Xtandi (enzalutamide)

P2, N=25, Recruiting, H. Lee Moffitt Cancer Center and Research Institute

This study identified a list of AR/SRF common interactors that represent a pipeline of druggable targets for the treatment of PCa.

Androgen receptor (AR) signaling is the principal driver of prostate cancer, and drugs that target this pathway (e.g., abiraterone and enzalutamide) are standard treatments for metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer (mCRPC). These promising preclinical data supported clinical development of bavdegalutamide as a potential treatment for patients with prostate cancer. Bavdegalutamide was the first PROTAC protein degrader to enter human clinical trials, specifically in patients with mCRPC in a phase 1/2 study (NCT03888612).

P1, N=174, Recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Apr 2025 --> May 2029 | Trial primary completion date: Dec 2024 --> Aug 2025

P=N/A, N=24, Completed, UNC Lineberger Comprehensive Cancer Center | Recruiting --> Completed

P3, N=49, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | N=100 --> 49

We develop a custom targeted cfDNA sequencing assay, named AR-ctDETECT, to detect ctDNA in limiting plasma cfDNA available from mCRPC patients in the Alliance A031201 randomized phase 3 trial of enzalutamide with or without abiraterone. ctDNA-positive patients have significantly worse median overall survival than ctDNA-negative patients (29.0 months vs. 47.4 months, respectively). Here, we show that mCRPC patients identified as ctDNA-positive using the AR-ctDETECT assay have poor survival despite treatment with potent AR inhibitors in a phase 3 trial.

P1/2, N=102, Terminated, Epizyme, Inc. | Active, not recruiting --> Terminated; Sponsor decision, no safety concern

Results suggest that TALA + ENZA may provide improvements in clinical outcomes relative to OLAP + AAP and NIRA + AAP in 1 L mCRPC; however, inherent limitations associated with the complexity of the analyses must be considered.

P2/3, N=102, Active, not recruiting, Sir Mortimer B. Davis - Jewish General Hospital | Recruiting --> Active, not recruiting | Trial primary completion date: Apr 2025 --> Apr 2027

P=N/A, N=2903, Active, not recruiting, Pfizer | Completed --> Active, not recruiting | N=1800 --> 2903 | Trial completion date: Feb 2024 --> Jan 2025 | Trial primary completion date: Feb 2024 --> Jan 2025

hsa-miR-221-3p and miR-222-3p were upregulated in all concentrations both intracellularly and in EVs. The developed 3D-spheroid model effectively replicated the ENZ resistance to ENZ in an AR-independent manner, underscoring the importance of EVs-derived miRNAs in this adaptive process.

Notably, in this model, we found that vaccination in combination with enzalutamide, an AR antagonist, suppressed these aggressive immune suppressive cancers and resulted in enhanced survival in comparison to control vaccinated and enzalutamide-treated mice. While anti-PD-1 immune checkpoint inhibition (ICI) alone slowed tumor growth, the majority of vaccinated mice that received anti-PD-1 therapy showed complete tumor elimination. Collectively, these results validate the importance of AR signaling in prostate cancer immune suppression and suggest the potential of AR-V7-specific vaccines as therapeutic strategies against prostate cancer, offering significant protective and therapeutic anti-tumor responses, even in the presence of androgen signaling inhibitors.

An enhancement in inhibition of tumor growth and suppression of c-MYC expression was further confirmed when enzalutamide combined with KRLS-017 in an MDA-MB-453 mouse model. Our study suggests that KRLS-017 enhances the antitumor efficacy of enzalutamide by inhibiting c-MYC-mediated tumorigenesis and presents a potential new approach for treating AR+ LAR TNBC.

P=N/A, N=1000, Completed, Pfizer | Active, not recruiting --> Completed | Trial completion date: Oct 2024 --> Apr 2024 | Trial primary completion date: Oct 2024 --> Apr 2024

The VCaP and VCaP-enzalutamide-resistant PCa cell lines express secretory (sPAP) and TMPAP...Finally, treatment of VCaP tumor-bearing mice with inhibitors of adenosine receptors reduces tumor growth. This data demonstrates that TMPAP is a novel therapeutic target in advanced prostate cancer.

P2, N=53, Recruiting, Syntrix Biosystems, Inc. | Initiation date: Jun 2024 --> Nov 2024

P1/2, N=307, Enrolling by invitation, Evopoint Biosciences Inc.

P3, N=575, Active, not recruiting, Exelixis | Trial completion date: Aug 2024 --> Oct 2026

P2, N=132, Recruiting, University Health Network, Toronto | Active, not recruiting --> Recruiting | N=66 --> 132

P=N/A, N=42, Completed, Medical College of Wisconsin | Active, not recruiting --> Completed

P1, N=128, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Dec 2024 --> Aug 2024

Loss of PKCλ/ι promotes a switch during enzalutamide treatment to a non-canonical EZH2 cistrome that triggers the transcriptional activation of the translational machinery to induce a transforming growth factor β (TGFβ) resistance program. The increased reliance on protein synthesis creates a synthetic vulnerability in PKCλ/ι-deficient CRPC.

