LAST WEEK TODAY!

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

Hello fellow warriors! As you can probably tell, every now and then I blow off steam by generating images with AI! This week we have quite a few updates on the clinical trial front, as well as some interesting insights from preclinical research.
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 1 Trial: GTB-5550 NK-targeted Therapy for mCRPC​
  ​GTB-5550 has recently entered Phase 1 clinical testing in solid tumors, with an initial focus on metastatic castration-resistant prostate cancer (mCRPC) where B7-H3 is highly expressed. The therapy is administered subcutaneously, which may offer a more convenient delivery method than typical infusions. It is designed to recruit natural killer (NK) cells to attack tumors by targeting B7-H3 while utilizing the TriKE platform for immune stimulation. Preclinical research showed that GTB-5550 significantly boosts NK-cell function against prostate cancer cells, even in difficult enzalutamide-resistant or hypoxic environments.​
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• Phase 1 Trial: INR731 for mCRPC​
  ​INR731 is an oral, investigational drug currently undergoing first-in-human Phase 1 testing in men with mCRPC. The trial is evaluating the drug’s safety and pharmacokinetics through three arms: INR731 as a monotherapy, and in combination with either enzalutamide or abiraterone. While its exact molecular target has not been publicly disclosed, the trial’s exclusion of patients previously treated with cereblon-based degraders suggests INR731 may operate through a cereblon-dependent degradation mechanism.​
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• Phase 1 Trial: Next-Gen PSMA Radioligand 177Lu-LNC1011​
  ​177Lu-LNC1011 is a next-generation PSMA-targeted radioligand therapy engineered to improve upon existing treatments like Pluvicto by incorporating a modification for prolonged intratumoral retention. Early Phase 1 results demonstrated that patients in the highest dose cohort achieved significant PSA reductions, with 66.7% experiencing at least a 50% decline. The therapy showed a favorable safety profile with no dose-limiting toxicities or renal issues, and it delivered a significantly higher radiation dose to tumors compared to previous standards.​
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• Phase 1/2 Trial: GDC‑1261 in Advanced Prostate Cancer​
  ​GDC-1261 is being evaluated in a first-in-human Phase 1/2 trial for men with advanced or metastatic prostate cancer who have progressed after standard systemic therapies. The study has a relatively large estimated enrollment of 260 participants, reflecting an intention to move quickly from initial safety assessments to broader expansion cohorts. While specific details about the drug’s molecular target or chemical class remain confidential, the trial is designed to identify the recommended dose and dosing schedule for future development.​
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• Phase 1/2 Update: Concurrent Enzalutamide–Cabazitaxel​
  Updated data from a Phase 1/2 trial of concurrent enzalutamide and cabazitaxel in chemo-naïve mCRPC patients showed deep biochemical responses, with 61.1% of patients achieving a PSA90 decline. The trial reported a median radiographic progression-free survival (PFS) of 22.2 months, although pharmacokinetic testing revealed a drug-drug interaction where enzalutamide reduced exposure to cabazitaxel. These results are considered hypothesis-generating, and randomized comparisons are needed to confirm if these deep responses translate into a long-term survival advantage.​
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• Phase 1/2 Trial: Targeted Alpha Therapy Plus PARP Blockade​
  The PROSPECTOR trial is a Phase 1/2 platform testing three distinct options for metastatic prostate cancer: a PSMA-targeted alpha therapy (AZD2265), AZD2265 combined with a PARP1 inhibitor (AZD9574), and standard docetaxel chemotherapy. The rationale for the combination is that the alpha therapy delivers intense, localized DNA damage while the PARP inhibitor prevents the cancer cells from repairing that damage. Preclinical data for AZD9574 showed it is highly selective for PARP1 and can cause deep tumor regressions, especially in models with DNA-repair defects.​
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• Phase 1 Trial: PSMA‑Targeted CAR‑NK Cells for mCRPC​
  A first-in-human Phase 1 trial has explored the use of off-the-shelf, PSMA-targeted CAR-NK cells for patients with mCRPC. Unlike CAR-T cells, these were engineered using a nonviral method to shorten manufacturing timelines and potentially offer a safer toxicity profile. Initial results were promising, with all eight treated patients showing PSA reductions from baseline and 50% achieving a PSA decline of more than 30%.​
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• Therapeutic Signal: OncoACP3‑DOTA Beyond PSMA​
  ​OncoACP3-DOTA is a small-molecule ligand targeting prostatic acid phosphatase (ACP3), a protein that remains present in many prostate tumors even when PSMA expression is low or absent. In a small compassionate-use study, four heavily pretreated men who had progressed on PSMA-targeted therapies were treated with 177Lu-OncoACP3-DOTA. The treatment demonstrated negligible salivary-gland uptake and stable tumor retention, with one patient achieving a deep PSA decline lasting over 200 days.​
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• Phase 2 Trial: Darolutamide Plus ADT in Metastatic Hormone-Sensitive Prostate Cancer (ARASEC)​
  The ARASEC trial provides prospective evidence for the use of darolutamide combined with androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC). To address the ethical challenge of a traditional control group, this Phase 2 study utilized an innovative design by comparing 223 treated patients to a matched external control group from the historical CHAARTED trial. The results demonstrated substantial clinical benefit, including a 71% reduction in the risk of disease progression or death and a 50% reduction in the risk of death compared to those receiving ADT alone. The combination also showed a favorable safety profile consistent with previous studies, with only 8% of patients discontinuing darolutamide due to adverse events, offering clinicians and patients a validated doublet therapy option specifically evidenced for a contemporary US population.​

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Preclinical Research & Reviews

• Telmisartan: Repurposing a Blood Pressure Pill for Cancer​
  Telmisartan, a common cardiovascular drug, has shown unexpected promise in preclinical research for boosting the effectiveness of PARP inhibitors like olaparib. It appears to increase DNA damage in cancer cells and stimulate the immune system, even in tumors without typical BRCA-type defects. Based on these findings, a small clinical trialhas been launched at Dartmouth Cancer Center to test telmisartan in combination with olaparib for men with mCRPC.​
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• BCL-2 Inhibition to Prevent Castration Resistance​
  Researchers have identified that prostate cancer cells often compensate for androgen blockade by ramping up BCL-2, an anti-apoptotic protein that helps them survive treatment. Preclinical studies show that simultaneously blocking both the androgen receptor and BCL-2 with drugs like venetoclax can prevent the development of castration resistance. A recently completed Phase 1b trial demonstrated that the combination of enzalutamide and venetoclax is safe and produced clinical responses in a small group of heavily pretreated mCRPC patients.​
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• DNA‑barcoded Gold Nanoparticles for Subcellular Delivery​
  A new platform using DNA-barcoded gold nanoparticles allows researchers to test many different particle designs simultaneously to find those that best deliver therapy to specific cell structures like mitochondria. This high-throughput method significantly reduces the number of animals required for research while providing detailed data on how particle size and shape affect delivery. In preclinical models, cubic gold nanoparticles delivering genetic therapy combined with mild heat therapy resulted in 99% tumor regression.​
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• Orlistat@Cys8E Nanoparticles: Remodeling Lipids to Kill Cancer​
  Scientists have developed Cys8E nanoparticles to deliver the weight-loss drug orlistat directly into prostate cancer cells. Orlistat blocks an enzyme essential for fat production in cancer cells, and the nanoparticle delivery system shifts the cells’ lipid composition toward more oxidizable fatty acids. This remodeling increases lipid peroxidation and triggers programmed cell death, leading to significantly reduced tumor growth in animal studies with fewer side effects than free orlistat.​

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And…that’s all folks! For today at least!
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Have a great weekend!

Max