Xtandi (enzalutamide)

C4-2B and 22Rv1 CRPC cell lines were treated with increasing QRC concentrations, with or without enzalutamide (Enz)...Enz cotreatment with QRC did not produce additive effects, consistent with a model in which QRC acts upstream of ligand-driven AR activation and thereby limits the incremental benefit of AR antagonism under these conditions. These data support QRC as an AKT-AR axis modulator in CRPC and provide a target engagement framework beyond simple ROS scavenging.

In summary, this study defines a core epigenetic pathway, showing that increased SMARCA4 activity promotes luminal-to-neuroendocrine transformation by enhancing histone acetylation and chromatin accessibility at the PROX1 locus. Targeting the SMARCA4-PROX1 axis provides a valuable therapeutic strategy for combating enzalutamide resistance and NEPC progression.

Olaparib plus durvalumab demonstrated modest activity in HRR-unselected mCRPC, with clinical benefit enriched in BRCA2-variant disease. Integrated ctDNA and peripheral immune analyses support ongoing efforts to refine molecular and immune selection strategies and to better define mechanisms of benefit and resistance for combination approaches in mCRPC.

P1/2, N=360, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Feb 2030 --> Apr 2031 | Trial primary completion date: Feb 2030 --> Apr 2031

P3, N=1314, Active, not recruiting, Merck Sharp & Dohme LLC | Suspended --> Active, not recruiting

P3, N=675, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting

The AR antagonist enzalutamide sensitises AR expressing melanoma cells to RSL3 and erastin independent of phenotype state, but in FAOhigh BRAFi relapsed tumours AR up-regulation correlates with the undifferentiated/neural-crest like (UD/NC) state, and enzalutamide synergises with ranolazine in ferroptosis-induction in UD/NC cells. Thus, therapeutically combining ranolazine with the AR inhibitor enzalutamide to induce ferroptosis can circumvent dedifferentiation related BRAFi resistance and could increase therapeutic activity and long-term efficacy.

When appended to the BET bromodomain inhibitor JQ1, this optimized handle yielded a potent and selective BRD4 degrader whose activity was dependent on RNF126. Importantly, transplantation of this handle onto a previously non-inhibitory ligand targeting the androgen receptor (AR) and its truncation variant, AR-V7, enabled selective degradation of both AR and AR-V7 in androgen-independent prostate cancer cells, thereby robustly inhibiting AR transcriptional activity beyond the established AR antagonist enzalutamide. Collectively, these findings demonstrate an optimized RNF126-based covalent handle for the rational development of molecular glue degraders against transcriptional regulators, including undruggable variants such as AR-V7.

This model can accurately predict the clinical prognosis of prostate cancer patients after surgery. Moreover, IGFBP3 can be used as a potential therapeutic target for ENZ resistance in prostate cancer.

Functional validation demonstrated GRN's critical role in driving epithelial-mesenchymal transition in vitro and conferring resistance to enzalutamide (ENZ) in patient-derived organoids...Furthermore, we identified three novel stromal populations [decorin (DCN)+ endothelial cells, C-C motif chemokine ligand 7 (CCL7)+ fibroblasts, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1)+ neutrophils associated with disease relapse. These findings illuminate the tumor-immune crosstalk underlying treatment resistance and unveil promising therapeutic targets for overcoming lineage plasticity-driven resistance in advanced prostate cancer.

P1, N=453, Recruiting, Pfizer | Trial completion date: Mar 2029 --> Jul 2029