Enzalutamide
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Enzalutamide: From Prostate Cancer to Prostate Cancer/Brain Cancer Susceptibility
One-Sentence Summary
Enzalutamide is an androgen receptor (AR) signaling inhibitor, originally used to treat prostate cancer. The TxGNN model predicts it may be effective for prostate cancer/brain cancer susceptibility (top-ranked prediction), but this prediction rests on model output only, with 0 clinical trials and 0 publications directly supporting it. Broader related terms (such as "male reproductive organ cancer" and "prostate neoplasm") show extensive evidence, but it is almost entirely for prostate cancer, which is already the approved use.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Prostate cancer (the Singapore licence record contains no indication text; the original indication comes from the knowledge graph: prostate cancer, familial prostate carcinoma, prostate carcinoma) |
| Predicted New Indication | Prostate cancer/brain cancer susceptibility |
| TxGNN Prediction Score | 99.71% |
| Evidence Level | L5 (for the top prediction) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the data compiled for this report. Based on known pharmacology, enzalutamide blocks androgen binding to the AR, prevents AR nuclear translocation, and impairs AR binding to DNA. Its efficacy in prostate cancer is well established.
The top prediction most likely reflects a shared prostate cancer gene-disease association in the knowledge graph, not a true biological link. Nothing in the data connects enzalutamide to a brain cancer susceptibility phenotype, so this prediction should be treated as a model artefact until proven otherwise.
The other top-10 predictions are also weakly supported. Rare prostatic stromal tumours (leiomyoma, fibroma, phyllodes tumours) could in theory depend on AR signaling, and Brenner tumour (an ovarian neoplasm) has no known AR dependence. None has any trials or publications. The broader terms "male reproductive organ cancer", "prostate neoplasm" and "benign neoplasm of prostate" carry evidence that concerns malignant prostate cancer, not new uses.
Clinical Trial Evidence
The top prediction has no related trials. The table below shows the most relevant trials mapped to the broader term "prostate neoplasm". All concern prostate cancer, the existing indication, not the predicted new indication.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02446405 | Phase 3 | Active, not recruiting | 1125 | ENZAMET: enzalutamide vs conventional anti-androgen added to first-line ADT in metastatic prostate cancer |
| NCT06551324 | Phase 3 | Active, not recruiting | 600 | MEVPRO-1: mevrometostat + enzalutamide vs enzalutamide or docetaxel in mCRPC after abiraterone |
| NCT03834493 | Phase 3 | Terminated | 1244 | KEYNOTE-641: pembrolizumab + enzalutamide vs placebo + enzalutamide in mCRPC |
| NCT02987543 | Phase 3 | Completed | 387 | PROfound: olaparib vs enzalutamide or abiraterone in mCRPC with HRR gene mutations |
| NCT06136624 | Phase 3 | Recruiting | 1310 | OMAHA-003: opevesostat vs abiraterone or enzalutamide in heavily pretreated mCRPC |
| NCT06496581 | Phase 3 | Recruiting | 500 | Standard of care ± 177Lu-PSMA-617 in poorly responding mHSPC (enzalutamide likely part of background therapy) |
| NCT03641560 | Phase 4 | Completed | 52 | Single-arm safety and efficacy study of enzalutamide in Indian mCRPC patients after docetaxel |
| NCT07512076 | Phase 2 | Not yet recruiting | 26 | Dose optimization of enzalutamide in elderly patients with advanced prostate cancer |
| NCT06228053 | Phase 2 | Recruiting | 53 | SX-682 (CXCR1/2 inhibitor) + enzalutamide in ARPI-resistant mCRPC |
| NCT06059118 | Phase 2 | Recruiting | 50 | DFMO and high-dose testosterone sequenced with enzalutamide in asymptomatic mCRPC |
Literature Evidence
The top prediction has no related publications. The table below shows key publications mapped to the broader term "prostate neoplasm"; all concern prostate cancer.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 22894553 | 2012 | RCT (AFFIRM, Phase 3) | N Engl J Med | Enzalutamide improved survival in castration-resistant prostate cancer after chemotherapy |
| 29949494 | 2018 | RCT (PROSPER, Phase 3) | N Engl J Med | Enzalutamide in nonmetastatic castration-resistant prostate cancer with rapidly rising PSA |
| 31329516 | 2019 | RCT (ARCHES, Phase 3) | J Clin Oncol | Enzalutamide + ADT vs placebo + ADT in metastatic hormone-sensitive prostate cancer |
| 41124201 | 2026 | RCT (EMBARK) | N Engl J Med | Improved survival with enzalutamide in biochemically recurrent prostate cancer |
| 42223064 | 2026 | RCT | N Engl J Med | Talazoparib added to enzalutamide plus ADT in metastatic prostate cancer |
| 41633900 | 2026 | Post hoc analysis | Eur Urol | ARCHES 5-year efficacy and safety of enzalutamide + ADT in mHSPC |
| 39417629 | 2025 | Network meta-analysis | Prostate | Comparison of abiraterone, enzalutamide and apalutamide in mHSPC |
| 32534790 | 2020 | Review | Trends Cancer | Treatment advances in advanced prostate cancer, including enzalutamide |
| 39275993 | 2024 | Review | Expert Rev Anticancer Ther | Current uses and resistance mechanisms of enzalutamide |
| 38859590 | 2024 | Preclinical | Adv Sci | Enzalutamide sensitizes CRPC cells to copper-mediated cell death |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN14829P | XTANDI™ Soft Capsules 40 mg | Capsule, liquid filled (oral) | Not stated in the available record |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted/hormonal therapy (non-steroidal AR inhibitor), not a conventional cytotoxic |
| Myelosuppression Risk | Low (not a typical myelosuppressive agent); please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Low |
| Monitoring Items | Blood pressure, liver function, seizure risk, falls and fracture risk, cognitive effects; please refer to the package insert |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
- Drug Interactions: 100 interactions were identified. Examples of major interactions: bupropion, dolasetron, eliglustat. Examples of moderate interactions: famotidine, rabeprazole, omeprazole, hydrocortisone, dexamethasone, clarithromycin, aprepitant, loperamide, saxagliptin, linagliptin, empagliflozin. Enzalutamide is a strong CYP3A4 inducer, so all concomitant medications should be reviewed.
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The top prediction (prostate cancer/brain cancer susceptibility) is supported by model output only (L5), with no trials, no literature, and no plausible mechanistic link to enzalutamide. The strong Phase 3 evidence found for broader terms reflects the existing prostate cancer indication, not a new repurposing opportunity. For those label-aligned terms, use would be "Proceed with Guardrails" (L1) as confirmation of existing use only.
To proceed, the following is needed:
- Clarification of what the "prostate cancer/brain cancer susceptibility" term represents, and any biological or clinical rationale linking enzalutamide to it
- Detailed mechanism of action data (MOA)
- Package insert warnings and contraindications from the Singapore regulator, plus the approved indication text for SIN14829P
- Any preclinical or clinical signal in the predicted new indication before reconsidering
- For label-aligned prostate cancer use: a review of concomitant medications given the CYP3A4 induction and the 100 listed interactions
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.