Advances in Androgen Deprivation Therapy-Sparing Strategies: Ongoing Studies in Metastatic Castration-Sensitive...

Androgen deprivation therapy (ADT) reduces testosterone levels and is a standard treatment for patients with advanced prostate cancer (PC). However, ADT is associated with significant short-term effects (hot flashes, sleep disturbances, fatigue) and medical complications (depression, cardiovascular disease, skeletal complications, and cognitive impairment), which can be associated with increased morbidity and mortality. This treatment burden has prompted exploration of alternative approaches that can minimize or avoid the use of ADT while still effectively managing PC. Recent phase III studies demonstrate that the addition of an androgen receptor pathway inhibitor (ARPI) to ADT leads to significantly improved overall survival (OS) in patients with metastatic castration-sensitive PC (mCSPC) versus placebo plus ADT. In many patients, the maximum androgen blockade observed with ADT plus an ARPI leads to rapid and deep prostate-specific antigen (PSA) responses, with improved OS, radiographic progression-free survival, and time to castration resistance. Potential ADT- and ARPI-sparing strategies for mCSPC include the complete omission of ADT and/or ARPI, or a fixed course of ADT and/or ARPI followed by either treatment cessation or dose de-escalation (via interruption or intermittent treatment). Ongoing phase II and III studies (LIBERTAS, EORTC GUCC 2238, and A-DREAM) are testing whether ADT-sparing strategies will lessen the treatment burden of ADT in patients with mCSPC without compromising overall cancer control outcomes. Achievement of rapid and deep PSA decline with the addition of an ARPI to ADT has been shown to be associated with improved survival outcomes in addition to longer preservation of overall health-related quality of life and physical well-being. These results suggest that a subgroup of patients with excellent biochemical response may preserve favorable long-term outcomes with reduced toxicity using a de-escalated ADT regimen.