P2, N=254, Not yet recruiting, West China Hospital

P2, N=40, Recruiting, Icahn School of Medicine at Mount Sinai | Trial primary completion date: Dec 2026 --> Dec 2027

Pharmacogenomic analysis identified nine compounds (Shikonin, Bicalutamide, Bryostatin-1, Epothilone-B, JNK-9L, LFM-A13, QS11, VX-680, and Z-LLNle-CHO) exhibiting differential sensitivity between the dichotomous risk strata. This study yields findings that hold significant clinical implications for refining prognostic stratification and deciphering the immune landscape in ESCC. Moreover, they offer novel perspectives that may pave the way for more precise prognostic assessment and the formulation of targeted therapeutic interventions.

The patient had undergone laparoscopic radical prostatectomy 5 years prior and received intermittent postoperative endocrine therapy with leuprorelin acetate and bicalutamide...Following a change in the endocrine therapy regimen to rezvilutamide combined with degarelix, the patient's hematuria significantly improved. This case highlights the critical importance of rigorous postoperative surveillance and timely, standardized endocrine therapy in prostate cancer management. It also contributes to the limited literature on visceral metastases in castration-sensitive prostate cancer (HSPC) and underscores the need for further exploration of optimal treatment strategies for advanced metastatic disease.

Although enzalutamide (ENZA) has improved the overall survival of patients with metastatic prostate cancer, ENZA resistance (ENZA-resistant) inevitably develops, largely limiting its efficacy...In AR-sensitive LNCaP cells, changes in EARS2 expression were explored before and after stimulation with dihydrotestosterone (DHT) or bicalutamide...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.

The compound with a N-2,2,2-trifluoroethyl substitution (KCI838) was the fastest acting and most potent inhibitor of AR-dependent cell growth and colony formation in PCa model cells, including exclusively AR splice variant-dependent and other enzalutamide-resistant cells, without affecting growth of AR-negative cell lines...Additionally, ALZET osmotic pumps were used to establish proof-of-concept for reversible in vivo anti-tumor activity of KCI838PME administered in a low dose, controlled release mode. The results warrant investigation of KCI838PME in a controlled-release formulation, to treat PCa that is resistant to current AR-targeted therapies while obviating the need for testosterone suppression.

In this pilot cohort, concomitant ARSi therapy did not significantly enhance tumor absorbed doses in patients receiving [177Lu]Lu-PSMA-617 or [177Lu]Lu-PSMA-I&T RLT. Further prospective studies with larger patient numbers are needed to evaluate the impact of concomitant ARSi treatment on the absorbed doses in mCRPC tumor lesions.

P2, N=21, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2027 --> Nov 2026 | Trial primary completion date: Apr 2027 --> Nov 2026

Mechanistically, our data indicate that ELF1 transcriptionally regulates EGFR and that ERK1/2 interacts with ELF1, suggesting the existence of a positive ELF1/EGFR/ERK feedback loop that sustains resistance. This study elucidates a possible mechanism of resistance to AR inhibition driven by an ELF1/EGFR/ERK feedback loop in AR-Vs positive cells and provides a rationale for combining EGFR inhibitors with AR-targeted therapy as a potential treatment strategy for patients with advanced, enzalutamide-resistant prostate cancer.

Additionally, it mitigated the hepatotoxic effects of flutamide. Therefore, this combination may represent a new treatment strategy for PCa.

P1, N=36, Completed, Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting --> Completed | N=18 --> 36

Leveraging these insights, we perform structure-based virtual screening based on the identified druggable conformations and identify K53, a rationally designed AR-NTD antagonist, which exhibits potent anti-proliferative activity in enzalutamide-resistant prostate cancer cells. K53 directly binds the AR-NTD, suppresses AR transcriptional activity, and demonstrates high selectivity for cancer cells. This work provides a rational design paradigm for targeting intrinsically disordered proteins and offers a therapeutic candidate for resistant prostate cancer.