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Predicting Efficacy of Bipolar Androgen Therapy (BAT) in Prostate Cancer
Key Predictive Biomarkers and Mechanisms
Based on recent clinical trials and mechanistic studies, the following factors predict BAT efficacy:
Biomarker/Mechanism Predictive Value Evidence Source
AR Alterations in ctDNA Patients with AR amplification or mutations (e.g., T878A, L702H) benefit from BAT. TRANSFORMER Trial (ASCO 2024): 53% of patients with AR alterations in ctDNA had improved PFS/OS vs. Enzalutamide. No AR alterations → worse outcomes on BAT.
High AR Activity (ARA MW Score) ARA MW score >0.6 (gene signature of AR activity) predicts tumor regression and survival. PMC9711876: High AR activity drives MYC suppression. Patients with ARA MW >0.6 had median OS of 47.4 vs. 29.0 months (low AR activity).
MYC Downregulation BAT-induced MYC suppression correlates with clinical response. Preclinical/clinical data: High AR activity enables MYC suppression, reducing proliferation.
Low Tumor-Suppressor Loss BAT + PARPi may benefit patients with BRCA2/P53 loss (preclinical synergy). ScienceDirect Study: Combined tumor-suppressor loss (e.g., BRCA2/P53) linked to BAT resistance; PARPi may resensitize.
Clinical Implications
Patient Selection:
• Favorable: AR alterations (ctDNA), high AR activity (ARA MW >0.6), MYC overexpression.
• Unfavorable: No AR alterations, low AR activity, tumor-suppressor loss (BRCA2/P53).
Recommendations
• Use ctDNA to detect AR alterations (amplifications/mutations) and calculate ARA MW score.
• Prioritize BAT for AR-altered/high AR activity tumors.
Therapeutic Strategies:
• For AR-altered tumors: BAT ± immunotherapy (BATRAD trial).
• For AR-wild-type tumors: Enzalutamide or combination therapies (e.g., PARPi + BAT).
Conclusion
BAT efficacy is predictable via AR status and activity biomarkers. Patients with AR-driven tumors (ctDNA alterations, high ARA MW score) derive significant benefit, while others should receive alternative therapies. Ongoing trials (e.g., STEP-UP, BATRAD) aim to optimize sequencing and combinations.
Grade of Evidence: B (Phase II/III trial data, validated preclinical models).
References:
1. TRANSFORMER Trial (ASCO 2024)
Title: Blood-Based Markers of Differential Efficacy of Bipolar Androgen Therapy and Enzalutamide in the Randomized TRANSFORMER Trial
URL: ASCO 2024 Abstract
2. Sena et al. (PMC9711876)
Title: Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC
URL: PMC9711876
3. ScienceDirect Study (Tumor-Suppressor Loss)
Title: Clinical Efficacy of Bipolar Androgen Therapy in Men with Metastatic Castration-Resistant Prostate Cancer and Combined Tumor-Suppressor Loss
URL: ScienceDirect Article