NSD2 Inhibitors in Advanced Prostate Cancer: An Emerging Therapeutic Strategy
NSD2 inhibitors represent a promising experimental strategy for reversing treatment resistance in advanced prostate cancer, particularly in aggressive neuroendocrine subtypes, but they remain investigational and are not yet part of standard clinical practice or guideline-recommended treatment algorithms. 1
Current Guideline-Recommended Treatments for Advanced Prostate Cancer
The established treatment landscape for advanced prostate cancer does not include NSD2 inhibitors, as these agents are still in preclinical and early clinical development. Current evidence-based options include:
For Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)
- Triplet therapy with ADT + docetaxel + darolutamide is recommended as first-line treatment, showing significant overall survival benefits (OS gain: 23.0 months, HR: 0.68) 2
- ADT + docetaxel + abiraterone + prednisone is recommended for fit men with de novo mHSPC, especially those with multiple bone metastases or visceral disease 2
- Novel hormone agents (abiraterone, apalutamide, enzalutamide) combined with ADT represent standard options 2
For Metastatic Castration-Resistant Prostate Cancer (mCRPC)
- Multiple FDA-approved agents with proven survival benefits include: docetaxel, cabazitaxel, abiraterone, enzalutamide, sipuleucel-T, radium-223, and olaparib (for BRCA1/2 alterations) 3
- 177Lu-PSMA-617 (Pluvicto) is recommended for PSMA-positive mCRPC after progression on androgen receptor pathway inhibitors and taxane chemotherapy, with significant improvements in overall survival (15.3 vs 11.3 months; HR 0.62) 4
The Scientific Rationale for NSD2 Inhibition
Mechanism of Action and Preclinical Evidence
NSD2 (Nuclear Receptor Binding SET Domain Protein 2) is a histone methyltransferase that drives lineage plasticity and treatment resistance in castration-resistant prostate cancer through H3K36 dimethylation. 1
Key findings from preclinical research:
- NSD2 upregulation correlates with poor survival outcomes in CRPC-NE (neuroendocrine prostate cancer), and NSD2-mediated H3K36 dimethylation regulates enhancers of genes associated with neuroendocrine differentiation 1
- CRISPR-mediated targeting of NSD2 in patient-derived organoids reverts CRPC-NE to adenocarcinoma phenotypes, restoring canonical androgen receptor programs and responsiveness to enzalutamide 1
- Pharmacological NSD2 inhibition with first-in-class small molecules synergizes with enzalutamide to suppress growth and promote cell death in human patient-derived organoids of multiple CRPC subtypes 1
- NSD2 expression is abnormal in approximately 80% of patients with advanced prostate cancer, and elevated expression is associated with PSA progression, imaging progression, and overall survival in univariable analyses 5
The Clinical Problem NSD2 Inhibitors Address
Lineage plasticity mediates resistance to androgen receptor inhibitors and progression to aggressive neuroendocrine subtypes, which are currently recalcitrant to standard treatments 1. The emergence of CRPC-NE following potent AR inhibitor therapy represents a major clinical challenge, as these tumors:
- Display increased lineage plasticity and often lack AR expression 6
- Are highly aggressive and lethal with limited treatment options 6
- Do not respond to AR-targeted therapies that are effective in adenocarcinoma 1
Current Clinical Status and Limitations
Why NSD2 Inhibitors Are Not Yet Recommended
No major guideline organization (ASCO, ESMO, NCCN, AUA/ASTRO/SUO, St. Gallen APCCC) includes NSD2 inhibitors in their treatment recommendations for advanced prostate cancer. 3, 2
Critical gaps in evidence:
- No phase III randomized controlled trials have been completed or published demonstrating clinical efficacy in human patients 1
- Current evidence is limited to preclinical studies using genetically engineered mouse models and patient-derived organoids 1, 6
- Safety and tolerability data in human patients are not yet available from clinical trials 1
- Optimal patient selection criteria, dosing, and combination strategies remain undefined 1
The Evidence Hierarchy Problem
The strongest available evidence for NSD2 inhibition comes from a 2025 Nature publication showing reversal of plasticity in organoid models, but this represents preclinical research rather than clinical trial data 1. In contrast, guideline-recommended therapies are supported by multiple phase III trials with survival endpoints:
