LAST WEEK TODAY!

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

Hello fellow warriors! Autumn is here, bringing with it the wave of new research we look forward to every year. For now, sit back, relax, and enjoy this little taster of what’s to come. 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: KMV002 Therapeutic Vaccine for mCRPC​
  A new phase 1 clinical trial is evaluating KMV002 (also known as IPT-PAP), an experimental therapeutic cancer vaccine designed for patients with metastatic castration-resistant prostate cancer (mCRPC / mAPMR). The therapy combines SN3001C,an engineered protein delivering prostatic acid phosphatase (PAP) directly to dendritic cells, with a CpG ODN adjuvant to elicit a PAP-specific T-cell response. Primary objectives focus on assessing safety, tolerability, and optimal dosing, alongside secondary endpoints measuring PAP-specific T-cell activity, radiographic progression-free survival, and PSA reductions of at least 50%.​
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• Phase 1 Trial: VIR-5500 PSMA-Targeted T-Cell Engager​
  The FDA has granted Fast Track designation to VIR-5500 (formerly AMX-500), a bispecific T-cell engager for heavily pretreated mCRPC / mAPMR that directs T cells against PSMA-expressing tumor cells using dual-masking technology to minimize systemic toxicity. Updated phase 1 trial results demonstrated significant efficacy among patients, achieving an 82% PSA50 response rate, a 53% PSA90 response rate, and a 45% objective response rate (5 of 11) in measurable disease. Clinical development is expanding into earlier metastatic settings in combination with enzalutamide, docetaxel, and darolutamide, with phase 3 trials planned for 2027.
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• Phase 1/2 Trial: Dual Bispecific Combination of REGN21353 and Nezastomig​
  A phase 1/2 trial is evaluating REGN21353, a STEAP1×CD3 bispecific antibody, both as monotherapy and in combination with nezastomig (REGN5678), a PSMA×CD28 costimulatory bispecific antibody, in patients with pretreated mCRPC / mAPMR. The therapeutic rationale hinges on co-targeting two distinct prostate cancer antigens (STEAP1 and PSMA) while delivering two complementary immune signals: CD3-mediated T-cell activation and CD28 costimulation. By addressing antigen heterogeneity and potential escape across metastatic lesions, the study aims to establish whether dual costimulatory targeting provides deeper and more durable antitumor responses than CD3 engagement alone without triggering excessive immune-related toxicity.
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• Phase 2 Trial: SOAR Trial Evaluating ADT-Free Metastasis-Directed Therapy​
  The phase 2 SOAR trial investigated whether metastasis-directed therapy (MDT),comprising radiotherapy, salvage lymph-node dissection, or both, can safely delay the need for androgen deprivation therapy (ADT) in men with PET-defined oligorecurrent prostate cancer (up to 10 nodal or bone metastases). Among 20 enrolled patients, 40% achieved a PSA reduction of ≥50% at six months, while achieving an estimated 12-month PSA progression-free survival of 74.1% and an ADT-free survival of 71.4%. Notably, 18 of the 20 participants had nodal-only recurrence, and pathological analysis following lymph-node dissection frequently revealed more extensive microscopic disease than detected by PSMA-PET imaging, underscoring the potential need to treat broader anatomical regions at risk.
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• Phase 2 Trial: ENV-105 (Carotuximab) Combined with Apalutamide​
  Updated phase 2 clinical data demonstrate that adding ENV-105 (carotuximab) to apalutamide substantially prolongs progression-free survival in patients with mCRPC. ENV-105 is an antibody targeting CD105 (endoglin), a cell-surface protein implicated in angiogenesis, tumor signaling, and anti-androgen resistance. Patients treated with the combination of ENV-105 and apalutamide achieved a median progression-free survival of 17.7 months, compared to just 2.0 months for apalutamide alone. Based on these persistent disease control signals, trial enrollment is expanding to evaluate ENV-105 alongside enzalutamide at earlier stages of emerging hormonal resistance.
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• Phase 2/3 Trial: Bipolar Androgen Therapy Followed by Darolutamide​
  A randomized phase 2/3 trial is investigating Bipolar Androgen Therapy (BAT),deliberate exposure to supraphysiological testosterone via monthly injections, followed sequentially by darolutamide in 432 patients with mCRPC / mAPMR who progressed on prior AR pathway inhibitors. The strategy aims to leverage the upregulation of androgen receptors caused by chronic ADT to induce cell-cycle stress and DNA damage, thereby resensitizing tumors to subsequent AR blockade. The trial’s phase 2 primary endpoint is PFS2 (progression-free survival through both treatment lines), supported by prior TRANSFORMER trial evidence where post-BAT enzalutamide yielded a 77.8% PSA50 response rate and extended median PFS to 10.9 months.
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• Phase 3 Trial: 177Lu-ludotadipep Radioligand Therapy for mCRPC​
  A randomized phase 3 trial is comparing 177Lu-ludotadipep (FC705) plus standard care against standard care alone in 114 patients with progressive PSMA-positive mCRPC. Ludotadipep incorporates an albumin-binding moiety that extends blood circulation, enabling high tumor radiation absorption at approximately half the administered activity per cycle of Pluvicto (177Lu-PSMA-617). In a prior phase 2 study, multi-cycle administration demonstrated a 46.7% confirmed PSA50 response rate (and a 73.3% unconfirmed response rate) among 15 evaluable patients while remaining within organ radiation safety limits.
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• Phase 3 Trial Analysis: Decipher Genomic Classifier for ADT Personalization​
  A retrospective biomarker analysis of 395 patients from the randomized phase 3 NRG/RTOG 0815 trial indicates that the Decipher genomic classifier can identify which intermediate-risk prostate cancer patients derive significant benefit from adding short-term ADT to dose-escalated radiotherapy. Over a median follow-up of 10.2 years, adding ADT to patients with intermediate or high Decipher scores reduced the absolute 10-year distant metastasis risk by 8 percentage points, compared to an absolute reduction of only ~1 percentage point in men with low Decipher scores. These molecular selection criteria are being tested prospectively in the phase 3 NRG-GU010 GUIDANCE trial.
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Preclinical Research & Reviews

