LAST WEEK TODAY!

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

Hi fellow warriors! As you may have noticed, I have started writing about the research results that will be presented at ASCO 2025. And I still have many more to review and write about! I had to condense the information in this newsletter, so I recommend visiting the website prostatewarriors.com if you want more in-depth information! 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

• Enzalutamide Offers Long-Term Survival Benefit in ENZAMET Trial​
  The Phase 3 ENZAMET trial (NCT02446405), with a median follow-up of 98 months, demonstrated that adding enzalutamide to testosterone suppression—with or without early docetaxel—significantly prolonged overall survival in men with metastatic hormone-sensitive prostate cancer (mHSPC) compared to standard non-steroidal anti-androgens (NSAAs). Enzalutamide extended median overall survival by 25 months (95 months vs. 70 months), translating to a 27% reduction in the risk of death.Clinical progression-free survival was also substantially improved, with a 51% lower risk of progression or death. A prostate-specific antigen (PSA) level of ≤0.2 ng/mL at seven months emerged as a strong predictor of favorable survival outcomes. Importantly, the long-term data reaffirmed enzalutamide’s safety profile, showing no significant increase in toxicity with prolonged use.
  ​
• Promising Early Data on MHB088C in Metastatic Prostate Cancer​
  MHB088C is currently being evaluated in an ongoing phase 1/2 clinical trial. Early data from the dose expansion phase include results from a subset of patients with metastatic castration-resistant prostate cancer (mCRPC). As of January 3, 2024, 36 heavily pretreated mCRPC patients had received at least one dose of MHB088C; all had previously been treated with novel androgen axis drugs (NAAD), and 80% had also received docetaxel. Among 21 patients with measurable disease, the objective response rate (ORR) was 14.3%, and the disease control rate (DCR) reached 95.2%. The six-month radiographic progression-free survival (rPFS) was 87%, and improvements in prostate-specific antigen (PSA) levels were also observed. Overall, MHB088C demonstrated promising anti-tumor activity in this treatment-resistant population.
  ​
• TALAPRO-2 Confirms Survival Advantage of Talazoparib–Enzalutamide Combination
  ​Final results from the Phase 3 TALAPRO-2 trial confirmed that the combination of talazoparib, a PARP inhibitor, with enzalutamide significantly improves survival in men with metastatic castration-resistant prostate cancer (mCRPC). This benefit was observed regardless of homologous recombination repair (HRR) gene mutation status. Patients receiving the combination therapy had a median overall survival of 45.8 months compared to 37.0 months with enzalutamide and placebo—a reduction in the risk of death by approximately 20%. Radiographic progression-free survival was also extended (33.1 months vs. 19.5 months). Notably, patients with HRR mutationsexperienced even greater benefits. The safety profile was consistent with prior data; while serious side effects such as anemia and neutropenia were observed, they remained manageable.
  ​
• Olaparib and Radium-223 Combo Shows Potential in COMRADE Trial​
  Initial findings from the Phase 2 COMRADE trial (NCT03317392) suggest that combining olaparib with radium-223 may significantly improve outcomes in mCRPC patients with bone metastases. The combination doubled the median radiographic progression-free survival (rPFS) to 8.6 months compared to 4.0 months with radium-223 alone.Importantly, this benefit was observed regardless of HRR gene mutation status. The therapy also extended the time to next treatment and reduced the incidence of symptomatic skeletal events within the first year. While generally manageable, the combination did lead to a higher rate of severe adverse events than radium-223 alone.
  ​
• Mevrometostat Plus Enzalutamide Improves rPFS in Phase 2 Study
  ​A Phase 2 study (NCT03460977) investigating the EZH2 inhibitor mevrometostat in combination with enzalutamide and androgen deprivation therapy (ADT) showed encouraging results in mCRPC patients previously treated with abiraterone. The median rPFS was 14.3 months with the combination, compared to 6.2 months for enzalutamide alone. Secondary endpoints also favored the combination, including a higher objective response rate and a greater proportion of patients achieving at least a 50% PSA decline. Though adverse events were more frequent in the combination group, they were generally manageable.
  ​
• PT-112 Approved for Phase 3 Trial in Advanced Prostate Cancer
  ​The FDA has approved a Phase 3 trial for PT-112, a novel small-molecule conjugate of pyrophosphate designed for oncology. Its mechanisms include inhibition of ribosomal biogenesis, induction of immunogenic cell death, and recruitment of immune cells to tumors. PT-112’s affinity for bone tissue (osteotropism) makes it particularly suited for cancers that metastasize to the skeleton. In earlier Phase 1 studies, 17% of patients achieved progression-free survival beyond six months, and some mCRPC patients experienced sustained tumor marker reductions and survival extending beyond two years. The safety profile was notable, with Grade 3 adverse events in 27% of patients but no Grade 4 or 5 events.
  ​
• Pasritamig Shows Early Promise as KLK2-Targeting Immunotherapy
  ​Pasritamig (JNJ-78278343), a bispecific antibody targeting KLK2 and CD3 receptors to redirect T-cell activity, demonstrated promising results in a first-in-human Phase 1 study (NCT04898634) in men with mCRPC. The therapy was generally well-tolerated, with most treatment-related adverse events being mild to moderate. Among patients treated at the recommended Phase 2 dose, 42.4% achieved a PSA50 response.The median rPFS was 6.77 months, and an objective response rate of 16.1% was seen in those with measurable disease. These findings support further investigation, with Phase 3 trials in planning.
  ​
• Real-World Data Suggest Survival Benefit for Sipuleucel-T
  ​A retrospective study using data from the SoNaR database indicates that Sipuleucel-T, an autologous cellular immunotherapy, may significantly prolong survival in men with mCRPC. Median overall survival was 44 months for treated patients, compared to 24 months for untreated ones. While these results are compelling, the retrospective nature of the study and potential selection biases—such as differences in age and PSA levels—mean that the findings suggest correlation rather than causation.
  ​
• ¹⁷⁷Lu (Pluvicto) + Gotistobart (BNT316/ONC-392) Trial​
  This combination therapy merges ¹⁷⁷Lu, a PSMA-targeted radioligand, with gotistobart, an anti-CTLA-4 antibody that may counteract Treg-mediated immune suppression. In the ongoing PRESERVE-006 trial (NCT05682443), early Phase 1 data (as of December 2024) show a manageable safety profile with no deaths, no dose-limiting toxicities, and no grade 4–5 treatment-related adverse events. The combination outperformed ¹⁷⁷Lu alone in efficacy, with PSA50 responses in 66.7% of patients in the 3 mg/kg gotistobart arm and 50% in the 10 mg/kg arm,versus just 16.7% in the control arm.
  ​
• ¹⁷⁷Lu-NYM032 Trial​
  ¹⁷⁷Lu-NYM032 is a novel PSMA-targeted radioligand therapy designed to maximize tumor targeting while sparing healthy tissues. It is under investigation in a Phase 1/2 trial (NCT06383052) in China for men with PSMA-positive mCRPC who have progressed after AR-targeted therapy and docetaxel or are unfit for chemotherapy. Preliminary Phase 1 results (as of January 2025) show excellent tolerability, with most adverse events being mild to moderate and no dose-limiting toxicities. Among nine patients who completed two cycles, 78% had PSA declines, and 67% achieved PSA50 responses.​
  ​
• ¹⁷⁷Lu-JH020002 Trial​
  This investigational PSMA-targeted radioligand therapy is being tested in a multicenter Phase 1/2 trial (NCT06139575). Preliminary data from the JH020002-01C study (January 2025) include 12 heavily pre-treated mCRPC patients, most with bone metastases. The therapy demonstrated a favorable safety profile with no grade 4/5 adverse events and no dose-limiting toxicities. Among 11 patients in higher-dose cohorts, 63.6% had PSA declines of at least 50%, and 27.3% had declines of 90% or more. One patient achieved a partial radiographic response.
  ​
• ¹⁶¹Tb-PSMA-I&T Trial​
  An especially promising newcomer is ¹⁶¹Tb-PSMA-I&T, which uses the radionuclide terbium-161 instead of lutetium-177. Like 177Lu, terbium-161 emits beta particles but also releases Auger electrons, which may offer added efficacy by damaging micrometastases and isolated cancer cells. Preclinical studies suggest 161Tb may outperform 177Lu in terms of cell-killing potential. The VIOLET trial, a phase 1/2 study conducted in Australia, treated 30 patients with progressive mCRPC. The therapy was well-tolerated, with a maximum tolerated dose of 7.4 GBq and no dose-limiting toxicities. Efficacy outcomes were notable: 70% of patients achieved a ≥50% PSA reduction, 40% reached a 90% reduction, and the median PSA progression-free survival was 9.0 months. Radiographic progression-free survival reached a median of 11.1 months.

