Yao Zhu

Objectives: To assess whether treatment‐period serum testosterone breakthrough >35 ng/dL is associated with clinical outcomes during intensified therapy for metastatic hormone‐sensitive prostate cancer. Patients and Methods: We performed post hoc analyses of the experimental arms of the ARASENS (darolutamide plus androgen deprivation therapy [ADT] and docetaxel; ClinicalTrials.gov identifier NCT02799602) and LATITUDE (abiraterone acetate plus prednisone and ADT; NCT01715285) phase III trials. Cohort‐specific fixed‐window landmark analyses classified exposure as any eligible testosterone result >35 ng/dL after treatment initiation and through Day 147 in the LATITUDE trial or Day 266 in the ARASENS trial. Treatment‐initiation/Day‐1 and end‐of‐treatment measurements were excluded. Follow‐up began at the landmark. The primary outcome was overall survival (OS); the LATITUDE progression‐free survival (PFS) and the ARASENS time to castration‐resistant prostate cancer (CRPC) were progression endpoints. Multivariable Cox regression was primary; landmark and time‐dependent sensitivity analyses were also performed. Results: At the landmark, 564 LATITUDE and 578 ARASENS patients were classifiable for OS. In the LATITUDE trial, breakthrough was associated with worse OS (adjusted hazard ratio [HR], 1.49, 95% confidence interval [CI] 1.07–2.08; P = 0.019); the PFS estimate was directionally similar but imprecise (HR 1.40, 95% CI 0.98–2.00; P = 0.065). In the ARASENS trial, the overall associations were not statistically significant for OS (HR 1.18, 95% CI 0.85–1.62; P = 0.322) or CRPC (HR 0.86, 95% CI, 0.60–1.23; P = 0.397). Exploratory piecewise modelling suggested time variation for CRPC (interaction P = 0.028). Conclusion: Testosterone breakthrough >35 ng/dL was associated with worse post‐landmark OS in the LATITUDE trial, whereas the overall associations with OS and CRPC in the ARASENS trial were not statistically significant. These within‐cohort findings are exploratory and do not establish causality, a difference between treatment mechanisms, or a clinical testosterone target.

This study reports the first clinical comparison of the novel modular Carina robotic platform with the established da Vinci system for robot-assisted radical prostatectomy (RARP), including 6-month outcomes. This single-center study included a prospective cohort of 32 patients undergoing Carina RARP and a retrospective cohort of 105 patients treated with da Vinci RARP. Pre-, intra-, and postoperative data were analyzed. Groups were matched 1:2 using propensity scores based on preoperative characteristics. All patients underwent 6-month follow-up assessing feasibility, safety, oncological outcomes, and urinary continence. Following matching, 32 Carina patients were compared with 64 da Vinci patients. Baseline characteristics were largely well balanced after matching. Total operative time was modestly longer in the Carina group than in the da Vinci group (median 138 vs. 130 min), whereas console time (91 vs. 85 min) and docking time (5 min for both) were comparable between systems. Operative time decreased as platform-specific experience accumulated in later Carina cases. At 6 weeks, the satisfactory biochemical response rate (PSA < 0.1 ng/mL) was identical between groups (90.6%). Urinary continence rates at 1 week, 3 months, and 6 months were 34.4%, 81.3%, and 90.6% for Carina versus 31.3%, 76.6%, and 87.5% for da Vinci, with no significant differences. The Carina system appears safe and feasible for RARP, with early oncological and continence outcomes similar to those observed with the da Vinci system in this pilot matched cohort.

Tumor immunity is shaped not only by the cellular composition of the tumor microenvironment (TME), but also by how stromal and immune elements are spatially organized within it. Among these regulators, cancer-associated fibroblasts (CAFs) and tertiary lymphoid structures (TLS) have emerged as two major determinants of the spatial niche of anti-tumor immunity. CAFs comprise heterogeneous and plastic stromal populations that can remodel the extracellular matrix, restrict lymphocyte infiltration, sustain chronic inflammation, and promote therapeutic resistance, while selected subsets may also support antigen presentation and lymphoid organization. In contrast, TLS function as ectopic immune hubs that coordinate local T- and B-cell priming, clonal expansion, and B-cell maturation, and are increasingly associated with favorable prognosis and improved responses to immune checkpoint blockade. In this review, we synthesize recent advances from single-cell and spatial multi-omics studies to examine how CAF states and TLS maturation programs arise, interact, and remodel the immune landscape across tumor types. We propose that the balance between CAF-driven stromal restriction and TLS-associated immune organization is a central determinant of immune exclusion versus immune activation. We discuss how this spatial framework may refine tumor classification, improve patient stratification, and guide therapeutic strategies aimed at stromal reprogramming, TLS induction or maturation, and rational combination immunotherapy, while highlighting innate immune-stromal circuits, including IL-33-activated ILC2s, NCR⁺ ILC3s, LTi-like programs, and myeloid organizer cells, as upstream regulators of TLS neogenesis. By integrating CAF biology, TLS dynamics, and spatial context, this review provides a conceptual framework for understanding and targeting the stromal architecture of tumor immunity.

