LAST WEEK TODAY!

A summary of what was published on ProstateWarriors.com during the past week

Hi fellow warriors! As you probably know, last week was the week of AACR 2025 (American Association for Cancer Research) and AUA 2025 (American Urological Association), so we have a very packed newsletter! Enjoy the read! Stay strong and fight on!

As usual, we also have a podcast if you prefer to listen to the newsletter, you can find it HERE.​

Clinical Research

• ABBV-969 – Bispecific ADC Targeting STEAP1 and PSMA​
  ABBV-969 is an innovative bispecific antibody-drug conjugate designed to recognize and bind two key antigens frequently expressed on prostate cancer cells: STEAP1 and PSMA. This dual-targeting approach improves tumor specificity and may mitigate the challenge of antigen heterogeneity that limits the efficacy of monovalent PSMA-targeted therapies. Preclinical models have demonstrated that this bispecific ADC has potent anti-tumor activity, including in PSMA-low tumors, and significantly outperforms single-target ADCs. ABBV-969 is currently being evaluated in a Phase 1 dose-escalation trial in patients with metastatic castration-resistant prostate cancer (mCRPC) and other advanced solid tumors, with the goal of establishing safety and preliminary efficacy.
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• APG-5918 – EED Inhibitor​
  APG-5918 is a first-in-class inhibitor of EED, a core scaffolding component of the polycomb repressive complex 2 (PRC2), which mediates gene silencing through trimethylation of histone H3 at lysine 27 (H3K27me3). In prostate cancer, PRC2 contributes to oncogenic progression by repressing tumor suppressor genes and reinforcing AR signaling via chromatin modifications. By blocking EED, APG-5918 destabilizes the entire PRC2 complex, effectively shutting down its gene-silencing function. Preclinical studies in AR-positive prostate cancer models, including LNCaP and C4-2B cells, have shown that APG-5918 reduces levels of EZH2, MYC, and AR target genes, induces cell cycle arrest and apoptosis, and enhances the activity of anti-androgens such as enzalutamide. A Phase 1 clinical trialÂis ongoing in patients with solid tumors harboring PRC2 pathway activation or EZH2 gain-of-function alterations, including those with CRPC.
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• CTS2190 – PRMT1 InhibitorÂ​
  CTS2190 is an oral inhibitor of PRMT1, an arginine methyltransferase that modifies histones and non-histone proteins to regulate transcription, DNA damage repair, and RNA splicing. PRMT1 activity is upregulated in CRPC and contributes to tumor progression by enhancing AR signalingÂand promoting the expression of AR splice variants like AR-V7, which are known mediators of therapy resistance. By inhibiting PRMT1, CTS2190 disrupts the methylation of histone H4R3 and other transcriptional coactivators, leading to widespread transcriptional reprogramming and suppression of oncogenic signaling.ÂPreclinical data have shown that CTS2190 inhibits tumor cell proliferation, induces apoptosis, and synergizes with PARP inhibitors and taxanes, making it a candidate for combination therapy. In prostate cancer models, the drug performed better than enzalutamide, docetaxel, and even AR-targeting PROTACs in terms of tumor growth suppression. The current Phase 1/2 clinical trial is assessing safety and efficacy in advanced solid tumors, including prostate cancer.
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• GDC-2992 (RO7656594) – AR PROTAC DegraderÂ​
  GDC-2992, also known as RO7656594, is an androgen receptor degrader that induces the selective destruction of the AR protein via the cereblon E3 ubiquitin ligase. Unlike traditional AR antagonists that block the receptor’s ligand-binding domain, GDC-2992 eliminates AR protein expression altogether, including mutant forms that retain partial activity or are resistant to drugs like enzalutamide and abiraterone. Preclinical studies have demonstrated that this degrader suppresses both full-length AR and AR variants, reduces PSA levels, and leads to tumor regression in enzalutamide-resistant CRPC xenografts. Importantly, it is active even in models expressing AR with gain-of-function mutations such as T878A and H875Y. A Phase 1 clinical trial is currently underway to determine the maximum tolerated dose and pharmacodynamic effects in men with metastatic CRPC.
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• NXP900 – SRC/YES1 Kinase Inhibitor​
  NXP900 targets two members of the Src family kinases—SRC and YES1—which are implicated in the progression and metastasis of advanced prostate cancer. These kinases regulate pathways involved in AR signaling, epithelial-to-mesenchymal transition (EMT), and tumor invasiveness. NXP900 is an inhibitor that binds both active and inactive conformations of these kinases, locking them into an inactive stateÂand disrupting downstream signaling cascades. In CRPC models, NXP900 reduces AR transcriptional output and suppresses EMT markers. It has shown synergy with enzalutamide in resistant models and enhances response to EGFR inhibition in neuroendocrine prostate cancer lines. Early data from the Phase 1 trialÂshow that the drug is well-tolerated and exhibits biological activity in solid tumors. NXP900 may represent a valuable tool for delaying or reversing resistance in AR-driven tumors, or for treating transdifferentiated forms such as neuroendocrine prostate cancer.
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• SYN818 – POLQ InhibitorÂ​
  SYN818 inhibits DNA polymerase theta (POLQ), an enzyme essential for microhomology-mediated end joining (MMEJ), a backup DNA repair pathway that becomes critical in tumors with homologous recombination repair (HRR) defects. Prostate cancers with BRCA1/2, ATM, or PALB2 mutations rely on POLQ when the homologous recombination pathway is disrupted, creating a synthetic lethality context. By blocking POLQ, SYN818 selectively induces DNA damage and apoptosis in HRR-deficient cancer cells. Preclinical studies confirm this mechanism and show strong anti-tumor activity in BRCA-deficient models, with additional synergy observed when combined with PARP inhibitors. A Phase 1 clinical trial is recruiting prostate cancer patients with mutations in HRR genes to assess safety and early efficacy.
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• Estradiol Use in nmCRPC Challenges​
  Transdermal estradiol (tE2) patches are emerging as a potentially transformative option for androgen deprivation therapy in prostate cancer. A recent phase IIIÂrandomized trial in non-metastatic patientsÂdemonstrated that tE2 can suppress testosterone as effectively as standard LHRH agonists, while causing fewer hot flashes and preserving bone mineral density-key quality-of-life benefits. Despite these advantages, estradiol remains off-label for men, facing obstacles related to physician prescription, insurance reimbursement, and lack of manufacturer incentives for formal approval. Patients often rely on generic patches with variable dosing and without robust safety data, and reviews have shown significant variability in serum estradiol levels among different patch brands. Application site also significantly impacts estradiol uptake. To overcome these barriers, rigorous pharmacokinetic studies, cost-effectiveness analyses, and regulatory support are needed. The potential rewards include a therapy that matches standard ADT efficacy but with fewer side effects and possibly lower costs, making tE2 an underused but promising strategy for prostate cancer care.