Preclinical Research

• ACBP Identified as a Driver of Bone Metastasis​
  Researchers using CRISPR technology have identified acyl–coenzyme A binding protein (ACBP) as a key contributor to cancer metastasis in bone. Elevated ACBP expression, confirmed in mouse models and human data from lung and breast cancers, correlates with increased bone metastasis and poorer survival outcomes. ACBP supports metastatic cancer cells by enhancing energy production through fatty acid oxidation (FAO) and protecting them from ferroptosis, a form of programmed cell death. Compounds targeting ACBP function—such as imidazole ketone erastin (IKE) and etomoxir—effectively blocked bone metastases in mice, highlighting FAO inhibition and ferroptosis induction as promising therapeutic strategies.
  ​
• ASH1L Revealed as an Epigenetic Driver of Bone Spread​
  The ASH1L protein has been identified as a critical epigenetic regulator that primes cancer cells to colonize bone. It is frequently amplified and overexpressed in metastatic prostate cancer, and its presence is linked to advanced disease and worse patient prognosis. Suppressing ASH1L in aggressive prostate cancer models significantly reduced bone metastases and improved survival in mice. ASH1L interacts with HIF-1α and reprograms immune cells, particularly macrophages in the bone, to create a tumor-supportive microenvironment. Targeting ASH1L or its downstream pathways may represent a viable treatment approach, supported by encouraging preclinical data using ASH1L inhibitors.
  ​
• Single-Cell RNA Sequencing Uncovers Immune Diversity in Bone Metastases​
  Advanced single-cell RNA sequencing of bone metastases across cancer types revealed three distinct immune archetypes within the tumor microenvironment. These included immune profiles dominated by: (1) macrophages and osteoclasts, (2) regulatory and exhausted T cells, and (3) monocyte-rich infiltrates. Notably, these immune landscapes often differed from the immune profiles of the primary tumor site. This discovery suggests that bone metastases may require treatment strategies tailored to their unique immune context, rather than a one-size-fits-all approach based on the primary cancer. The study also identified novel therapeutic targets specific to each immune archetype, opening new avenues for personalized immunotherapy in metastatic bone disease.
  ​

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