- Docetaxel-based regimens show proven survival benefits with HR 0.68-0.76 2
- AR pathway inhibitors demonstrate substantial survival advantages in mHSPC and mCRPC 3
- 177Lu-PSMA-617 shows HR 0.62 for overall survival in pretreated mCRPC 4
Clinical Decision-Making Algorithm for Treatment-Resistant Advanced Prostate Cancer
When facing resistance to conventional therapies in advanced prostate cancer, prioritize established guideline-recommended options before considering investigational approaches:
Step 1: Confirm Disease State and Prior Treatments
- Verify castration-resistant status (testosterone <50 ng/dL with rising PSA) 3
- Document prior therapies including AR pathway inhibitors, chemotherapy, and radiopharmaceuticals 3
- Assess for BRCA1/2 or other DNA repair alterations (consider olaparib if present) 2
Step 2: Evaluate for PSMA-Targeted Therapy
- Obtain PSMA PET imaging if not previously done to assess for PSMA-positive disease 4
- Consider 177Lu-PSMA-617 if PSMA-positive and prior AR inhibitor + taxane exposure, as this has proven survival benefit 4
Step 3: Consider Remaining Approved Options
- Cabazitaxel if docetaxel-pretreated with adequate performance status 3
- Alternative AR pathway inhibitor if not previously used (abiraterone, enzalutamide, apalutamide) 3
- Radium-223 for symptomatic bone metastases without visceral disease 3
Step 4: Clinical Trial Enrollment
- Strongly encourage enrollment in clinical trials for patients who have exhausted standard options 3, 2
- NSD2 inhibitor trials would be appropriate at this stage, particularly for patients with neuroendocrine features or AR-null phenotypes 1
Common Pitfalls and Caveats
Avoiding Premature Use of Investigational Agents
The most critical error would be prioritizing NSD2 inhibitors over proven therapies with survival benefits. The current evidence hierarchy clearly favors:
- Established combinations showing 23-month OS gains (triplet therapy) 2
- FDA-approved agents with phase III trial support 3
- Radiopharmaceuticals with proven efficacy in heavily pretreated patients 4
Patient Selection Considerations
If NSD2 inhibitors become available in clinical trials, optimal candidates would likely include:
- Patients with confirmed neuroendocrine differentiation or AR-null phenotypes 1, 6
- Those who have progressed through multiple lines of standard therapy 1
- Patients with high NSD2 expression confirmed by immunohistochemistry 5
- Those with adequate performance status for investigational therapy 1
The Sequencing Challenge
Large-scale prospective randomized trials testing optimal sequencing of treatments have not been reported, and predictive markers to facilitate patient selection for specific therapies remain an unmet need 3. This uncertainty extends to where NSD2 inhibitors might fit in treatment algorithms if they prove effective in clinical trials 3, 7.
Future Directions and Research Needs
The preclinical evidence for NSD2 inhibition is compelling, but translation to clinical benefit requires:
- Phase I/II trials establishing safety, tolerability, and preliminary efficacy in human patients 1
- Biomarker development to identify patients most likely to benefit from NSD2 inhibition 5
- Combination studies with AR inhibitors to validate the synergy observed in organoid models 1
- Phase III randomized trials with survival endpoints comparing NSD2 inhibitor combinations to standard of care 1
Various cell signaling, DNA repair, and epigenetic enzymatic pathways are being targeted with small-molecule inhibitors to identify treatment strategies for CRPC, including PARP, EZH2, hedgehog pathway, and MDM2/p53 inhibitors 7. NSD2 inhibitors represent one component of this broader investigational landscape 7, 1.
Bottom Line for Clinical Practice
Continue using guideline-recommended, evidence-based therapies for advanced prostate cancer, as these have proven survival benefits in phase III trials. 3, 2 NSD2 inhibitors show promising preclinical activity for reversing treatment resistance, particularly in neuroendocrine subtypes, but remain investigational and should only be accessed through clinical trials after exhausting standard options. 1 Strongly encourage clinical trial participation for patients with advanced disease, as this accelerates the development of novel therapies while providing access to potentially beneficial treatments. 3, 2