LAST WEEK TODAY!

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

Hello fellow warriors! Before we dive into a new weeks of trials and research…
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Clinical Research

• Phase 1 Trial: EZH2 Degrader AXT-1003 Combined with Enzalutamide in Metastatic Prostate Cancer​
  A new open-label, nonrandomized Phase 1a/1b trial is investigating AXT-1003, an oral EZH2 degrader, in combination with enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC). AXT-1003 features a dual mechanismthat both inhibits EZH2 enzymatic activity and degrades the EZH2 protein via the ubiquitin–proteasome pathway, aiming to disrupt epigenetic mechanisms driving lineage plasticity and resistance to androgen receptor (AR)-targeted therapies. Preclinical data presented at AACR 2026 demonstrated synergistic antitumor activity when combined with enzalutamide in mouse xenografts. Early Phase 1 monotherapy data presented at ESMO 2026 confirmed target engagement across solid tumors.
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• Phase 1 Trial: ROR1-Targeting ADC HDM2005 in Heavily Pretreated mCRPC​
  Early results from a multicenter, open-label Phase 1 trial presented at ESMO 2026 evaluated HDM2005, an antibody-drug conjugate (ADC) targeting ROR1 carrying a monomethyl auristatin E (MMAE) payload, in heavily pretreated mCRPC patients. Among 17 treated patients, nearly 95% of whom had received at least three prior lines of therapy, evaluable patients achieved a 30% partial response rate (3/10) and an 80% disease control rate, with 56.3% (9/16) achieving a PSA reduction of at least 30% and 25% achieving a PSA reduction of at least 50%. However, toxicity was substantial, even if no treatment-related deaths or treatment-related discontinuations were reported.
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• Phase 1/2 Trial: STAR0602 Plus Nivolumab Investigated in Metastatic Prostate Cancer​
  A newly registered Phase 1b/2 trial will evaluate invikafusp alfa (STAR0602) combined with the PD-1 inhibitor nivolumab in patients with mCRPC. STAR0602 is a bifunctional antibody–cytokine fusion protein that selectively targets specific groups of T cells to activate them and help them multiply. The trial aims to test whether combining STAR0602 with nivolumab can overcome resistance to immune checkpoint blockade.
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• Phase 2 Trial: TIDE-PC Evaluates Testosterone-Guided ADT De-Escalation​
  The newly registered single-arm Phase 2 TIDE-PC trial will evaluate whether men with metastatic hormone-sensitive prostate cancer (mHSPC) who have maintained a prolonged response to therapy can safely reduce androgen deprivation therapy (ADT) injection frequency. The trial plans to enroll 56 patients who have received continuous ADT combined with an androgen receptor pathway inhibitor (ARPI) for at least 18 months and maintain PSA levels below 4 ng/mL and testosterone below 50 ng/dL. Unlike traditional intermittent ADT, TIDE-PC will use serum testosterone levels to guide treatment, withholding scheduled GnRH agonist injections while testosterone remains below castrate levels (<50 ng/dL) while continuing ARPI therapy uninterrupted.
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• Phase 3 Trial: ProBio Trial Demonstrates Benefit of Niraparib Plus Abiraterone in BRCA-Mutated mCRPC​
  Findings from the randomized Phase 3 ProBio platform trial evaluated niraparib combined with abiraterone and prednisone versus standard care in 99 mCRPC patients categorized by circulating tumor DNA (ctDNA) profiling. Among homologous recombination repair (HRR)-positive patients, the combination extended median time to no longer clinically benefiting (NLCB) to 19.1 months versus 14.4 months for standard care. The greatest clinical benefit occurred in patients with BRCA1/2 alterations (median NLCB of 15.3 vs 7.0 months), whereas TP53-mutated patients derived no meaningful benefit. Overall survival in the HRD-positive cohort was similar between treatment arms (24.4 vs 24.9 months).
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• Phase 3 Trial: JNJ-6143 RIPTAC Therapy Advances with Overall Survival Endpoint​
  A double-blind, randomized Phase 3 trial is evaluating oral JNJ-6143, a first-in-class Regulated Induced Proximity Targeting Chimera (RIPTAC) therapy, plus best supportive care versus placebo in approximately 400 patients with mCRPC. JNJ-6143 acts by bringing the androgen receptor (AR) into an abnormal complex with BRD4, exploiting AR expression to disrupt cell function and trigger cell death. The trial’s primary endpoint is overall survival. The decision to advance JNJ-6143 to Phase 3 follows Phase 1 data (just presented at ESMO 2026) at the 50 mg daily dose showing a 77% PSA50 response rate and a 75% objective radiographic response rate in heavily pretreated patients.
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• Metabolic Blood Profiles May Predict Survival and Treatment Response​
  An exploratory metabolomic analysis of blood samples from 166 mCRPC patients in the randomized SAKK 08/14 trial(enzalutamide vs. enzalutamide plus metformin) evaluated circulating blood metabolites. The analysis identified no metabolic signature predicting additional benefit from adding metformin to enzalutamide, consistent with main trial results showing no overall survival improvement.
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• Identification of a Potential Immunotherapy Window During Androgen Deprivation Treatment​
  An observational translational study published in the Journal for ImmunoTherapy of Cancer analyzed prostatectomy tissue from 43 patients who received neoadjuvant ADT. The study identified a transient window of peak immune activation at 3–5 months of ADT, characterized by enhanced antigen presentation and dense infiltration of CD8+ and CD4+ T cells near tumor cells. Beyond 6 months of ADT, immune activation waned as immunosuppressive M2-like macrophages and regulatory T cells became predominant, suggesting that combining immune checkpoint inhibitors with early ADT may optimize treatment timing.
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Preclinical Research & Reviews

