LAST WEEK TODAY!

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

Hi fellow warriors! Get ready, folks! This newsletter is going to be veeeery long and packed with news. This year too, the ESMO conference brings us plenty of updates, both on clinical trials and on preclinical and observational studies. 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.
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Clinical Research

• Phase 3 Trial: EMBARK Trial Enzalutamide Combination​
  The Phase 3 EMBARK trial investigated the use of enzalutamide combined with standard hormone therapy for men with biochemically recurrent prostate cancer (BRPC) who had no detectable metastases on conventional imaging. This combination treatment demonstrated a significant clinical breakthrough, reducing the risk of death by more than 40% over eight years compared to hormone therapy alone. The efficacy of blocking androgen receptor signaling with enzalutamide in this population, where hormone therapy alone previously lacked a survival benefit, is poised to redefine the standard of care for high-risk BRPC patients.
• Phase 3 Trial: ARASAFE Regimen for mHSPC​
  The Phase 3 ARASAFE trial evaluated an innovative, alternative docetaxel dosing regimen (50 mg/m² every 2 weeks) combined with darolutamide and androgen deprivation therapy (ADT) for metastatic hormone-sensitive prostate cancer (mHSPC). The goal was to maintain efficacy while reducing the severe toxicities associated with the standard docetaxel schedule (75 mg/m² every 3 weeks). The alternative regimen achieved a statistically and clinically significant reduction in grade 3 to 5 adverse events (61.2% versus 78.9%), including dramatically lower rates of grade 3-4 neutropenia and death rates (24.0% versus 64.1%). Crucially, this improved safety was achieved while maintaining comparable oncologic outcomes across secondary efficacy endpoints, positioning the ARASAFE regimen as a potential new standard of care.
• Phase 3 Trial: ENZARAD Enzalutamide Intensification​
  The final results of the Phase 3 ENZARAD study evaluated the intensification of ADT and radiation with the androgen receptor inhibitor enzalutamide for high-risk localized or locally advanced prostate cancer. While the therapy did not significantly improve metastasis-free survival (MFS) in the overall population after eight years of follow-up (MFS was 74% with enzalutamide versus 72% in the control group), subgroup analyses revealed a clear benefit for patients with clinically node-positive (N1) disease or those receiving pelvic nodal irradiation. In these more advanced regional disease subgroups, five-year MFS reached 87% with enzalutamide compared with 77% in the control group, justifying the targeted use of the agent alongside ADT and radiation in specific patient cohorts.
• Phase 3 Trial: PRESTO Trial Apalutamide Progression-Free Survival​
  The Phase 3 PRESTO trial evaluated androgen blockade intensification using apalutamide (an androgen receptor inhibitor) added to ADT for high-risk biochemically relapsed prostate cancer patients who had no detectable metastases. Adding apalutamide to ADT significantly prolonged prostate-specific antigen progression-free survival (PSA-PFS) compared to ADT alone, improving the median PSA-PFS from about 20 months to nearly 25 months. Although a triple therapy regimen including abiraterone showed a marginally longer PSA-PFS, it led to higher toxicity (especially hypertension) and did not offer a clear clinical benefit beyond the ADT plus apalutamide regimen, supporting the latter as the effective and manageable treatment intensification strategy.
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• Phase 3 Trial: PSMAddition Trial Pluvicto​
  The Phase III PSMAddition trial assessed the innovative mechanism of Pluvicto (Lutetium-177, a radioligand therapy) in combination with standard hormonal therapy for PSMA-positive metastatic hormone-sensitive prostate cancer. The addition of Pluvicto to hormonal therapy reduced the risk of radiographic disease progression or death by 28 percent. Patients receiving the radioligand combination showed greater tumor response, with complete responses observed in 57.1 percent compared to 42.3 percent on hormonal therapy alone, and the treatment successfully delayed progression to the castration-resistant stage.
• Phase 2 Trial: ENV-105 CD105 Antagonist Interim Results​
  Interim efficacy results from an ongoing Phase 2 clinical trial of ENV-105 (carutoximab), a first-in-class CD105 antagonist, showed promising potential for metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed on prior hormone therapies. ENV-105 works by antagonizing CD105 (endoglin), a protein linked to resistance, thereby appearing to restore sensitivity to hormone therapy. Among treated patients, 86% experienced clinical benefit, and the median progression-free survival (PFS) of approximately 13 months notably surpasses the typical median PFS of about 3.7 months seen with standard second or third-line hormone therapies in this population.
• Phase 1/2 Trial: AlphaBet Dual Radionuclide Therapy​
  The Phase 1/2 AlphaBet study evaluated a novel dual radionuclide therapy combining lutetium-177 (177Lu−PSMA−I&T) and radium-223 (223Ra) for mCRPC, specifically targeting bone-dominant disease. This combination simultaneously uses the beta emitter (177Lu) for PSMA-expressing tumor cells and the alpha emitter (223Ra) for bone metastases. The approach was well tolerated, with no dose-limiting toxicities observed, and demonstrated a robust antitumor effect, with over 50% of patients achieving a PSA decline of at least 50%.
• Phase 1/2 Trial: PETRANHA Trial Saruparib (PARP1 Inhibitor)​
  The Phase 1/2 PETRANHA trial introduced saruparib (AZD5305), a highly selective PARP1 inhibitor, designed to minimize the myelosuppressive side effects of earlier broad-spectrum PARP inhibitors. When combined with ARPIs, saruparib showed strong efficacy signals in metastatic castration-sensitive prostate cancer (mCSPC) patients, achieving an objective response rate (ORR) of 88.5%, with undetectable PSA levels in 83%. Importantly, efficacy signals were observed in both HRR-mutated and wild-type tumors, suggesting a broad clinical utility extending beyond traditional biomarker selection. Following these promising results, saruparib is advancing into the global Phase 3 EvoPAR‑Prostate01 study.
• Phase 1/2 Trial: Gedatolisib Plus Darolutamide Combo​
  A Phase 1/2 trial is evaluating the combination of gedatolisib (an inhibitor of the PI3K/AKT/mTOR pathway) with darolutamide (an androgen receptor antagonist) for mCRPC. Gedatolisib’s innovative mechanism involves a comprehensive blockade of the PI3K/AKT/mTOR pathway by inhibiting all four class I PI3K isoforms and both mTOR complexes, aimed at overcoming resistance mechanisms. Early data indicated encouraging preliminary efficacy, showing a 6-month radiographic progression-free survival rate of 66%. The safety profile was favorable, with no treatment discontinuations and notably, no grade 3 hyperglycemia, a common issue with other PI3K inhibitors.
• Phase 1b Trial: ADVC001 Lead-212 Alpha Therapy​
  New clinical data from a Phase 1b dose escalation trial of ADVC001, a novel Lead-212-based PSMA-targeted alpha therapy (a form of radioligand therapy), demonstrated a favorable safety profile with no dose-limiting toxicities in mCRPC. This therapy uses the highly potent alpha-emitting isotope Lead-212 to maximize tumor cell kill. Efficacy signals were strong, with approximately 80% of patients receiving higher doses experiencing at least a 50% reduction in PSA, and all patients with measurable tumors demonstrating objective responses, including two complete responses. These findings represent the first clinical data for a Lead-212 PSMA-targeted alpha therapy.
• Phase 1 Trial: Alpha Radioligand Therapy AB001 (ARTISAN trial)​
  The Phase 1 ARTISAN trial is evaluating AB001, an investigational lead-212 (212Pb) alpha radioligand therapy targeting PSMA in mCRPC patients. This mechanism utilizes the alpha-emitting isotope 212Pb, which delivers highly localized, high-energy radiation, with preclinical findings suggesting it may offer stronger tumor control compared to beta-emitting agents like 177Lu−PSMA (Pluvicto). The trial includes patients who are both naïve to and previously treated with 177Lu−PSMA.

