LAST WEEK TODAY!

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

Hello fellow warriors! The annual AACR 2026 meeting has just started and we already have some very interesting clinical and preclinical studies for you.
Stay strong and fight on!
​Picture: Borghetto sul Mincio (near my place), I cross the bridge quite often, this time I stopped for a quick smartphone picture!

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

Clinical Research

• Phase 1 Trial: Astatine-211 PSMA-5 Alpha Therapy
  ​This ongoing dose-escalation trial evaluated 211At PSMA-5, a targeted alpha therapy for refractory mCRPC patients. The treatment demonstrated swift and significant clinical responses, including the disappearance of bone and lymph node masses and sharp declines in PSA levels. SPECT/CT scans showed intense accumulation of the tracer in lesions with minimal bladder excretion. Furthermore, the study highlighted the scalability of production for astatine-211, which can be generated using domestic cyclotrons, potentially broadening patient access to alpha therapies.​
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• Phase 3 Trial: Deutenzalutamide in the HC-1119-04 Study
  ​The HC-1119-04 trial was a randomized, double-blind study conducted in China involving 417 patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously failed abiraterone. The study found that deutenzalutamide significantly improved radiographic progression-free survival (rPFS) compared to a placebo, yielding a median of 5.55 months versus 3.71 months. While the final overall survival analysis showed no statistically significant difference, sensitivity analyses adjusting for post-trial treatments suggested a potential survival benefit. The drug was generally well-tolerated; notably, no seizures or falls were reported, distinguishing its safety profile from other androgen-receptor inhibitors in its class.​
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• Phase 1b Trial: ZL-1310 for Neuroendocrine Carcinomas
  ​The ZL-1310-002 trial investigated a novel antibody-drug conjugate (ADC) targeting delta-like ligand 3 (DLL3), a protein frequently expressed in aggressive neuroendocrine prostate cancer (NEPC). In this Phase 1b study, patients who had progressed after platinum-based chemotherapy showed a striking objective response rate of 48%. This is significant because NEPC is historically resistant to standard androgen receptor-targeted therapies and lacks effective second-line options. The safety profile was considered manageable, with side effects like anemia and nausea consistent with the drug’s topoisomerase I inhibitor payload.​
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• Phase 1 Trial: ACE-106 Selective PARP1 Inhibitor
  ACE-106 is a highly selective PARP1 inhibitor designed to reduce the hematologic toxicity common in first-generation pan-PARP inhibitors. In an open-label dose-escalation study, the drug was well-tolerated with no dose-limiting toxicities, and hematologic toxicity did not increase with higher doses. Among patients with HRR-mutant mCRPC, the objective response rate was 50%, with one patient lacking a documented HRR mutation also achieving a partial response. Its long half-life supports once-daily dosing while maintaining exposures above efficacious levels.​
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• Phase 1 Trial: 225Ac-J591 Antibody-Based Radioligand Therapy
  ​This trial studied 225Ac-J591, which uses an antibody rather than a small molecule to deliver radioactive particles to PSMA-expressing tumors. The research compared standard dosing to a “fractionated” schedule, finding that the fractionated approach led to superior outcomes, with 68% of patients experiencing a PSA decline of more than 50%. Clinical benefits included a median progression-free survival of 5.2 months and an overall survival of 15.4 months in a heavily pretreated population. While side effects were mainly blood-related, patients reported stable quality of life and improved pain scores.​
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• Phase 1 Trial: HSK46575 CYP11A1 Inhibitor
  HSK46575 is a novel inhibitor designed to suppress the entire steroidogenesis pathway. Early data from 27 treated patients showed a PSA50 response rate of 30.8%, with responses notably enriched in patients harboring AR ligand-binding domain mutations. The safety profile appeared manageable, with low rates of high-grade adverse events despite the drug’s inherent suppression of glucocorticoids and mineralocorticoids. Researchers suggest HSK46575 could serve as a backbone for combination strategies with chemotherapy or PARP inhibition.​
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• ctDNA and Fragmentomics for Survival Prediction
  ​A prospective study of 140 patients found that circulating tumor DNA (ctDNA) fraction serves as a powerful prognostic marker for overall survival in patients receiving 177Lu-PSMA-617. Using a novel computational framework called Proteus, researchers extracted fragmentomic signals to infer tumor phenotypes like lineage plasticity and hypoxia. The study revealed that ATM gene mutations were associated with improved survival, whereas MYC amplification was linked to inferior outcomes. These findings suggest that liquid biopsies can capture complex aspects of disease burden that PSA levels alone cannot reflect.​

Preclinical Research & Reviews

• Dual-Action Nano-PROTAC Platform (ARV@MIL-HA-ss-HA)
  ​Researchers have developed a nanoplatform designed to treat advanced prostate cancer through the simultaneous mechanisms of targeted protein degradation and ferroptosis sensitization. The system uses an iron-based metal-organic framework (MIL-101) to deliver ARV-771, a PROTAC that degrades the BRD4 protein. In addition to drug delivery, the MIL-101 carrier acts as a nanozyme that promotes ferroptosis, a form of iron-dependent cell death, in the tumor environment. Preclinical tests in animal models showed strong antitumor activity, improved tumor accumulation, and acceptable biosafety.​
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• AM109: PSMA-Targeted CD137 Bispecific Antibody
  AM109 is a bispecific agent that creates a molecular bridge between PSMA-expressing prostate cancer cells and T cells by targeting the CD137 receptor. Unlike treatments that cause systemic immune activation, AM109 restricts activation to the tumor site, inducing robust CD8+ T-cell activation and cytokine secretion. In preclinical mouse models, the therapy led to complete tumor regression at very low doses. This approach aims to turn “cold” immunosuppressive tumor environments “hot” to enhance the durability of the immune response.​
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• Helicon Peptides for Active AR Degradation
  ​Unlike current therapies that target inactive androgen receptors, Helicon peptide degraders are designed to recognize and destroy the active, agonist-bound form (ARON) of the receptor. These bifunctional peptides bind to the AF2 coactivator site and recruit the cell’s cleanup system to trigger AR degradation, effectively shutting down genes like PSA and TMPRSS2. Preclinical models showed that these degraders outperformed enzalutamide in AR-amplified xenografts and remained effective in AR-mutant settings. This strategy may deliver more durable responses by overcoming the limitations of ligand-competitive therapies.​
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• ITRI-148: NTD-Targeted AR PROTAC
  ITRI-148 represents a shift in treatment by targeting the N-terminal domain (NTD) of the androgen receptor rather than the ligand-binding domain. Because the NTD is shared by both full-length AR and splice variants like AR-V7, ITRI-148 can degrade resistant variants that allow cancer cells to bypass traditional treatments. In preclinical models, the compound demonstrated stronger antiproliferative effects than enzalutamide and led to tumor regression in xenograft models. The discovery of a druggable pocket in the NTD could open the door for a new class of therapies independent of the ligand-binding domain.​
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• ProTCE-PSMA: Next-Generation T-Cell Engager
  ProTCE-PSMA is a preclinical candidate engineered to improve the therapeutic window of T-cell engagers by masking CD3 engagement until the drug reaches the tumor. The molecule utilizes a multi-enzyme activation strategy, requiring proteases enriched in the tumor microenvironment to cleave its linker. Preclinical studies in monkeys showed that ProTCE-PSMA induced tenfold lower cytokine levels compared to earlier-generation constructs, suggesting a significantly reduced risk of cytokine release syndrome. This design also features kinetic tuning to limit sustained systemic T-cell activation.​

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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