• Rinzimetostat Limits Lineage Plasticity and Restores Therapeutic Targets​
  Preclinical and translational findings presented at ESMO 2026 evaluated rinzimetostat (ORIC-944), an experimental epigenetic inhibitor targeting the EED subunit of the PRC2 complex. In preclinical models, rinzimetostat prevented lineage plasticity, reinforced AR-dependent cell characteristics, increased sensitivity to AR inhibitors, and retained activity against EZH2-mutant cells. Analysis of paired biopsies and ctDNA from mCRPC patients treated with rinzimetostat showed increased AR signaling and elevated expression of PSMA and KLK2 therapeutic targets.
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• 177Lu-M3-12 Demonstrates Higher Tumour Uptake Than 177Lu-PSMA-617​
  A preclinical study published in EJNMMI Research reports results for 177Lu-M3-12, an experimental PSMA-targeted radioligand incorporating a hydrophilic linker. In mouse models bearing PSMA-positive LNCaP prostate cancer tumors, 177Lu-M3-12 achieved a tumour uptake of 44.69% of the injected dose per gram at 24 hours compared with 24.09% for 177Lu-PSMA-617 (Pluvicto), representing 1.85 times greater tumor accumulation. It also demonstrated a 2.73 times higher tumour-to-kidney uptake ratio and dose-dependent antitumour activity up to 29.6 MBq without significant toxicity, suggesting molecular modifications can improve tumor radiation delivery while sparing healthy organs.
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• ADCT-241 PSMA-Targeted ADC Exhibits Bystander Activity​
  A preclinical study published in Molecular Cancer Therapeutics investigated ADCT-241, an antibody–drug conjugate combining a PSMA-targeting antibody with an exatecan topoisomerase I inhibitor payload. ADCT-241 demonstrated antitumor activity in prostate cancer cell lines and patient-derived xenograft mouse models. Notably, researchers observed a bystander killing effect, where released cytotoxic payload damaged neighboring PSMA-negative cells, offering a novel approach to treat tumors with heterogeneous PSMA expression.
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And…that’s all folks! For today at least!
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Have a great weekend!

Max