LAST WEEK TODAY!

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

Hi fellow warriors! New week, new articles. Given my academic and professional background, the most incredible news this week is the first one you’ll find under preclinical research. It hasn’t made much noise, but believe me, it’s something that would have been unthinkable even just two or three years ago. 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

• Phase 3 Trial of Xaluritamig (AMG 509) Plus Abiraterone in mCRPC
  A large international Phase 3 clinical trial is underway, evaluating the combination of xaluritamig (AMG 509) and abiraterone acetate for men with metastatic castration-resistant prostate cancer (mCRPC) who have not yet received chemotherapy in the castration-resistant setting. Xaluritamig is a bispecific T-cell engager designed to activate T-cells by connecting the immune system’s CD3 receptors with STEAP1, a protein expressed on more than 95% of prostate tumors. Abiraterone, a standard therapy, inhibits androgen synthesis through CYP17 blockade. The study compares this pairing of immune activation and hormonal suppression against standard treatments (including docetaxel, cabazitaxel, or abiraterone alone).
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• Phase 1 Trial of Alpha Radioligand Therapy AB001 (ARTISAN trial)​
  The Phase 1 ARTISAN trial is currently evaluating AB001, an investigational lead-212 (²¹²Pb) alpha radioligand therapy targeting prostate-specific membrane antigen (PSMA) in patients with metastatic castration-resistant prostate cancer (mCRPC). This therapy pairs a PSMA-targeted small molecule with the alpha-emitting isotope ²¹²Pb. Alpha particles deliver highly localized, high-energy radiation, which aims to improve tumor targeting while limiting exposure to surrounding healthy tissue. Preclinical findings suggest that ²¹²Pb, which has a half-life of 10.6 hours, may offer stronger tumor control compared to beta-emitting agents like ¹⁷⁷Lu-PSMA (Pluvicto), particularly when administered in fractionated doses. The trial includes both patients who are naïve to and those who have been previously treated with ¹⁷⁷Lu-PSMA.​
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• Phase 1/2 Study of Tulmimetostat (DZR123) and JSB462
  A new global Phase I/II clinical trial is set to evaluate a combination therapy for men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed following prior treatments. The combination pairs tulmimetostat (DZR123), an oral inhibitor of EZH2 and EZH1 enzymes, with JSB462 (also known as luxdegalutamide or ARV-766), which is an oral androgen receptor (AR) degrader from the PROTAC drug class. Tulmimetostat disrupts tumor growth and sensitizes cells by disabling DNA repair mechanisms. JSB462 promotes the degradation of both normal and mutated androgen receptors to overcome resistance common with standard hormone therapies. The combination offers a dual-attack approach targeting epigenetic pathways and AR signaling, supported by preclinical data indicating synergy.
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• Phase 2 Trial for Optimal PSA-Triggered Intermittent Therapy in mHSPC
  This Phase II study investigates a novel PSA-triggered intermittent therapy approach for metastatic hormone-sensitive prostate cancer (mHSPC). This strategy aims to mitigate the enduring side effects associated with traditional continuous androgen deprivation therapy (ADT) combined with androgen receptor pathway inhibitors (ARPIs). Patients initially receive continuous relugolix (an oral GnRH antagonist) combined with an ARPI. Relugolix is particularly suitable as it offers rapid and reversible testosterone suppression. Once a deep PSA response is achieved, therapy is halted, and treatment only resumes when PSA levels rise beyond a predetermined threshold. The study’s primary goal is to measure the proportion of patients who can remain off treatment for at least one year using this adaptive, PSA-guided strategy.
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• Phase 2 Co-PSMA Trial for 64Cu-SAR-bisPSMA Imaging Agent
  The Phase 2 Co-PSMA trial evaluated ⁶⁴Cu-SAR-bisPSMA, a novel copper-based PET imaging agent, against the standard ⁶⁸Ga-PSMA-11 tracer in patients experiencing biochemical recurrence of prostate cancer with low PSA levels. Results showed that ⁶⁴Cu-SAR-bisPSMA detected a statistically greater number of PSMA-positive lesions per patient. The agent’s superior performance is attributed to the longer half-life of copper-64 (12.7 hours), which enables improved lesion contrast through delayed imaging. Next-day imaging with ⁶⁴Cu-SAR-bisPSMA resulted in nearly double the number of lesions detected compared to same-day imaging or standard ⁶⁸Ga-PSMA-11 scans. Comparative trials also demonstrated that ⁶⁴Cu-SAR-bisPSMA could identify lesions as small as 2 mm up to six months earlier than the standard of care
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Preclinical Research & Reviews

