Xtandi (enzalutamide)

P2, N=100, Not yet recruiting, Hoffmann-La Roche

PARPi + NHA represent a significant advance in mCRPC therapy. Molecular genetic testing for HRR mutations, especially BRCA 1/2, is crucial for treatment planning.

Androgen deprivation therapy (ADT) and next-generation AR blockade (e.g., enzalutamide) are initially effective, but virtually all patients develop castration-resistant prostate cancer (CRPC), which frequently transitions to treatment-emergent neuroendocrine PCa (tNEPC) following AR suppression...Thus, we uncover a single stress-induced node (PSMA2) that both maintains AR-dependent survival under ADT and fuels the neuroendocrine transition. PSMA2 marks an AR-hypersensitized transitional state and is itself a therapeutically actionable driver of tNEPC evolution, revealing an opportunity for rational interception of the lethal ADT-CRPC-tNEPC trajectory.

Both CRISPR-mediated knockout and pharmacologic inhibition of Notch signaling depleted these progenitor cells and restored enzalutamide sensitivity. These findings demonstrate that the level, rather than the binary presence, of Notch signaling dictates lineage directionality and therapeutic response in CRPC, establishing it as a tunable and actionable driver of resistance.

P1/2, N=72, Not yet recruiting, GlaxoSmithKline

We detail the evidence supporting the integration of systemic agents like abiraterone, enzalutamide, and darolutamide into both hormone-sensitive and castration-resistant settings. Furthermore, we highlight the expanding role of radioligand therapies, including radium-223 and Lutetium-177-labeled PSMA-617 (Lu-PSMA-617), as well as the growing impact of PARP inhibitors in genomically selected patients. The emergence of theranostic strategies and next-generation sequencing has paved the way for personalized treatment algorithms, moving toward a truly precision oncology model in PCa. This comprehensive review synthesizes current therapeutic strategies, clinical trial evidence, and future directions aimed at optimizing outcomes and quality of life for patients with advanced prostate cancer.

CAS significantly enhanced ABI's cytotoxic efficacy in 22Rv1 cells, as evidenced by synergistic interactions (CI: 0.31-0.71); however, no such synergy was observed in LNCaP cells or with enzalutamide. Docking and molecular dynamics simulations indicated a stable CAS-AKR1C3 interaction, characterized by crucial hydrogen bonding and aromatic stacking within the active site. These results suggest that CAS is a promising chemosensitizer targeting AKR1C3 to overcome ABI resistance in CRPC.

P1/2, N=39, Recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Oct 2029 --> Jan 2030 | Trial primary completion date: Oct 2027 --> Jan 2028

To functionally validate this finding, we employed lipid nanoparticle (LNP)-mediated co-delivery of si-circPPFIA2 and enzalutamide, which effectively restored drug sensitivity and inhibited tumor growth in resistant PCa models. Our findings highlight circPPFIA2 as both a prognostic biomarker and a promising therapeutic target for advanced PCa, providing a rationale for developing circRNA-directed therapies to overcome treatment resistance.

P=N/A, N=1300, Completed, Pfizer | Recruiting --> Completed

P1/2, N=174, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

Similarly, targeting SphK1 with the inhibitor SKI-II suppressed SphK1 activity, reduced S1P production, enhanced enzalutamide sensitivity, and significantly inhibited resistant tumor growth while enhancing enzalutamide sensitivity. Collectively, these findings highlight IGFBP3-mediated SphK1 signaling as a critical mediator of enzalutamide resistance and suggest that targeting the IGFBP3/SphK1/S1P axis represents a promising therapeutic strategy to overcome resistance in advanced prostate cancer.