enzalutamide

P2, N=192, Recruiting, Sun Pharmaceutical Industries Limited | Not yet recruiting --> Recruiting | Trial completion date: Jun 2026 --> Dec 2027 | Trial primary completion date: Jun 2025 --> Dec 2027

P2, N=108, Not yet recruiting, Georgetown University

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.

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.

We retrospectively analyzed 148 patients with mHSPC treated with either ARPI (abiraterone, enzalutamide, or apalutamide) plus androgen deprivation therapy (ADT) (n = 98) or docetaxel plus ADT (n = 50). In this real-world cohort, ARPI-based therapy was associated with an improvement in rPFS compared with docetaxel, while OS outcomes remained comparable. In the absence of direct randomized comparisons, these findings may provide supportive real-world evidence for the clinical relevance of ARPI-based therapy as a first-line treatment option for patients with mHSPC.

P2, N=50, Recruiting, Sean Sachdev | Trial primary completion date: Nov 2028 --> Nov 2030

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.

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.

P2, N=132, Recruiting, University Health Network, Toronto | Trial completion date: Mar 2026 --> Feb 2031 | Trial primary completion date: Mar 2026 --> Feb 2031

P2, N=53, Recruiting, Syntrix Biosystems, Inc. | Trial primary completion date: Jun 2026 --> Jun 2027