The mainstay of treatment for advanced prostate cancer is sustained suppression of androgen receptor activity. This significantly increases survival; however, tumours inevitably develop varying mechanisms of resistance. Patients also experience mounting side-effects that reduce their quality of life, including increased risk of cardiovascular events. An emerging approach to address these challenges is Bipolar Androgen Therapy (BAT), where patients receive testosterone injections to oscillate between low (castrate) and high (supraphysiological) androgen levels. Here we used preclinical models to identify the features of BAT responsive tumours and determine the broader impact of treatment on health, including cardiovascular function.
We used 16 patient-derived xenografts (PDXs) with diverse features from the Melbourne Urological Research Alliance (MURAL). Mice received fortnightly cycles of vehicle control or BAT (testosterone cypionate injections). Reflecting response rates in clinical trials, ~30% of castration-resistant tumours were sensitive to BAT. The BAT-sensitive PDXs had high copy number amplifications of the AR gene, low levels of AR-variants, diverse pathologies, and sustained responses (≥ 100 days) compared to the standard-of-care (enzalutamide). BAT-resistant PDXs included tumours with genomic structural rearrangements of the AR associated, disruption of the autoregulation of AR expression, and muted transcriptional responses to treatment. Single-cell multiomics showed widespread changes in transcriptional profiles and chromatin accessibility, and sustained suppression of growth-related pathways in responsive tumours over time.
We also examined the impact of treatment on integrated cardiovascular endpoints including mean arterial pressure monitoring via radiotelemetry; echocardiography; kidney function (transcutaneous measurement of glomerular filtration rate, proteinuria); and body composition (DEXA scan). Standard-of-care (enzalutamide) induced mild cardiovascular disfunction, reflected by a reduction in global longitudinal strain, increased in myocardial performance index, and greater fibrosis. These adverse effects were abrogated by BAT
In summary, consistent with clinical trials, BAT responsiveness is associated with robust androgen receptor signalling and sustained suppression of growth signalling pathways, providing avenues to increase response rates with combination therapies. Furthermore, BAT has distinct impacts on cardiovascular features compared to standard-of-care, warranting further into long-term survivorship.