LAST WEEK TODAY!

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

Hello fellow warriors! Next week I’ll be traveling a bit, but I’ll do my best to keep posting and prepare the next newsletter. For now, here are this week’s news.
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: Confirmed Efficacy and Manageable Safety of Rucaparib in BRCA-Mutated mCRPC
  ​The TRITON3 trial has confirmed the efficacy and predictable safety profile of rucaparib in chemotherapy-naïve patients with BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC). Toxicity was largely driven by hematologic effects, with anemia affecting 46% of patients and leading to a 28% transfusion rate. While dose interruptions and reductions were frequent, the discontinuation rate remained low at under 14%, suggesting that these toxicities are manageable without stopping treatment. The incidence of secondary malignancies like MDS or AML was consistent with the PARP inhibitor class at 1%.
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• Phase 2 Trial: 61Cu-NU101 vs. 18F-Piflufolastat in Metastatic Prostate Cancer61
  Cu-NU101 is a novel PSMA-targeted PET/SPECT tracer that offers a significant advantage over current tracers due to its 3.3-hour half-life, which allows for delayed imaging at 4 hours post-injection. This delayed window enables the detection of small metastases and tumors with low PSMA expression that standard tracers often miss. Furthermore, 61Cu-NU101 supports a true theranostic approach; if the 61Cu tracer identifies micrometastases, the same ligand can be labeled with 67Cu for targeted therapy to treat those specific lesions.
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• Phase 1 Trial: Memantine Shows Early Efficacy Signals in Neuroendocrine Prostate Cancer
  ​Prostate cancer can transition into a treatment-resistant neuroendocrine form (NEPC), a process driven by the transcription factor HOXD11 which activates NMDAR signaling. Memantine, a drug repurposed from other medical uses, has demonstrated the ability to block this biological switch in preclinical models. While evidence is currently limited, a Phase 1 clinical signal in a patient with advanced NEPC showed radiographic regression following treatment with memantine.
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• BRCA-Altered mCSPC Progresses Faster on ARPIs: A Real-World Treatment Gap
  ​Real-world data involving 745 patients indicates that BRCA1/2 mutations significantly accelerate disease progression in metastatic castration-sensitive prostate cancer (mCSPC) treated with androgen receptor pathway inhibitors (ARPIs). Patients with these mutations had a median time-to-next-treatment of 19.6 months, compared to over 24 months for those with other HRR alterations or no alterations. This highlights that the biological disadvantage of BRCA alterations is present early in the disease state, long before patients reach the castration-resistant stage.
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• Real-World OPTYX Study: Sustained Castration and Rapid Testosterone Recovery with Relugolix​
  The OPTYX study, a prospective observational analysis of 999 patients, confirms that the oral ADT relugolix (Orgovyx) achieves castration levels (<50 ng/dL) in over 92% of patients in routine clinical practice. Upon discontinuation, testosterone levels recovered relatively quickly, reaching a mean of 214 ng/dL within three months. Importantly, PSA control persisted in 66% of patients six months after stopping therapy, suggesting relugolix may be particularly well-suited for intermittent ADT strategies.

Preclinical Research & Reviews

• Arginase 1 Suppression Makes Exercise Effective Against Prostate Cancer
  ​Preclinical research identifies the suppression of arginase 1 (Arg1) as a primary mechanism through which exercise inhibits tumor growth. Arg1 typically depletes arginine, a nutrient essential for T-cell function, thereby creating an immune-suppressive environment. By downregulating Arg1, exercise preserves arginine availability and restores anti-tumor immune responses, providing a mechanistic foundation for integrating structured physical activity into prostate cancer management.
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• NRG1-Driven Microenvironmental Resistance to PI3K Inhibition in Prostate Cancer
  ​Resistance to PI3K inhibitors in prostate cancer is often driven by Neuregulin 1 (NRG1), a factor derived from the tumor microenvironment stroma. NRG1 activates the HER3/HER2 axis, which reactivates the PI3K/AKT pathway and allows tumor cells to bypass therapeutic inhibition. Preclinical models show that combining HER3 inhibition (such as the antibody seribantumab) with standard PI3K and AR signaling inhibitors significantly improves tumor control.
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• Tipifarnib Shows Early Promise as an Adjuvant in Enzalutamide-Resistant Prostate Cancer
  Tipifarnib is a repurposing candidate that may combat enzalutamide resistance by suppressing the release of exosomes from aggressive cancer cells. These exosomes are used by tumors to share pro-survival signals and adapt to therapy pressure. By reducing exosome biogenesis by approximately 30%, tipifarnib could function as a promising adjunct to enzalutamide, weakening the signaling networks that support resistant disease.
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• Ultrasound-Driven Cavitation Reprograms Drug Response and Immune Sensitivity in NEPC
  Acoustic cavitation, using lipid microbubbles and targeted ultrasound, overcomes biological barriers in neuroendocrine prostate cancer by physically disrupting cellular membranes to enhance drug uptake. Beyond delivery, this “sonoporation” improves tumor oxygenation, which reverses hypoxia-driven resistance mechanisms. This process also primes the immune microenvironment, increasing CD8+ T cell infiltration and making “cold” NEPC tumors more susceptible to immune checkpoint blockade.
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• ZNF281 Emerges as a Novel Driver and Therapeutic Target in Advanced Prostate CancerThe transcription factor ZNF281 has been identified as a key driver of metastasis, with significantly higher expression found in metastatic lesions compared to primary tumors. It acts as a co-activator for the androgen receptor and promotes cellular plasticity through EMT-related proteins. In patient-derived organoids, a novel small-molecule inhibitor of ZNF281 demonstrated superior activity compared to enzalutamide, suggesting it could be a potent future target for advanced disease.

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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