Preclinical Research & Reviews

• mRNA-Based Vaccines Enhance Immunotherapy​
  Retrospective clinical data presented at the 2025 ESMO Congress, analyzing over 1,000 cancer patients, indicated that mRNA-based COVID-19 vaccines can significantly improve outcomes for patients undergoing immunotherapy. Patients receiving an mRNA vaccine around the time of starting immune checkpoint inhibitors (within 100 days) had double the likelihood of surviving three years. This immune-stimulating effect was particularly strong in “immunologically cold” tumors, where vaccinated patients saw nearly a five-fold improvement in long-term survival, supported by preclinical data showing mRNA vaccination upregulating PD-L1 expression.
• ARON-3 Triplet Therapy in mHSPC​
  Real-world data from the international retrospective ARON-3 study confirmed the advantage of triplet therapy (ADT + ARPIs + docetaxel) in high-volume metastatic hormone-sensitive prostate cancer (mHSPC) with bone metastases. The study showed that triplet therapy provided a 56% reduction in the risk for treatment failure and a 50% survival benefit compared to doublet treatment in patients with more than 10 bone metastases or visceral metastases. For patients with lower metastatic burden (10 or fewer bone metastases), doublet and triplet regimens yielded comparable outcomes, emphasizing the need to tailor therapeutic intensity based on metastatic extent.
• KLS-3021 Oncolytic Virus Therapy​
  ​KLS-3021 is a novel oncolytic virus therapy using a recombinant vaccinia virus engineered for prostate cancer treatment. Its innovative mechanism involves carrying three therapeutic genes (PH-20, IL-12, and sPD1-Fc) designed to stimulate anti-tumor immune responses, inhibit immune checkpoints, and degrade the extracellular matrix. Preclinical studies demonstrated that a single administration significantly reduced tumor size, outperforming the chemotherapy drug docetaxel, and showed efficacy in tumors with lymph node metastases. KLS-3021 is currently moving toward Phase 1 clinical trials.
• Role of AI in Cancer Treatment and Biomarker Discovery​
  The ESMO Congress 2025 highlighted the pivotal role of artificial intelligence (AI) in transforming cancer treatment through novel biomarker applications. AI models are now used to analyze pathology images, imaging data, and genomic profiles to improve predictions of patient responses to therapies, such as identifying patients likely to benefit from immune checkpoint inhibitors or PARP inhibitors in various cancer types. This research underscores a shift toward precision oncology, utilizing AI tools to provide objective, reproducible, and early prediction of treatment benefits and risks.
• Rapid Genome Sequencing​
  A collaborative effort achieved a world record for sequencing and analyzing a whole human genome in under four hours, demonstrating that complete genomic workflows can be finished in less than eight hours from sample to result. This advance in genomic technology, using SBX sequencing, is transitioning genomics from the research environment into urgent care settings, allowing same-day sequencing to guide time-sensitive medical decisions and integrating precision medicine within the operational rhythm of intensive care.

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