LAST WEEK TODAY!

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

Hi fellow warriors! Research really picked up over the past week, we’re diving into new discoveries at full speed now. 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

• Clinical StudiesAnti-PD-L1 Therapy for MMR-Deficient mCRPC​
  A recent study explored anti-PD-L1 immunotherapy, utilizing drugs such as atezolizumab or durvalimab, for men diagnosed with metastatic castration-resistant prostate cancer (mCRPC) who possess DNA mismatch repair (MMR) deficiencies. This genetic characteristic, found in approximately 5% of advanced mCRPC cases, often correlates with microsatellite instability-high (MSI-H) status, which makes the tumors more susceptible to immune recognition. Unlike the majority of mCRPC cases that typically resist immune-based treatments, this subgroup showed promising results: an objective response rate of 46% and 60% achieving a PSA-50 decline. The therapy also led to a median progression-free survival of 7.7 months and a median overall survival of 27 months. The study underscores the importance of genetic testing to identify MMR deficiencies for personalized treatment approaches.
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• Decipher Test as a Predictor for Chemotherapy Benefit​
  New research from the multicenter, prospective, phase 3 STAMPEDE trial, published in Cell, highlights the Decipher Prostate Genomic Classifier as a significant tool for guiding treatment decisions in metastatic prostate cancer, particularly in predicting which patients will benefit from chemotherapy with docetaxel. This 22-gene panel, developed via RNA whole-transcriptome analysis, demonstrated that metastatic patients with a high Decipher score experienced substantially improved survival when docetaxel was added to standard androgen deprivation therapy, a benefit not observed in those with lower scores. This predictive capability remained consistent across both low- and high-volume metastatic subgroups. Further analysis revealed that patients with PTEN-inactive tumors, when combined with a high Decipher score, saw a 45% reduction in the risk of death with docetaxel, a subgroup representing 28% of the metastatic tumors studied.
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• PSA Nadir at 6 Months as a Long-Term Survival Predictor in CHAARTED Trial​
  A long-term, post hoc analysis of the CHAARTED trial, updated with 10-year survival data, confirmed that achieving a prostate-specific antigen (PSA) nadir below 0.2 ng/mL at six months is a powerful predictor of long-term outcomes in metastatic hormone-sensitive prostate cancer (mHSPC). Patients who reached this low PSA threshold experienced more than double the median overall survival compared to those whose PSA remained at or above 0.2 ng/mL, and the benefit was consistent across all prespecified subgroups. Overall, in the ADT + Docetaxel group OS was 100.3 vs. 45.4 months, in the ADT alone group: 116.8 vs. 31.8 months.
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• Xaluritamig (AMG 509) in mHSPC Clinical Trial​
  Xaluritamig (AMG 509), an innovative bispecific T-cell engager immunotherapy, is currently undergoing a Phase 1 clinical trial for metastatic hormone-sensitive prostate cancer (mHSPC) in combination with existing androgen receptor pathway inhibitors (ARPIs) such as abiraterone and darolutamide. This drug is designed to bridge the body’s immune system with cancer cells by targeting STEAP1, a protein highly expressed on prostate cancer cells, and CD3 on T cells, initiating a precise immune attack. Building on encouraging early results in metastatic castration-resistant prostate cancer (mCRPC), where Xaluritamig monotherapy showed a 41% response rate in heavily pretreated patients, this trial aims to evaluate its safety, tolerability, and effectiveness in mHSPC. The study will monitor tumor shrinkage, time to disease progression, overall survival, and PSA level reductions, with the potential to redefine treatment and delay progression to mCRPC.
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• Lartesertib and Tuvusertib Targeting DNA Repair in mCRPC​
  A Phase 1 clinical trial is currently evaluating Lartesertib and Tuvusertib, both administered orally, in men with metastatic castration-resistant prostate cancer (mCRPC), particularly those harboring ATM mutations. These drugs operate by disrupting the DNA damage response (DDR) system, which cancer cells rely on to repair DNA and evade treatments. Specifically, Lartesertib inhibits ATM (ataxia telangiectasia mutated), a protein critical for fixing double-strand DNA breaks, while Tuvusertib targets ATR (ataxia telangiectasia and Rad3-related), which manages DNA damage during cell division. Given that 20–30% of mCRPC cases have DDR gene mutations like ATM, these tumors are vulnerable to such targeted therapies. Preclinical findings suggest that ATM-deficient tumors are highly sensitive to ATR inhibitors like Tuvusertib, and combining it with ATM inhibitors like Lartesertib may create a “double hit” effect, overwhelming the cancer cells’ repair mechanisms.
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• SPIDERMAN Trial for mHSPC with Supraphysiologic Testosterone and Darolutamide​
  The SPIDERMAN trial, a Phase 2 study, is investigating a novel first-line treatment for men with metastatic hormone-sensitive prostate cancer (mHSPC): the combination of supraphysiologic testosterone therapy and darolutamide. This approach is rooted in the concept of bipolar androgen therapy (BAT), which involves alternating between high and low testosterone levels to modulate the androgen receptor’s adaptive responses. The earlier BATMAN study showed that BAT was safe in mHSPC patients and could extend the period of hormone sensitivity. The SPIDERMAN trial seeks to determine if combining BAT with darolutamide, an androgen receptor inhibitor known for its minimal central nervous system activity and potentially fewer side effects like seizures, can further prolong the duration of response and reduce adverse effects.

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Preclinical Research

• The Promise of In Vivo CAR T Cell Therapies​
  In vivo CAR T cell therapies are currently undergoing their first-ever human clinical trials, signifying a potential revolutionary advancement in cancer treatment. Traditional CAR T cell therapies, while effective for certain blood cancers, are prohibitively expensive, costing up to $400,000 per dose, and logistically complex, resulting in less than 20% of eligible patients globally receiving treatment. The in vivo approach seeks to overcome these barriers by modifying T cells directly inside the patient’s body, essentially transforming the patient into a “CAR T cell factory”. This innovation aims to drastically reduce the cost and complexity, making CAR T cell therapy accessible to millions more cancer patients worldwide. Successful outcomes in these Phase 1 trials could pave the way for expanding CAR T cell therapy into challenging areas like solid tumors and even other serious conditions such as autoimmune diseases.
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• Plant Virus-Based Cancer Immunotherapy with Cowpea Mosaic Virus​
  Scientists at the University of California, San Diego, have identified the Cowpea Mosaic Virus (CPMV), a plant-specific virus harmless to humans, as a powerful agent for supercharging the immune system to target cancer. When directly injected into a tumor, CPMV acts as a potent immune stimulant, attracting immune cells like neutrophils, macrophages, and natural killer cells and triggering the release of interferons. This systemic immune activation not only helps destroy the treated tumor but also facilitates the eradication of cancer cells at distant sites and establishes long-lasting immune memory. CPMV’s efficacy has been demonstrated across various cancers in preclinical studies involving mice and dogs. Its advantages include its broad effectiveness, inherent safety in humans, cost-effective production in plants, and the potential to fight cancer systemically with fewer side effects.

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