December 2025 Newsletter: Recent Advances in Prostate Cancer Care

Informed Prostate Cancer Support Group

December 2025 Newsletter: Recent Advances in Prostate Cancer Care

Comprehensive Summary of Clinical Trials, FDA Approvals, and Research Breakthroughs

Executive Summary

November and December 2025 witnessed remarkable progress in prostate cancer diagnosis, treatment, and precision medicine. Landmark developments include multiple FDA approvals for diagnostic tools and treatment technologies, breakthrough clinical trial results demonstrating superior outcomes with novel therapies, advances in artificial intelligence for cancer detection, and important findings on treatment strategies for both localized and advanced disease. This newsletter provides a comprehensive overview of achievements that may significantly impact patient care and treatment decisions.

1. FDA Regulatory Approvals and Clearances

IsoPSA Blood Test Approval (December 1, 2025)

The FDA approved IsoPSA as an in vitro diagnostic kit through the Premarket Approval process to aid biopsy decisions for men aged 50 years or older with elevated PSA levels. This blood-based test analyzes prostate cancer-specific structural variants of the PSA protein using the IsoClear platform, which investigates protein biomarkers at a structural level.

Clinical Performance: In prospective multicenter studies involving over 1,000 patients, IsoPSA demonstrated superior performance compared to total PSA and percentage free PSA. For high-grade prostate cancer risk, the area under the curve (AUC) was 0.783 with IsoPSA compared with 0.672 with total PSA. The test achieved sensitivity of 90.2% and specificity of 45.5% for high-grade cancer, with positive and negative predictive values of 47.7% and 89.3% respectively. Analysis indicated that 46% of high-grade and 42% of any-grade biopsies could be avoided in low-risk patients while maintaining high sensitivity. The test is now included in the 2025 NCCN Prostate Cancer Early Detection Guideline and has been available as a Laboratory-Developed Test since 2020, with Medicare and growing commercial payor coverage.

Vanquish Water Vapor System (December 2, 2025)

The FDA granted 510(k) clearance to the Vanquish Water Vapor System for prostate tissue ablation in patients with intermediate-risk prostate cancer. This represents a significant advance in minimally invasive focal therapy options that better balance oncologic control with quality of life preservation.

VAPOR 2 Trial Results: The approval was supported by 12-month data from the prospective VAPOR 2 trial involving 110 patients with intermediate-risk, localized prostate cancer across 26 clinical sites in the United States. At 6 months, 91% of eligible patients showed no targeted MRI-visible intermediate-risk disease following a single Vanquish procedure. The trial remains ongoing with plans to enroll 235 patients total, and longer-term data will support a pre-market approval submission for an expanded indication. Dr. Samir Taneja of Northwell Health emphasized that FDA clearance provides patients an alternative that better balances oncologic risk with quality of life, with early results showing water vapor may provide efficacious cancer management with lower risk of side effects compared to conventional therapies.

ArteraAI Prostate De Novo Authorization

The FDA granted de novo authorization to ArteraAI Prostate, making it the first AI-powered tool authorized to prognosticate long-term outcomes in patients with localized prostate cancer. This multimodal AI (MMAI) technology analyzes digital images from patient biopsies plus clinical data to predict 10-year risk of distant metastasis and prostate cancer-specific mortality.

Clinical Validation and Impact: The tool was validated using data from several phase 3 trials and previously received breakthrough device designation from the FDA in July 2025. According to data published in Nature, the ArteraAI test demonstrated 9.2% to 14.6% relative improvement over standard NCCN risk stratification models across all endpoints at median 11.4-year follow-up. The test can identify the 34% of patients who may benefit from short-term hormone therapy and demonstrated superior performance in prognosticating distant metastasis, biochemical failure, prostate cancer-specific mortality, and overall survival. Data presented at the 2025 ASCO Annual Meeting showed the MMAI algorithm could accurately identify which patients with high-risk non-metastatic prostate cancer were most likely to benefit from adding abiraterone plus prednisone with or without enzalutamide to standard androgen deprivation therapy. The de novo authorization establishes a new product code category for future AI-powered digital pathology risk-stratification tools and enables implementation at the point of diagnosis at qualified pathology labs across the United States.

