vivo. EARS2 was knocked down in C4-2B-ENZA-resistant, and the relationship between EARS2 and mitochondrial biogenesis and reactive oxygen species (ROS) homeostasis was investigated in PCa cells. Finally, the relationship between EARS2 and striatin 4 (STRN4) was explored. EARS2 expression was elevated in PCa and correlated with ENZA-resistant, and high EARS2 expression was associated with poorer patient prognosis. In androgen-sensitive LNCaP cells, DHT inhibited EARS2 expression, and silencing AR increased EARS2 expression. Suppressing EARS2 inhibited the proliferation, colony formation, migration and invasion ability, down-regulated the IC50 of ENZA in ENZA-resistant cells, and promoted apoptosis. Stable EARS2 downregulation in C4-2B-ENZA-resistant significantly inhibited tumor growth. Suppressing EARS2 in ENZA-resistant cells may lead to increased mitochondrial biogenesis and ROS generation. Mechanistically, EARS2 inhibited mitochondrial biogenesis and ROS generation in PCa cells by targeting STRN4. EARS2 targets STRN4 to modulate mitochondrial biogenesis and ROS homeostasis mediating ENZA-resistant.

Dihydrotestosterone binding to the androgen receptor inhibits apoptosis in ovine undifferentiated granulosa cells via AMH signaling.

Androgen receptor signaling inhibitors (ARSIs) are widely used for non-metastatic castration-resistant prostate cancer (nmCRPC). However, real-world data comparing clinical outcomes and treatment persistence among ARSIs in Asian populations remain limited. This study aimed to evaluate real-world effectiveness and tolerability of ARSIs in Japanese patients with nmCRPC. We retrospectively reviewed 100 Japanese patients with nmCRPC treated with enzalutamide (ENZ), apalutamide (APA), or darolutamide (DARO) at Kansai Medical University and its affiliated hospitals between May 2020 and December 2024. Progression-free survival (PFS), overall survival (OS), prostate-specific antigen (PSA) response, treatment sequencing, and adverse event-related dose modification or discontinuation were analyzed using Kaplan-Meier and log-rank tests. The median PFS for the entire cohort was 21.5 months. ENZ showed significantly longer PFS compared with APA (p=0.03), while DARO demonstrated comparable outcomes to both agents. OS did not differ significantly among groups. Patients receiving ARSI as first-line therapy had significantly longer PFS than those treated with second-line ARSIs. Initiation of ARSI therapy at PSA levels <2.0 ng/ml was associated with improved PFS. Second-line ARSI therapy showed limited PSA response and shorter PFS. Adverse event-related dose reduction or treatment discontinuation was associated with poorer PFS, with dermatologic toxicity being the main cause of APA discontinuation. In Japanese real-world practice, ARSI effectiveness in nmCRPC appears influenced by treatment persistence, timing of initiation, and treatment sequencing. Early initiation and careful management of adverse events may optimize outcomes, whereas sequential ARSI use shows limited benefit.

The introduction of next-generation androgen receptor signaling inhibitors (ARSIs) like enzalutamide (ENZ), has improved the clinical management of castration-resistant prostate cancer (CRPC). However, acquired resistance to these therapies often develops rapidly, and the underlying resistance mechanisms remain largely unclear. Here, we identified the aryl hydrocarbon receptor (AHR) as a crucial operator of ENZ-resistant CRPC. AHR is upregulated in three ENZ-resistant human CRPC cell lines (C4-2BENZR, CWR-R1ENZR, and VCaPENZR) as well as in high-grade prostate tumors from patients receiving ENZ treatment. Stable knockdown of AHR substantially reduced the growth of ENZ-resistant CRPC cells and xenografts. Mechanistically, AHR engages in distinct transcriptional programs in a cellular context-dependent manner. AHR directly regulates the transcription and expression of androgen receptor (AR)/glucocorticoid receptor (GR) co-target genes in CWR-R1ENZR cells, suggesting an AR-dependent mechanism of ENZ resistance. AHR promotes neuroendocrine differentiation while suppressing the expression of AR/GR targets in C4-2BENZR cells, indicating an AR-indifferent mechanism of ENZ resistance. The diverse mechanisms triggered by ENZ were also manifested in clinical samples. Collectively, these findings characterize AHR's contribution to ENZ resistance in CRPC and illuminate the potential of targeting AHR for treating ARSI-resistant advanced prostate cancer.

Enzalutamide resistance (EnzR) is a major challenge in the current treatment of castration-resistant prostate cancer, as tumors frequently progress to drug resistance after an initially effective treatment. Therefore, there is an urgent need to characterize the genes alterations that accompany EnzR in prostate cancer and to identify new therapeutic targets. In this study, we analyzed a total of 1273 publicly available transcriptomics datasets from patients who underwent prostate cancer surgery. We investigated transcriptomic changes after enzalutamide (ENZ) treatment, identified key genes involved in the process of EnzR, and developed EnzR scores to predict tumor progression. We further investigated the role of IGFBP3 in the regulation of EnzR in prostate cancer. The effect of IGFBP3 expression level on the malignant degree of EnzR cells was explored in vitro. In addition, we explored the downstream mechanism of IGFBP3 involvement in EnzR. We found that epithelial-mesenchymal transition (EMT), cancer stem cell-like properties, and neuroendocrine transformation occurred in tumor cells after ENZ treatment. Subsequently, we developed and validated EnzR scores to predict prostate cancer tumor progression. Furthermore, we experimentally confirmed that IGFBP3 promotes the proliferation of drug-resistant cells and enhances ENZ resistance via EMT signaling. Overall, we established a new EnzR scoring model through multidimensional analysis of EnzR patterns. This model can accurately predict the clinical prognosis of prostate cancer patients after surgery. Moreover, IGFBP3 can be used as a potential therapeutic target for ENZ resistance in prostate cancer.

Chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (ABI) have a higher cardiovascular (CV) event-related hospitalization risk than those treated with enzalutamide (ENZA). This study aimed to assess CV event risk in chemotherapy-naïve patients with mCRPC treated with ENZA or ABI and to provide outcome data based on CV disease (CVD) history using the US Medicare database. Chemotherapy-naïve patients with mCRPC (≥ 65 years) who initiated ENZA or ABI (September 2014 − May 2017) were included. The primary endpoint was a 4-point major adverse CV event (MACE; a composite of acute myocardial infarction, stroke, unstable angina/revascularization, and heart failure). Atrial fibrillation, venous thromboembolism, and all-cause death were also analyzed. Further, the risk of adverse CV outcomes was compared between ENZA- and ABI-treated cohorts (overall population and by CVD-risk subgroup). Sensitivity analysis was performed using a 5-point MACE (4-point MACE plus CV-related death) as the endpoint. Of 6319 patients (ENZA: 2934; ABI: 3385), 2913 propensity score-matched patients were included from each group (prior CVD: 76%). ABI was associated with a significantly higher risk of 4-point MACE (hazard ratio [HR]: 1.12; 95% confidence interval [CI]: 1.02–1.24; P = 0.028), unstable angina/revascularization (HR: 1.13; 95% CI: 1.01–1.26; P = 0.041), atrial fibrillation (HR: 1.73; 95% CI: 1.31–2.29; P < 0.001), venous thromboembolism (HR: 1.37; 95% CI: 1.02–1.85; P = 0.037), and all-cause death (HR: 1.13; 95% CI: 1.07–1.19; P < 0.001) versus ENZA. In the sensitivity analyses, these results were confined to the subgroup of patients with a history of CVD. ABI-treated patients with mCRPC had a higher risk of developing composite 4-point MACE and other CV events than ENZA-treated patients.

While lineage plasticity is a well-established driver of therapy resistance in prostate cancer, the role of tumor-infiltrating immune cells in mediating phenotype switching remains poorly understood. Here, we employed single-cell multi-omics to systematically characterize immune infiltration dynamics, transcriptional reprogramming, and intercellular communication networks during prostate cancer progression. Our analysis revealed that granulin (GRN)-expressing macrophages orchestrate the transition from adenocarcinoma (Adeno) to a therapy-resistant multilineage state exhibiting vimentin (VIM)+ mesenchymal and stem-like features through GRN/ tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) interaction and the subsequent activation of the nuclear factor kappa-B (NF-κB) pathway. Intriguingly, these plastic tumor subclones reciprocally enhanced GRN expression in macrophages via colony stimulating factor 1 (CSF1) and CSF1 receptor (CSF1R) receptor-ligand axis, establishing a feedforward signaling loop that sustains lineage plasticity. Functional validation demonstrated GRN's critical role in driving epithelial-mesenchymal transition in vitro and conferring resistance to enzalutamide (ENZ) in patient-derived organoids. Therapeutic intervention studies in transgenic Adeno of the mouse prostate (TRAMP) models showed that CSF1R inhibition disrupted this vicious cycle, reducing GRN + macrophages and suppressing multilineage subclone emergence. Spatial mapping revealed direct physical interactions between VIM + tumor cells and GRN + macrophages, while single-cell proteomics in castration-resistant patients confirmed the clinical relevance of this axis. Furthermore, we identified three novel stromal populations [decorin (DCN)+ endothelial cells, C-C motif chemokine ligand 7 (CCL7)+ fibroblasts, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1)+ neutrophils associated with disease relapse. These findings illuminate the tumor-immune crosstalk underlying treatment resistance and unveil promising therapeutic targets for overcoming lineage plasticity-driven resistance in advanced prostate cancer.

This population-based study aimed to quantify fracture risk after ARPIs in PCa patients by pre-existing health conditions. Patients were identified from the SEER-Medicare files who received abiraterone with prednisone (AAP) or enzalutamide (ENZA) between 1/1/2013 and 12/31/2020. Health and fracture history were based on claims one year before ARPI with follow-up through 12/31/2020. The main outcome of the study was the cumulative fracture risk after first date of ARPI. Fine and Gray's sub-distribution hazard model was used to obtain adjusted relative risks with confounding factors. This study included 10,463 patients (6,037- AAP; 4,426-ENZA). The 3-year fracture risk after ARPI was high, exceeding 25% among those without a prior fracture. Among 1,445 men with a fracture the year before ARPI, 3-year fracture risk exceeded 50%, and remained high (above 44%) despite using bone health agents (BHA). A recent history of fracture was associated with a 2.84-fold fracture risk (aHR: 2.84, 95% CI 2.58-3.12). Pre-existing osteoporosis and a comorbidity score ≥ 2 were associated with 15% (aHR : 1.15, 95% CI 1.03-1.29) and 11% (aHR : 1.11, 95% CI 1.00 to 1.24) higher fracture risks. Bone health agent (BHA) use was associated with a 23% lower fracture risk (aHR: 0.77, 95% CI 0.70-0.83). Fracture risk after ARPI was high, exceeding 44% within 3 years in those with prior fractures despite BHA, suggesting limited benefit in patients with poor bone quality. Early identification and intervention for patients at high risk of fractures is critical.

Real-World Effectiveness and Treatment Persistence of Darolutamide, Apalutamide, and Enzalutamide in Non-Metastatic Castration-Resistant Prostate Cancer: A Multicenter Study.