LAST WEEK TODAY!

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

Hi fellow warriors! Get ready, folks! I knew I shouldn’t have used up all the best articles last week! This week seems rather poor in comparison, but fear not…the research goes on! 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 of 177Lu-PSMA-617 with Sipulecel-T​
  City of Hope Medical Center, collaborating with the National Cancer Institute, is initiating a randomized phase 1 study in metastatic castration-resistant prostate cancer (mCRPC). This trial compares lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617 or Pluvicto) alone versus the radioligand combined with sipuleucel-T. The primary objectives are to quantify the induced anti-tumor immune response alongside safety and early efficacy signals. Specifically, the prespecified primary endpoint is the anti-prostatic acid phosphatase (PAP) immunoglobulin G (IgG) response rate. Patients in both arms receive 177Lu-PSMA-617 intravenously every six weeks for up to six cycles, while the experimental arm adds sipuleucel-T starting in week eight, administered every two weeks for up to three infusions. The scientific rationale for this combination is based on the capacity of targeted radionuclide therapy to provoke immunogenic cell death and remodel the tumor microenvironment. Timing the sipuleucel-T addition after initial 177Lu-PSMA-617 cycles aligns with preclinical and translational insights suggesting that sequential priming by radiopharmaceuticals followed by immune augmentation optimizes antigen release and microenvironmental shifts while limiting radiation exposure to the immune effectors.
  ​
• Phase 1/2 Trial of HLD-0915 for Drug-Resistant mCRPC​
  Encouraging early results have been reported for HLD-0915, a novel oral therapy for metastatic castration-resistant prostate cancer (mCRPC), derived from a first-in-human clinical trial. HLD-0915 employs regulated induced proximity targeting chimera (RIPTAC) technology. This first-in-class approach targets both the androgen receptor (AR) and BRD4 simultaneously, aiming to suppress crucial drivers of disease progression and overcome resistance mechanisms that activate alternate survival pathways when AR signaling is conventionally inhibited. Results showed that 59% of participants who completed at least two treatment cycles achieved a PSA50 response (at least 50% reduction in prostate-specific antigen levels), with 32% achieving PSA90 responses. Furthermore, all patients with measurable soft tissue lesions, based on RECIST criteria, showed partial responses at the first imaging assessment, and one patient with both bone and soft tissue involvement experienced complete resolution of soft tissue disease.
  ​

​

Preclinical Research & Reviews

• Helicon Degraders Targeting the ERG Oncogenic Driver​
  The discovery of a novel peptide-based degrader within the Helicon class represents a major advance in prostate cancer biology by achieving the potent and selective elimination of the transcription factor ERG. ERG is an oncogenic driver that was long considered unreachable by medicinal chemistry. A single administration of the ERG Helicon degrader led to persistent suppression of ERG activity for at least a week. The implication for therapy is significant, as ERG fusions are associated with resistance to standard androgen receptor-directed drugs; integrating ERG degradation with complementary approaches could potentially overcome adaptive resistance and deliver deeper tumor control in advanced prostate cancer.
  ​
• pre|CISION Platform for Dual-Payload Delivery The pre|CISION® platform is a novel dual payload peptide drug conjugate technology designed to deliver two complementary anticancer therapies from a single molecule. This technology achieves targeted delivery by leveraging the fibroblast activation protein (FAP), which is selectively present within the tumor microenvironment, especially in advanced prostate cancers like castration-resistant prostate cancer. FAP is highly expressed by cancer-associated fibroblasts in the tumor stroma, allowing for precision targeting while minimizing systemic toxicity. The dual-payload design includes combinations such as microtubule inhibition (monomethyl auristatin E or MMAE) paired with topoisomerase I inhibition (exatecan), both of which are potent against androgen-independent prostate cancer models. Another promising strategy pairs topoisomerase I inhibition with DNA damage response (DDR) inhibitors (like PARP or ATR inhibitors), exploiting common genetic defects in metastatic prostate cancer. Preclinical data show that this dual approach results in a 4-5 fold increase in tumor cell killing compared to single-agent treatment, directly counteracting resistance mechanisms.

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.

If you this newsletter was delivered to your SPAM folder, make sure to let your email system know that it is not spam.
​
​
Have a great weekend!

Max