Ibex Prostate Detect AI Clearance (December 2025)

The FDA granted 510(k) clearance to Ibex Prostate Detect (formerly Galen Second Read), an AI-powered digital pathology solution that aids in identifying small and rare prostatic cancers in tissue biopsies. This represents Ibex Medical Analytics' first regulatory clearance. The software analyzes whole slide images of prostate core needle biopsies stained with hematoxylin and eosin, generating heat maps that highlight areas of potential malignancy and alerting pathologists to suspicious regions that may have been overlooked. Validation studies demonstrated 99.6% positive predictive value for heat map accuracy. The AI system identified 13% of prostate cancer cases that had been missed by pathologists during initial diagnoses—cases subsequently confirmed upon review. A pivotal study published in Lancet Digital Health reported AUC of 0.991 for identifying prostate cancer, 0.957 for detecting perineural invasion, and 0.971 for detecting Gleason pattern 5 tumors.

2. Landmark Clinical Trial Results

LUNAR Trial: PSMA Radioligand Therapy Plus SBRT

UCLA Health researchers published groundbreaking results from the phase 2 LUNAR trial in the Journal of Clinical Oncology, presented at the 2025 American Society for Radiation Oncology Annual Meeting. The trial demonstrated that patients with recurring oligorecurrent prostate cancer treated with PSMA-targeted radioligand therapy (177Lu-PNT2002) before stereotactic body radiotherapy (SBRT) went more than twice as long without disease progression compared to those who received SBRT alone.

Trial Design and Results: The study enrolled 92 men with recurrent prostate cancer, randomly assigning them to SBRT alone or two doses of 177Lu-PNT2002 followed by SBRT. Men receiving the radioligand drug had median progression-free survival of 17.6 months compared to 7.4 months with SBRT alone—a 63% reduction in risk of cancer returning, need for hormone therapy, or death. This translated to median time to hormonal therapy initiation of 24.3 months versus 14.1 months. Benefits were consistent across all patient subgroups regardless of disease stage or number of lesions, with minimal side effects. Dr. Amar Kishan emphasized this gives patients more time before needing hormonal therapy, which carries significant side effects like fatigue and bone loss.

Clinical Significance: Dr. Jeremie Calais noted this trial showcases the full potential of PSMA-based theranostics technologies, leveraging PSMA-PET imaging to guide SBRT targeting with superior precision, combined with PSMA radioligand therapy to treat both visible and microscopic disease too small to detect on PET scans. This is the first randomized trial demonstrating that PSMA-targeting radioligand can significantly delay progression when added to metastasis-directed radiation. Despite clear benefits, 64% of men still experienced progression, underscoring that microscopic cancer remains a major challenge requiring further research to optimize response rates.

CAN-2409 Immunotherapy Phase 3 Results (ASTRO 2025)

Dr. Glen Gejerman presented results from a randomized, placebo-controlled phase 3 trial of CAN-2409 plus prodrug in combination with external beam radiotherapy for newly diagnosed localized prostate cancer at the 2025 ASTRO meeting. CAN-2409 is an investigational gene therapy that uses a virus to deliver the herpes simplex virus thymidine kinase gene into tumor cells, which convert oral valacyclovir into a toxic substance causing immunogenic cell death, acting as an in-situ vaccination.

Trial Results: The trial enrolled 745 eligible participants with newly diagnosed clinically localized, intermediate- or high-risk prostate cancer, randomized 2:1 to CAN-2409 or placebo plus standard radiotherapy. The primary endpoint was disease-free survival. Patients in the CAN-2409 arm had a 38% reduction in prostate cancer recurrences or prostate cancer-related deaths (HR 0.62, 95% CI 0.44-0.87, p=0.0046). Results remained consistent across subgroups stratified by use of short-term ADT and radiation regimen. CAN-2409 significantly increased the proportion achieving PSA nadir <0.2 ng/ml and improved 2-year biopsy pathological complete response rates (80.4% vs 63.6%, p=0.0015)—particularly significant given known associations between positive biopsies at ≥2 years after radiotherapy and subsequent metastases and mortality. This could represent the first new therapy in over 20 years for men with localized prostate cancer seeking cure.

EMBARK Trial Overall Survival Data (NEJM, October 2025)

Long-term follow-up results from the EMBARK trial were published in The New England Journal of Medicine in October 2025, with presentation at the European Society for Medical Oncology Congress. The trial evaluated enzalutamide plus leuprolide versus either drug alone in men with nonmetastatic castration-sensitive prostate cancer with high-risk biochemical recurrence after surgery or radiation.

Eight-Year Survival Results: After eight years of follow-up, the combination therapy reduced risk of death by 40.3% compared to the other treatment arms. Dr. Stephen Freedland of Cedars-Sinai, co-principal investigator, noted these patients are at high risk of developing metastatic disease and dying unless offered meaningful treatment options. The results are expected to solidify this drug combination as standard of care for patients with high-risk biochemically recurrent prostate cancer. Dr. Hyung Kim, chair of Urology at Cedars-Sinai, stated these findings identify a treatment that prolongs survival in men with aggressive prostate cancer and will change how patients are managed.