• AI Generates and Validates New Cancer Treatment Hypothesis
  A collaboration between Yale University and Google DeepMind utilized the Cell2Sentence-Scale 27B foundation model, an artificial intelligence system trained on single-cell RNA sequencing data, to generate and experimentally validate a novel hypothesis for cancer treatment. Operating within Google’s Gemma framework, the AI functions as a “virtual cell” to interpret complex biological data. The model proposed a dual-context simulation, reasoning that the compound silmitasertib (a CK2 kinase inhibitor) would enhance antigen presentation only when combined with low levels of interferon. Yale biologists experimentally confirmed this prediction using human neuroendocrine tumor cell models: the combination produced approximately a fifty-percent increase in MHC-I antigen presentation, effectively making the tumor cells more visible to the immune system, validating a therapeutic mechanism proposed independently by the AI.
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• Combination Therapy for Advanced Prostate Cancer
  Scientists identified a promising two-pronged drug combination aimed at benefiting up to 40 percent of men with advanced prostate cancer whose tumors are resistant to hormone therapy. The combination targets two essential survival proteins: MCL1 and AKT. Researchers achieved the desired MCL1 reduction using fadraciclib, a CDK9 inhibitor that indirectly lowers MCL1 levels, and paired this with AKT inhibitors, such as ipatasertib or capivasertib. Laboratory studies confirmed that this combination triggers prostate cancer cell death, whereas neither agent used alone was effective. This therapy proved most responsive in tumors characterized by PTEN loss and PI3K activation. The research team is actively seeking funding to advance these findings into clinical trials, noting that the individual components are already in late-stage development or approved for other uses, potentially accelerating clinical translation.
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• Dual Enzyme Blockade Weakens Prostate Cancer
  Preclinical research has identified two enzymes, protein disulfide isomerases PDIA1 and PDIA5, as crucial molecular guardians of prostate cancer cell survival. These enzymes stabilize the androgen receptor (AR) by ensuring its proper folding, even under cellular stress conditions. When PDIA1 and PDIA5 are inhibited, the AR becomes unstable, undergoes degradation, and triggers cancer cell death, resulting in measurable tumor shrinkage in both cultured cells and animal models. This blockade also attacks the cancer cell’s metabolic machinery, causing mitochondrial dysfunction, impaired energy production, and elevated oxidative stress. The combination of PDIA1 and PDIA5 inhibitors with the prescribed AR antagonist enzalutamide demonstrated a synergistic enhancement of cancer cell death, yielding results superior to enzalutamide used alone.
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• Self-Assembled Nano-PROTAC for Castration-Resistant Prostate Cancer
  A major advancement in targeted cancer therapies involves the development of an in vivo self-assembled nano-PROTAC (proteolysis targeting chimera) system designed for dual-targeted degradation in castration-resistant prostate cancer (CRPC). While conventional PROTACs are limited by issues like poor membrane permeability and suboptimal pharmacokinetics, the nano-PROTAC addresses these challenges by forming stable nanostructures that enhance circulation stability and controlled tumor penetration. This novel system employs a dual-targeting strategy that simultaneously degrades two proteins essential for CRPC survival, thereby amplifying efficacy and minimizing compensatory signaling that leads to resistance. In animal models, the nano-PROTAC demonstrated significant tumor growth inhibition with minimal systemic toxicity, ensuring selective degradation occurs primarily within the tumor microenvironment.

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