• Reversing Hormone Resistance via tRNA 1 Arg(UCU)​
  Research published in Nature revealed that a specific transfer RNA, tRNA 1 Arg(UCU), serves as a crucial epigenetic regulator of androgen receptor signaling and hormone therapy resistance in prostate cancer. Abundant in androgen-driven tumors, tRNA levels decline as disease progresses into aggressive, neuroendocrine-like states. Experimentally restoring tRNA 1 Arg(UCU) levels reprogrammed resistant cells back into a hormone-dependent state and restored sensitivity to enzalutamide, whereas tRNA depletion led to a fourfold increase in metastases in animal models through SWI/SNF chromatin remodeling complexes.
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• Targeting CALB2 to Disrupt Mechanical Shear Stress Resistance​
  A preclinical study revealed that circulating prostate cancer cells adapt to high fluid shear stress in the bloodstream by upregulating CALB2, which encodes the calcium-binding protein calretinin. PC3 prostate cancer cells subjected to mechanical fluid selection demonstrated enhanced survival and aggressive in vivo behavior. When researchers knocked out CALB2 using CRISPR technology, cell survival following mechanical shear stress dropped sharply to 35.6% compared to 77–79% in control cells, establishing CALB2 as a potential target to make circulating metastatic cells mechanically fragile.
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• Gallic Acid Suppression of the NF-κB/KLF7/L1CAM Signaling Axis​
  Preclinical investigation identified the NF-κB/KLF7/L1CAM axis as a key driver of prostate cancer proliferation, invasion, and metastatic migration. The natural plant polyphenol gallic acid was shown to bind to the NF-κB p65 subunit and inhibit its phosphorylation, thereby downregulating downstream KLF7 and L1CAM expression in PC-3 and LNCaP cell lines without harming normal prostate stromal cells. In mouse models, oral gallic acid significantly reduced tumor volume and weight with antitumor potency comparable to enzalutamide or bicalutamide.
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• De Novo Biological Design via AlphaProtein Novo AI​
  Beyond predicting existing protein structures, the artificial intelligence system AlphaProtein Novo utilizes machine learning to design entirely novel enzymes and amino-acid sequences tailored for specific catalytic functions. In initial benchmarks, the system created de novo enzymes capable of performing new-to-nature reactions—such as selective piperidine synthesis and environmental DEHP degradation—achieving performance comparable to or exceeding natural enzymes. This preclinical breakthrough establishes a foundation for future oncology applications, including engineering bespoke enzymes designed to selectively activate prodrugs or degrade critical tumor metabolites within microenvironments.

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

Max