Prime Time for Intermittent Androgen Suppression
Although androgen deprivation therapy (ADT) has been standard first-line systemic therapy for advanced prostate cancer (PCa) for 60 yr, prostate-specific antigen (PSA)induced stage and age migration has significantly altered the treatment landscape to include >90% high-risk localised or biochemical recurrent disease; only 5% of patients present with M1 disease. To improve ADT outcomes, clinical research has focussed on maximising androgen receptor (AR) pathway inhibition by combining luteinising hormone-releasing hormone (LHRH) analogues with AR antagonists. These maximal androgen blockade approaches will continue to evolve using newer steroidogenesis inhibitors (eg, abiraterone) and AR antagonists (eg, enzalutamide) and by cotargeting AR crosstalk signalling pathways. Research has also focussed on optimal timing and scheduling issues, with unresolved debates about early versus deferred ADT and continuous versus intermittent ADT. Clearly, timing of ADT must be guided by risk and age stratification as well as patient-oriented quality-of-life (QoL) and cost-of-treatment considerations. Earlier administration of ADT to defer progression of high-risk localised (usually in combination with radiotherapy), recurrent, or metastatic disease is supported by a large body of theoretical, preclinical, and clinical evidence [1–3]. Progressively earlier intervention raises the prospect of very long periods of ADT attended by clinical side effects that reduce QoL, including osteoporosis, anaemia, lipid disorders, and muscle wasting. This is more relevant now with median survival in M0 disease exceeding 10 yr [4] and in M1 disease often exceeding 4 yr [5]. These collective effects of stage migration and longer life expectancy with a trend towards earlier therapy are forcing clinicians to find strategies that balance the benefits of early ADT against its cumulative adverse metabolic and psychological effects on QoL as well as drug-related costs to the health care system. Intermittent androgen suppression (IAS) is an approach that balances the benefits of early ADT while reducing treatment-related side effects and expense. The rationale for IAS is based on the assumption that early ADT, when used in men at high risk of progression, will prolong survival compared to delayed therapy [1–3] and that adaptive changes in gene expression in tumour cells surviving ADT can be modulated by androgen replacement, with restoration of apoptotic potential and delayed progression to