Acquired resistance to hormonal therapy, particularly enzalutamide (ENZ), remains a significant obstacle in the treatment of advanced bone metastatic prostate cancer...Taken together, a potential mechanism is identified through which osteoblast-derived ECM1 drives resistance in bone metastatic prostate cancer under ENZ treatment. Additionally, the findings indicate that ECM1 and ENO1 may serve as potential targets for developing therapies for bone metastatic castration-resistant prostate cancer.

Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression...AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors.

Inhibition of NRG1 in CAFs attenuated their impact on enzalutamide resistance, providing insight into the role of NRG1 in mediating the crosstalk between CAFs and prostate cancer in the context of enzalutamide resistance. This study elucidates the pivotal role of CAF-secreted NRG1 in promoting enzalutamide resistance in prostate cancer, providing valuable insights for developing targeted therapeutic strategies to overcome resistance in advanced prostate cancer.

Our study unravels AR-V7 as a marker for poor clinical outcomes, predicting breast cancer aggressiveness, and encourages consideration of AR-V7 as a probable target for therapeutic intervention.

P3, N=675, Not yet recruiting, Amgen

Molecularly, in MDA-MB-231, both inhibitors modulated metastasis and epithelial to mesenchymal transition (EMT) markers ROCK1, ROCK2, c-Myc, E-cadherin and N-cadherin, with EPI-001 downregulating NF-ĸB level as well. We concluded that ARv7 indicated poor prognosis in the studied cohorts and that blocking of AR/ARv7 abated metastasis and key regulators of EMT in MDA-MB-231, at least in part by targeting ROCK/NF-ĸB/c-Myc axis.

D+T is active in mCRPC but patient selection remains a challenge. Further studies to develop predictive biomarkers are warranted.

P=N/A, N=13779, Active, not recruiting, Bayer | Trial completion date: Dec 2024 --> Jul 2025 | Trial primary completion date: Dec 2024 --> Jul 2025

Moreover, ATC-324 remains potent in enzalutamide-resistant PCa cells. These results demonstrate the potential of the AUTOTAC platform to target previously considered undruggable proteins and overcome certain drug resistance mechanisms.

P1, N=8, Active, not recruiting, Roswell Park Cancer Institute | Recruiting --> Active, not recruiting | N=18 --> 8 | Trial completion date: Jan 2025 --> Mar 2026

Introduction: TALAPRO-2 (NCT03395197) demonstrated that first-line talazoparib + enzalutamide significantly improved radiographic progression-free survival versus placebo + enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC). These results are supportive of the ability of F1LCDx to sensitively detect alterations in HRR genes, and the likely overall modest impact of CHiP in calling HRR gene alteration status in this study. These results support the complementary benefits of ctDNA testing to tumor tissue testing in assessing current disease alteration status, particularly AR.

P1/2, N=150, Active, not recruiting, ESSA Pharmaceuticals | Recruiting --> Active, not recruiting | Trial completion date: Jan 2026 --> Jan 2025 | Trial primary completion date: Aug 2025 --> Oct 2024

P3, N=430, Recruiting, Telix Pharmaceuticals (Innovations) Pty Limited | Not yet recruiting --> Recruiting

Especially, 4a showed superior efficacy against ARF876L/T877A and ARW741C mutants compared to darolutamide and enzalutamide. Moreover, 4a exhibited favorable pharmacokinetic profiles (F = 66.24%) in vivo and significant tumor growth inhibition in an LNCaP xenograft mouse model upon oral administration. These results highlight the potential of 4a as a promising oral AR antagonist for overcoming drug resistance in PCa.

Talazoparib plus enzalutamide had a generally manageable safety profile in patients with mCRPC within the all-comers and the HRR-deficient populations.

P3, N=439, Active, not recruiting, Curium US LLC | Trial completion date: Jun 2029 --> Feb 2029

P2, N=79, Active, not recruiting, Alliance for Clinical Trials in Oncology | Trial primary completion date: Jun 2024 --> Nov 2025

MYO6 has pro-tumor and Enz-resistant effects in CRPC, suggesting that targeting MYO6 may be beneficial for ENZ-resistant CRPC therapy through the AR/MYO6/FAK signaling pathway.

Moreover, enzalutamide-resistant C4-2B MDVR cells display higher HMGA2 levels compared to C4-2B cells, as well as sensitivity to RSL3 ferroptosis inducer, which is partially reversed by ferroptosis inhibitor, ferrostatin-1. Moreover, HMGA2-expressing cells including enzalutamide-resistant cells are susceptible to RSL-3-induced ferroptosis. Thus, ferroptosis sensitivity offers promising insights for the development of targeted therapeutic interventions for aggressive PCa.