Castration-Resistant Prostate Cancer

P3, N=370, Recruiting, Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting --> Recruiting

Notably, the combination of NXPH4 knockdown and enzalutamide treatment showed potent synergistic effects, significantly suppressing cell proliferation in vitro and substantially inhibiting tumor growth in vivo. These findings reveal a previously unrecognized mechanism of EnzR and identify the NXPH4-ALDH1L2 complex as a promising therapeutic target for CRPC treatment.

Results showed a mild, though non-significant, trend toward increased [18 F]F-PSMA-1007 in most groups compared to the control, except for those exposed to short pulses associated with high-pressure. These findings highlight the potential of USMB to enhance drug delivery for PSMA uptake but also underscore the necessity for careful consideration of ultrasound parameters to prevent tissue damage.

P2, N=7, Completed, Mayo Clinic | Active, not recruiting --> Completed | Trial completion date: Oct 2027 --> Apr 2025 | Trial primary completion date: Oct 2027 --> Apr 2025

P1, N=140, Recruiting, Bristol-Myers Squibb | Active, not recruiting --> Recruiting

P2, N=305, Active, not recruiting, Institute of Cancer Research, United Kingdom | Trial completion date: Sep 2025 --> Dec 2028 | Trial primary completion date: Sep 2025 --> Dec 2026

P1/2, N=37, Active, not recruiting, Weill Medical College of Cornell University | Recruiting --> Active, not recruiting | N=76 --> 37

This study developed and validated an LC-MS/MS method for simultaneous quantification of Talazoparib and Enzalutamide in rat plasma using Apalutamide as the internal standard. In pharmacokinetic studies on male Wistar rats, Talazoparib showed a Cmax of 0.88 ng/mL at 3 h and an AUC0-t of 20 ng·h/mL, while Enzalutamide exhibited a Cmax of 76.18 ng/mL at 1 h and an AUC0-t of 1702 ng·h/mL; both had 24 h half-lives. The validated method enables sensitive, rapid, and reliable bioanalysis for preclinical pharmacokinetic evaluation.

Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258-focused on FOSL1/AP-1 and PIM kinases, respectively-effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.

Based on the clinical candidate Opevesostat, two series of 23 new compounds were designed and synthesized using a 4H-pyran-4-one core to explore structure-activity relationships at the C2 and C6 positions.Compound II-4 exhibited potent inhibitory activity (95.2% at 100 nM; IC₅₀ = 26.7 nM), comparable to Opevesostat (IC₅₀ = 20.4 nM). Importantly, II-4 showed superior selectivity against CYP1A2, 2C9, and 2D6 (2- to 4-fold improvement), attributed to hydrophobic interactions between its C6 methyl group and Ile 84.These results highlight II-4 as a promising lead compound with optimized activity and selectivity, providing valuable insights for overcoming resistance in prostate cancer therapy.

Beyond the intracellular context, we discuss how proteostatic imbalances drive the senescence-associated secretory phenotype (SASP) to remodel the tumor microenvironment. Finally, we assess emerging therapeutic strategies, arguing that precision modulation of specific proteostasis nodes-such as distinct E3/DUBs or CMA pathways-represents a promising frontier to overcome castration-resistant prostate cancer (CRPC).

Immunohistochemical PSA and Ki-67 expression provide practical prognostic information for patients with metastatic castration-sensitive prostate cancer. Combined assessment with EOD ≥ 3 identifies a high-risk subgroup with unfavorable clinical outcomes.