LAST WEEK TODAY!

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

Hi fellow warriors! This week we have six interesting clinical trials. I’ve had a very busy week (one of my dogs is seriously ill and I’ve been at the vet very often!) and the preclinical research I managed to read is very interesting but very early-stage… so no, no preclinical studies this week! 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: 177Lu-DGUL Plus Pembrolizumab (Keytruda) in mCRPC​
  A pivotal clinical trial, dubbed KEYNOTE-G28, is currently underway to evaluate the safety and efficacy of combining Lutetium (177Lu) DGUL radioligand therapy with pembrolizumab (Keytruda) for patients with metastatic castration-resistant prostate cancer (mCRPC). This study enrolls men with PSMA-positive tumors whose disease has progressed after androgen receptor-targeted therapies but who have not yet received chemotherapy. 177Lu-DGUL specifically targets the prostate-specific membrane antigen (PSMA) to deliver targeted beta radiation to tumor DNA, while its compact thiourea linker is designed to cut kidney exposure compared to rival agents like Pluvicto. In prior phase 2 monotherapy, DGUL showed significant efficacy, including an 81% tumor response rate by PET criteria and nearly 9% complete remissions. The combination is predicated on the synergy where radiation from lutetium-177 induces immunogenic cell death, which primes tumors by boosting PD-L1 expression and danger signals, thereby enhancing T-cell activation provided by the PD-1 blocker, pembrolizumab.​
  ​
• Phase 1 Trial: GenSci143 Bispecific ADC​
  The Phase 1 dose-escalation study for GenSci143, a novel bispecific antibody-drug conjugate (ADC) targeting both B7-H3 and PSMA, is set to begin first-in-human clinical trials soon, with the estimated start date being December 20. This trial will enroll participants with advanced solid tumors, including metastatic castration-resistant prostate cancer (mCRPC), to evaluate its safety, tolerability, pharmacokinetics, and preliminary efficacy. The initiation of this study was authorized following recent regulatory approvals granted by the U.S. FDA and China’s National Medical Products Administration in late 2025. By simultaneously engaging two validated antigens (B7-H3 and PSMA) on tumor cells, this dual-target construct is designed to overcome the tumor heterogeneity and resistance often observed with therapies that target only a single antigen. Preclinical studies have supported this advancement by showing promising antitumor activity and a favorable safety profile.​
  ​
• Phase 1/2 Trial: MK-6070 Trispecific T-Cell Engager​
  MK-6070, an engineered trispecific T-cell engager, is currently being investigated in phase 1/2 clinical trials to determine its safety and efficacy in patients with DLL3-positive neuroendocrine cancers, including neuroendocrine prostate cancer (NEPC). The molecule targets a protein called DLL3, which is predominantly expressed on these aggressive tumors. MK-6070’s structure allows it to bind simultaneously to DLL3 on tumor cells and the CD3 receptor on T cells, effectively recruiting and activating the patient’s immune cells to destroy cancer cells. It also incorporates an albumin-binding domain, a feature intended to extend the drug’s circulation time and potentially enable less frequent dosing compared to similar molecules. Preclinical studies demonstrated potent cytotoxic effects, T cell activation, and the induction of cytokine release, alongside the capacity to orchestrate the killing of neighboring tumor cells lacking DLL3 via cytokine-mediated bystander mechanisms, a crucial feature for overcoming tumor heterogeneity.​
  ​
• Phase 1/2 Trial: Valemetostat Plus Darolutamide in mCRPC​
  A combined phase 1/2 clinical trial is initiating recruitment for men with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed following prior androgen receptor pathway inhibitors (ARPIs). This international study, targeting 60 patients, investigates the safety, tolerability, and preliminary efficacy of valemetostat (DS-3201b), a dual EZH1/2 inhibitor, in combination with the AR antagonist darolutamide. Valemetostat works by inhibiting both EZH1 and EZH2, targeting the Polycomb repressive complex 2 (PRC2) to prevent the EZH1 compensation that limits the effectiveness of EZH2-only blockers, thereby reducing repressive H3K27me3 marks. Since EZH2 overexpression often drives ARPI resistance and promotes neuroendocrine phenotypes in prostate cancer, the dual pathway blockade aims to be synergistic in overcoming resistance.​
  ​
• Phase 2 Trial: Fasudil Hydrochloride Plus PD-1 Immune Checkpoint Blockade​
  A Phase 2 open-label clinical trial is testing the combination of fasudil hydrochloride, a Rho-associated kinase (ROCK) inhibitor, with PD-1 immune checkpoint blockade for patients with advanced metastatic castration-resistant prostate cancer (mCRPC) who have previously progressed after chemotherapy and standard novel endocrine therapy. The underlying strategy of the combo focuses on overcoming the highly immunosuppressive tumor microenvironment prevalent in mCRPC. As a ROCK inhibitor, fasudil normalizes dysfunctional tumor blood vessels and improves oxygenation, leading to enhanced blood flow and immune cell infiltration. Crucially, fasudil reprograms pro-tumoral M2 macrophages to the pro-inflammatory M1 phenotype, thereby enhancing anti-tumor immunity that synergizes with the PD-1 blockade agent (likely triprilizumab or a similar monoclonal antibody). The ultimate goal is to modify the tumor stroma, enhance immune access, and convert immunologically “cold” tumors, which typically respond poorly to PD-1 inhibitors alone, into responsive “hot” tumors.​
  ​
• GTB-5550 Tri-Specific Natural Killer Cell Engager​
  GTB-5550 is a novel tri-specific natural killer (NK) cell engager drug that is currently in late preclinical development and is moving toward clinical evaluation, with the first patient enrollment forecasted by April 2026. This drug is designed to target the B7-H3 antigen, which is commonly overexpressed in aggressive solid tumors, including advanced prostate cancer. The tri-specific design ensures that GTB-5550 simultaneously binds to CD16 on NK cells, engages the B7-H3 on tumor cells, and delivers an interleukin-15 (IL-15) signal that supports NK cell activation and survival. Preclinical models demonstrated the drug’s strong capacity to induce NK cell cytotoxicity, cytokine production, and degranulation against tumor cells, even under suppressive conditions such as hypoxia and the presence of myeloid-derived suppressor cells (MDSCs). In prostate cancer models, it has shown potential to overcome resistance to androgen receptor pathway inhibitors.​
  ​

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 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