Androgen receptor suppression remains the cornerstone of treatment for advanced prostate cancer and has substantially improved survival. However, resistance inevitably develops, and treatment-related adverse effects can significantly affect quality of life, including increased cardiovascular risk. Bipolar Androgen Therapy (BAT) is an emerging strategy where patients receive testosterone injections to oscillate between low (castrate) and high (supraphysiological) androgen levels. We are using preclinical models to identify tumour characteristics associated with BAT response and to evaluate broader health effects, including cardiovascular outcomes.
We used patient-derived xenograft (PDX) models established from patients with diverse forms of advanced, therapy-resistant prostate cancer through the Melbourne Urological Research Alliance (MURAL). Mice received fortnightly cycles of vehicle control or testosterone cypionate. Consistent with clinical trial observations, approximately 30% of castration-resistant tumours responded to BAT. Responsive tumours commonly exhibited high androgen receptor (AR) gene amplification, low expression of AR variants, diverse pathological features, and durable responses (≥100 days) that exceeded those achieved with enzalutamide. In contrast, resistant tumours frequently harboured AR structural rearrangements, disrupted AR autoregulation, and weaker transcriptional responses. Single-cell multiomic analyses demonstrated widespread transcriptional and chromatin changes in responsive tumours, with sustained suppression of growth-related pathways.
We also assessed cardiovascular and systemic health outcomes using radiotelemetry, echocardiography, kidney function measurements, and DEXA body composition analysis. Enzalutamide produced mild cardiovascular dysfunction, including reduced global longitudinal strain,
increased myocardial performance index, and greater cardiac fibrosis. These adverse effects were not observed with BAT.
In summary, BAT responsiveness is associated with preserved AR signalling and sustained suppression of tumour growth pathways, highlighting opportunities to improve outcomes through patient selection and combination therapies. BAT also produces a cardiovascular profile distinct from standard androgen receptor pathway inhibition, supporting further investigation of its role in long-term survivorship.