Background Metastatic hormone-sensitive prostate cancer (mHSPC) with limited metastatic burden presents a therapeutic challenge, with residual PSMA-avid disease post-androgen receptor pathway inhibitor (ARPI) treatment poorly characterized in prospective studies. Patients and methods The CHAMPION trial (NCT05717582) was a multicenter, single-arm, phase II study designed to evaluate the efficacy and safety of a response-adapted treatment strategy incorporating consolidative therapy (TCT) for PSMA-avid residual resistant clones following ARPI in newly diagnosed mHSPC patients with ≤ 10 conventional imaging (CI)-defined distant metastases from March 2023 to August 2024. PSMA PET/CT scans were performed at baseline and after three cycles of apalutamide plus castration. Patients with > 10 PSMA-positive distant metastases continued apalutamide therapy, while those with ≤ 10 metastases underwent radical prostatectomy or radiotherapy, with stereotactic body radiotherapy targeting all remaining PSMA-positive lesions, if present. The primary endpoint was the proportion of patients achieving an undetectable PSA level (≤ 0.2 ng/mL) after 6 cycles of apalutamide. Results A total of 48 patients with a median baseline PSA level of 56.8 ng/mL were enrolled. Baseline CI revealed 1–3 distant metastases in 31 patients (64.6%) and 4–10 in 17 patients (35.4%). Baseline PSMA PET/CT showed 1–3 distant metastases in 17 patients (35.4%), 4–5 in 8 patients (16.7%), and > 5 in 23 patients (47.9%); the most common PSMA-positive sites were bone (47/48, 97.9%), regional lymph nodes (28/48, 58.3%), and distant lymph nodes (15/48, 31.3%). After 3-cycle of apalutamide, two patients with > 10 PSMA-positive metastases continued apalutamide, while the remaining 46 with ≤ 10 metastases received TCT. After six cycles, the overall undetectable PSA rate was 95.8% (46/48; 95% CI: 86.0%-98.8%), a 29.1% increase from the 66.7% (32/48) observed after three cycles. Only two patients (4.2%) experienced grade ≥ 3 rash. Post-treatment, distant lymph node metastases showed the highest response rate at 93.3% (140/150), followed by vertebral column and pelvis bone metastases at 78.5% (255/325), and other bone metastases at 50.0% (58/116), with significant differences between each metastatic site pair (p < 0.0001). Conclusions This novel treatment paradigm, integrating PSMA PET/CT-guided TCT for residual lesions with intensified systemic therapy, was associated with a high PSA response rate and manageable adverse event profile in newly diagnosed mHSPC patients with ≤ 10 distant metastases. Trial registration: NCT05717582. Registered: 8 February 2023.

Metastatic castration-resistant prostate cancer (mCRPC) remains lethal with limited treatment options. Antibody–drug conjugates (ADCs) have emerged as a transformative class across multiple solid tumors, yet their clinical application in prostate cancer has been limited. Izalontamab brengitecan (Iza-bren; BL-B01D1) is a bispecific ADC-targeting EGFR and HER3 that has demonstrated activity in other malignancies. Here, we evaluated its therapeutic potential in the treatment of prostate cancer. Multi-omics analyses revealed frequent EGFR and HER3 expression in CRPC adenocarcinoma but not in neuroendocrine subtypes. BL-B01D1 exerted potent, target-dependent cytotoxicity in prostate cancer cell lines, xenografts, and patient-derived organoids (PDOs). We highlight a representative patient with mCRPC with high EGFR/HER3 expression whose disease rapidly and durably mounted a clinical and radiologic response to BL-B01D1, concordant with matched PDO sensitivity. Mechanistic studies identified ABCG2 upregulation as a driver of acquired resistance, with genetic or pharmacologic inhibition restoring BL-B01D1 sensitivity. Importantly, tumor tissue obtained at progression after BL-B01D1 treatment confirmed ABCG2 upregulation, validating a clinically relevant resistance mechanism. These findings support BL-B01D1 as a promising therapeutic strategy in mCRPC and indicate ABCG2 may be a rational target for overcoming resistance.

Summary: Global clinical oncology research is experiencing a profound structural shift, evolving from a historical underrepresentation of minority groups in Western-centric trials to a new representational imbalance marked by an increasing reliance on Chinese patient populations due to the nation’s accelerating drug research and development. This article dissects this changing dynamic and proposes a systematic framework for a next-generation global oncology research and development paradigm that is inherently more inclusive, generalizable, and efficient for all patients worldwide.