Preclinical Research

• ATMN-400 Antibody Radioconjugate​
  ATNM-400 is a novel experimental antibody radioconjugate designed to combat advanced prostate cancer with a highly targeted radiation payload. Unlike therapies that use beta radiation to target PSMA, ATNM-400 employs an antibody to seek out a specific protein highly expressed on metastatic CRPC cells, delivering Actinium-225, an alpha particle-emitting isotope. This approach offers potent, localized cell killing with minimal damage to surrounding healthy tissues. Preclinical studies have shown ATNM-400 to be highly pure, to bind and enter cancer cells rapidly, and to induce dose-dependent killing in vitro. In mouse models, a single dose led to significant tumor growth inhibition, reducing tumor size by nearly 70% at a lower dose and almost completely (99.8%) at a higher dose, while being well-tolerated. Early safety assessments suggest an acceptable safety profile for human trials, and researchers are also evaluating ATNM-400 in models resistant to other radioligand therapies.
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• SHR3591 PROTACÂ​
  SHR3591 is a new oral AR PROTAC (proteolysis targeting chimera) under investigation for metastatic castration-resistant prostate cancer. Designed to degrade the androgen receptor protein, which drives prostate cancer progression even after resistance to existing therapies, SHR3591 has demonstrated powerful activity against both wild-type AR and a range of clinically relevant AR mutations that confer resistance. Preclinical studies have shown strong AR degradation at nanomolar concentrations, excellent selectivity, and robust tumor regression in animal models, with over 90% AR degradation and favorable pharmacokinetics. The drug is moving toward Phase 1/1b clinical trials and could offer a promising new strategy for patients with advanced, treatment-resistant prostate cancer.
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• SENTI-202, a New Interesting Approach
  The logic-gating approach, as featured in the context of SENTI-202 for acute myeloid leukemia (AML), offers a novel strategy for improving the precision of targeted therapies. This method proposes the use of Natural Killer (NK) cells, which can be sourced from healthy donors and tend to cause fewer side effects than T cells. SENTI-202 is a CAR-NK cell therapy engineered to recognize AML proteins CD33 and FLT3. Its distinguishing feature is the logic-gating mechanism: the CAR activates when it detects CD33 or FLT3, but an inhibitory receptor acts as a safety switch, preventing the NK cells from attacking if the cell also expresses EMCN, a marker found on healthy hematopoietic stem cells. This dual-signal “AND NOT” logic gate aims to spare healthy cells while targeting cancerous ones. While discussed in the context of AML, this logic-gating approach could inspire similar strategies for other cancers.
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• OST11098 a Novel CYP11A1 Inhibitor​
  OST11098 is an innovative, orally administered and highly selective CYP11A1 inhibitorÂthat demonstrates strong promise for treating castration-resistant prostate cancer (CRPC), particularly in cases where resistance to next-generation hormone agents has developed. By blocking CYP11A1, OST11098 effectively inhibits pregnenolone production, thereby shutting down the androgen receptor (AR) signaling axis. Notably, in CRPC xenograft mouse models-including those resistant to standard hormonal agents-OST11098 produced significant anti-tumor effects and maintained a favorable safety profile, suggesting it could represent a new class of therapies to overcome resistance to existing hormonal treatments.​
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And…that’s all folks! For today at least!
Please let me know if there is anything I can improve in my newsletters, and let me know if you have enjoyed the podcast.

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Have a great weekend!

Max