LAST WEEK TODAY!

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

Hi fellow warriors! This week’s photo features me and my better half! (Mine is the hand underneath.) We celebrated our anniversary, and here I am, still full from dinner, finishing up the newsletter! This week, too, we have some exciting updates on both the clinical and preclinical fronts. 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 2 Trial: Low-Dose Naltrexone for ADT-Related Fatigue
  A new single-arm study, planning to enroll 60 men over 30 months at the University of Arkansas, will test whether nightly low-dose naltrexone (LDN) at 3 mg can reduce fatigue in men with prostate cancer receiving androgen-deprivation therapy (ADT). Persistent fatigue is a major and prevalent toxicity of ADT, significantly undermining quality of life, daily function, and treatment adherence. The study will concurrently profile mitochondrial, inflammatory, and oxidative stress pathways that are thought to drive cancer-related fatigue. Eligibility extends to men receiving ADT alone or combined with contemporary AR-pathway agents such as darolutamide, apalutamide, abiraterone, or enzalutamide. Mounting evidence links ADT to a pro-inflammatory state characterized by elevations in cytokines like interleukin-6 (IL-6), which correlates with fatigue severity, suggesting inflammation is a modifiable biological driver. LDN has demonstrated immunomodulatory properties, including reducing pro-inflammatory cytokines like IL-6 and TNF-α, which could counteract the ADT-associated inflammatory milieu.
  ​More info here​
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• Phase 1 Trial: GenSci143 Dual-Target ADC
  GenSci143 (or GenSci-143) is a bispecific antibody-drug conjugate (ADC) currently under development for metastatic castration-resistant prostate cancer (mCRPC) and other solid tumors. This construct targets two antigens simultaneously, PSMA and B7-H3 (CD276), using a stable, cleavable linker coupled to a topoisomerase I inhibitor payload. This dual-targeting approach aims to improve tumor cell killing and bystander effects across the heterogeneous antigen expression landscapes common in prostate cancer, thereby potentially overcoming the efficacy constraints seen with single-target ADCs. Preclinical data showed robust anti-tumor activity, including tumor regression, in human cell-derived xenograft (CDX) prostate cancer models across various PSMA and B7-H3 expression levels. GenSci143 demonstrated superior preclinical efficacy compared to analogs of single-target comparators like ARX517 (anti-PSMA) and DS-7300 (anti–B7-H3).
  ​More info here.​
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• ARASENS Subgroup Analysis​
  A recent subgroup analysis of the large Phase 3 ARASENS trialinvestigated the impact of adding darolutamide to the standard ADT plus docetaxel treatment, specifically aiming to confirm that the benefits of this combination extend consistently to older patients by comparing outcomes in those younger than 75 years versus those aged 75 or older.The findings confirmed that darolutamide significantly improved overall survival in both age cohorts. The risk of death was reduced by 30% for patients under 75 and by 39% for those 75 or older. Moreover, the triplet therapy dramatically delayed the progression to castration-resistant prostate cancer and postponed the need to initiate new subsequent therapies. Importantly, the safety profile of the darolutamide combination proved consistent across ages, suggesting that age and common comorbidities should not preclude patients from receiving this effective regimen.
  ​More info here.​

Preclinical Research & Reviews

• Targeting PTGES3 to Disarm Androgen Signaling
  New research has identified a little-known protein called PTGES3, also known as p23, that assists prostate cancer cells in maintaining and utilizing male hormone signals for growth, even when patients are undergoing treatments designed to suppress those signals. Prostate cancer’s reliance on the androgen receptor (AR) often leads to treatments focusing on blocking the receptor or lowering hormones, but the cancer frequently re-ignites this AR switch. A large genetic screen using CRISPR technology highlighted PTGES3 as a critical helper required by cancer cells to keep the AR present and active. In human prostate cancer tumors grown in mice, dialing down PTGES3 slowed tumor growth and reduced the levels of the AR. High levels of PTGES3 in patient tumor samples were linked to poorer outcomes and earlier recurrence in patients receiving first-line AR-targeted therapies, suggesting PTGES3 may be a mediator of treatment resistance.
  ​More info here.​
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• AB-3028: Next-Generation CAR T Therapy
  AB-3028 represents a next-generation approach to solid-tumor CAR T therapy specifically engineered to address the unique difficulties of metastatic castration-resistant prostate cancer (mCRPC). Solid tumor CAR T treatments have historically been challenged by issues like heterogeneous antigen expression, off-target toxicity, chronic stimulation leading to exhaustion, and immune suppression by cytokines such as TGF-β. AB-3028 counters these barriers by using a tri-module, non-viral DNA cassette that integrates persistence, TME resistance, and tumor selectivity features. Central to its design is a sequential AND logic gate that necessitates dual-antigen recognition before full CAR T activation, a strategy intended to mitigate single-antigen escape and reduce the risk of on-target off-tumor toxicity. To resist the suppressive microenvironment, AB-3028 includes an shRNA–miR module that knocks down FAS and TGFβR2, protecting the T cells from TGF-β suppression and FasL-mediated apoptosis. Preclinical evaluations demonstrated that AB-3028 displayed strong activity against dual-antigen cells while eliciting minimal activity against single-antigen controls, confirming that the sequential gate functions as designed.
  ​More info here.​
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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