ProtecT 15-Year Analysis (NEJM)

The ProtecT trial published 15-year follow-up data comparing active monitoring, prostatectomy, and radiotherapy for PSA-detected, clinically localized prostate cancer. At median 15-year follow-up, prostate cancer-specific mortality remained very low (97% survival) regardless of treatment group, though radical treatments reduced incidence of metastasis, local progression, and long-term androgen-deprivation therapy by half compared to active monitoring. In the active-monitoring group, 24.4% of men remained alive without any prostate cancer treatment at follow-up end. The findings emphasize the long natural history of this disease and indicate that depending on extent of side effects associated with early radical treatments, more aggressive therapy can result in more harm than good. No differential effects on cancer-specific mortality were noted in relation to baseline PSA level, tumor stage or grade, or risk-stratification score, highlighting importance of individualized treatment decisions balancing benefits and harms.

3. Research Breakthroughs

PDIA1 and PDIA5 Enzymes as Therapeutic Targets

An international team led by Flinders University and South China University of Technology published groundbreaking research in Proceedings of the National Academy of Sciences (PNAS) in November 2025, identifying PDIA1 and PDIA5 as critical enzymes that prostate cancer cells use to survive and resist treatment.

Mechanism and Implications: These enzymes act like molecular bodyguards for the androgen receptor (AR), the main driver of prostate cancer. When blocked, the AR loses stability and breaks apart, causing cancer cells to die and tumors to shrink in both lab cultures and animal models. Researchers discovered combining drugs inhibiting PDIA1 and PDIA5 with enzalutamide made the standard treatment significantly more effective. The research revealed a previously unknown mechanism prostate cancer cells use to protect the androgen receptor. Additionally, blocking these enzymes disrupts the cancer's energy supply, creating a dual impact by hitting both the AR and the cancer's metabolic system simultaneously. While current PDIA1 and PDIA5 inhibitors are promising, they require refinement for patient use as some existing compounds can affect healthy cells. Future studies will focus on designing safer and more selective versions, potentially offering new pathways to overcome treatment resistance in advanced prostate cancer.

NSD2 Targeting Reverses Drug Resistance (Nature, November 26, 2025)

Researchers published in Nature demonstrating that inhibiting NSD2, a histone methyltransferase, can reverse lineage plasticity and treatment resistance in castration-resistant prostate cancer (CRPC). Lineage plasticity mediates resistance to androgen receptor inhibitors and progression from adenocarcinoma to aggressive subtypes including neuroendocrine prostate cancer (CRPC-NE).

Research Findings: NSD2 upregulation in CRPC-NE correlates with poor survival outcomes. NSD2-mediated H3K36 dimethylation regulates enhancers of genes associated with neuroendocrine differentiation. In prostate tumor organoids from genetically engineered mice and human CRPC-NE organoids, CRISPR-mediated targeting of NSD2 reversed neuroendocrine features and restored sensitivity to androgen receptor inhibition. Combined inhibition of NSD2 and the androgen receptor in preclinical models suppressed tumor growth and promoted cell death across multiple subtypes of CRPC. This discovery represents a potential therapeutic strategy to reverse plasticity-associated treatment resistance, offering hope for patients whose cancers have transformed into aggressive, treatment-resistant forms.

Intratumoral Immunotherapy Trial (Mount Sinai, October 2025)

A phase 1 clinical trial led by the Icahn School of Medicine at Mount Sinai, published in Med (a Cell Press journal) in October 2025, demonstrated that directly injecting poly-ICLC (a viral-mimicking immune-activating compound) into prostate tumors before surgery appears safe and may help the immune system recognize and attack cancer cells. The study tested neoadjuvant treatment in 12 men with intermediate- to high-risk prostate cancer, delivering the drug first into the tumor under MRI-ultrasound fusion guidance to trigger an immune response, then into muscle to boost it. Dr. Ash Tewari emphasized this is the first prostate cancer trial to test intratumoral immunotherapy, with methods that don't rely on a single tumor target but train the immune system to recognize the whole tumor. The approach shows even tumors once thought invisible to the immune system can potentially be made responsive. The team plans larger phase 2 trials to test clinical benefit and explore combination strategies with hormone therapies or other immunotherapies.

UK Targeted Screening Recommendation (November 28, 2025)

The UK National Screening Committee announced a draft recommendation for a targeted prostate cancer screening program following robust expert-led evidence review. The proposed program would invite men aged 45-61 with mutations in BRCA1 or BRCA2 genes for prostate cancer screening every two years. Men with BRCA2 mutations are more likely to develop faster-growing prostate cancers, and this targeted approach is more likely to identify fast-growing cancers before late-stage progression while minimizing overdiagnosis of slow-growing cancers. Current estimates suggest between 1 in 300 and 1 in 400 people have BRCA mutations. The recommendation addresses findings that when all men within a defined age range receive PSA screening, there are too many harms compared to benefits due to limitations of the PSA test. This targeted approach represents a significant step toward precision medicine in prostate cancer screening, focusing resources on those most likely to benefit. The recommendation requires approval before implementation, and health systems across the UK will need to determine optimal implementation strategies.

4. Expanding Treatment Landscape

Pluvicto Expansion to Pre-Chemotherapy Setting (March 2025)

In March 2025, the FDA expanded the indication for lutetium Lu 177 vipivotide tetraxetan (Pluvicto) to include adults with PSMA-positive metastatic castration-resistant prostate cancer who have been treated with androgen receptor pathway inhibitor therapy and are considered appropriate to delay taxane-based chemotherapy. This expansion, based on the PSMAfore trial, substantially increases the number of patients eligible for treatment.

Clinical Impact: Dr. Michael Morris of Memorial Sloan Kettering emphasized this represents a game changer for people whose prostate cancer has spread despite hormonal therapy. The standard approach had been to give androgen receptor-targeting drugs, then chemotherapy upon failure, but many doctors and patients were delaying taxane therapy due to side effects. The PSMAfore trial results suggest proceeding directly to 177Lu-PSMA-617 is appropriate, allowing patients to bypass or delay chemotherapy while maintaining disease control. PSMA-PET imaging is used to identify eligible patients with PSMA-positive disease. This precision medicine approach enables clinicians to see what they treat and treat what they see, leveraging theranostics to visualize cancer cells and destroy them while sparing normal tissue.

Illuccix Label Expansion (December 2025)

The FDA approved label expansion for Illuccix (gallium Ga-68 gozetotide kit for injection) to help select patients with metastatic castration-resistant prostate cancer for radioligand therapy in the pre-taxane setting. This PSMA-PET imaging agent identifies PSMA-positive tumors via PET scan, helping clinicians determine patient eligibility for treatment with Pluvicto before chemotherapy. The expansion supports the evolving treatment landscape with high diagnostic accuracy for PSMA-targeted therapy. Uptake of gallium Ga 68 gozetotide is not specific to prostate cancer and may occur with other cancers or noncancerous conditions, requiring clinical correlation including possible biopsy. Imaging performance may vary based on PSA levels, disease site, or Gleason score. Side effects reported in trials included nausea, diarrhea, dizziness, fatigue, constipation and vomiting, most occurring in fewer than 1% of patients.

Alpha DaRT Technology for Recurrent Disease (December 2, 2025)

Alpha Tau Medical announced FDA approval of an Investigational Device Exemption application to initiate a pilot study treating patients with locally recurrent prostate cancer using Alpha DaRT technology—an innovative alpha-radiation cancer therapy. This marks Alpha Tau's fifth simultaneous active U.S. IDE as the company expands Alpha DaRT's reach. Dr. Robert Den, Alpha Tau Chief Medical Officer, noted that with over 300,000 new prostate cancer cases expected in 2025 and clinical literature indicating up to 15% of patients treated with external beam radiation developing local recurrence within 15 years, there is strong demand from clinicians and patients for new, focused alpha-radiation based local salvage therapy. Patients with locally recurrent disease currently face limited poor alternatives, making this investigational approach particularly valuable.

5. Epidemiology Update

A major epidemiological study published in CA: A Cancer Journal for Clinicians (November-December 2025) provided updated statistics on prostate cancer in the United States. Prostate cancer remains the most common cancer among American men, with concerning trend reversals in recent years.

Key Findings: Prostate cancer incidence trends reversed from a decline of 6.4% per year during 2007-2014 to an increase of 3.0% annually during 2014-2021. The increasing trend is confined to distant-stage disease in men younger than 55 years and to regional/distant-stage disease in men aged 55-69 years, though it includes early-stage disease in men aged 70 years and older. This alarming rise in advanced prostate cancer cases, particularly in younger men, underscores the critical importance of advances in early detection, precision screening, and treatment options. The data emphasizes need for continued research into screening strategies that balance benefits of early detection against risks of overdiagnosis and overtreatment, while ensuring equitable access across all demographic groups.

Conclusion

November and December 2025 represent a watershed period in prostate cancer care, characterized by unprecedented progress across detection, treatment, and personalized medicine. The FDA approvals of multiple diagnostic tools—IsoPSA, ArteraAI Prostate, Ibex Prostate Detect, and the Vanquish Water Vapor System—demonstrate the rapid integration of advanced technologies into clinical practice. Landmark clinical trials including LUNAR, CAN-2409 phase 3, and long-term EMBARK survival data provide compelling evidence for novel therapeutic strategies that improve outcomes while preserving quality of life. Research breakthroughs identifying PDIA1/PDIA5 and NSD2 as therapeutic targets, along with innovative immunotherapy approaches, offer new hope for overcoming treatment resistance. The expansion of Pluvicto to the pre-chemotherapy setting and development of targeted screening programs reflect the shift toward precision medicine tailored to individual patient characteristics. As we move forward, these advances promise to transform the prostate cancer treatment paradigm, offering patients more effective, less toxic therapies with improved survival and quality of life outcomes.

References and Sources

The following sources provided information for this newsletter:

1. Cleveland Diagnostics. FDA Approves IsoPSA - Novel Blood-Based Prostate Cancer Test. News release. December 1, 2025. https://www.businesswire.com/news/home/20251201324198/en/

2. UCLA Health. New therapy delays progression of recurrent prostate cancer. Journal of Clinical Oncology, 2025. https://www.uclahealth.org/news/release/new-therapy-delays-progression-recurrent-prostate-cancer

3. Gejerman G. Phase 3 trial of CAN-2409 in combination with radiation for localized prostate cancer. Presented at: ASTRO 2025 Annual Meeting; September 28-30, 2025; San Francisco, CA.

4. Cedars-Sinai. Drug Combo Cuts Death Risk in Advanced Prostate Cancer 40%. October 2025. https://www.cedars-sinai.org/newsroom/drug-combo-cuts-risk-of-death-in-advanced-prostate-cancer-by-40/

5. Hamdy FC, et al. Fifteen-year outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med. 2025. https://www.nejm.org/doi/full/10.1056/NEJMoa2214122

6. ScienceDaily. Hidden weakness makes prostate cancer self-destruct. November 10, 2025. https://www.sciencedaily.com/releases/2025/11/251110021056.htm

7. Li JJ, et al. NSD2 targeting reverses plasticity and drug resistance in prostate cancer. Nature. Published November 26, 2025. https://www.nature.com/articles/s41586-025-09727-z

8. Mount Sinai. Early clinical trial tests immune-boosting therapy before prostate cancer surgery. Med (Cell Press). October 30, 2025. https://www.mountsinai.org/about/newsroom/2025/early-clinical-trial-tests-immune-boosting-therapy-before-prostate-cancer-surgery

9. Cancer Research UK. First steps towards a targeted prostate cancer screening programme. November 28, 2025. https://news.cancerresearchuk.org/2025/11/28/uk-nsc-draft-recommendation-targeted-prostate-cancer-screening-programme/

10. Francis Medical. FDA 510(k) Clearance for Vanquish Water Vapor System. News release. December 2, 2025. https://www.francismedical.com/

11. Artera. FDA grants de novo authorization to ArteraAI Prostate. News release. 2025. https://www.urologytimes.com/view/fda-grants-de-novo-authorization-to-arteraai-prostate

12. Targeted Oncology. FDA Grants 510(k) Clearance to Ibex Prostate Detect AI. December 10, 2025. https://www.targetedonc.com/view/fda-grants-510-k-clearance-to-ibex-prostate-detect-ai-for-prostate-cancer

13. U.S. FDA. FDA expands Pluvicto's metastatic castration-resistant prostate cancer indication. March 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication

14. CURE. Illuccix is FDA approved to guide radioligand use in prostate cancer. December 3, 2025. https://www.curetoday.com/view/illuccix-is-fda-approved-to-guide-radioligand-use-in-prostate-cancer

15. Alpha Tau Medical. FDA Approves IDE Application for Locally Recurrent Prostate Cancer Trial. News release. December 2, 2025. https://www.globenewswire.com/news-release/2025/12/02/

16. Kratzer TB, et al. Prostate cancer statistics, 2025. CA Cancer J Clin. 2025 Nov-Dec;75(6):485-497. https://pubmed.ncbi.nlm.nih.gov/40892160/

17. Memorial Sloan Kettering Cancer Center. FDA Expands New Treatment for Metastatic Prostate Cancer. 2025. https://www.mskcc.org/news/fda-approves-promising-therapy-advanced-prostate

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This newsletter was compiled from peer-reviewed publications, FDA announcements,

clinical trial registries, and reputable medical news sources.

For medical advice, please consult with your healthcare provider.