Dr Choudhury on Survival Advantages With AR Pathway Inhibitors in mHSPC

Atish D. Choudhury, MD, PhD, senior physician, chair, Gelb Center for Translational Research, Dana-Farber Cancer Institute; assistant professor, medicine, Harvard Medical School, discusses the background of the phase 2 A-DREAM trial (NCT05241860), which is evaluating the interruption of treatment in patients with metastatic hormone-sensitive prostate cancer (mHSPC) who show exceptional responses to initial treatment with a combination of androgen deprivation therapy (ADT) and a novel androgen receptor (AR) pathway inhibitor.

The use of AR pathway inhibitors and hormone-blocking drugs, alongside testosterone-lowering agents, has been tested in phase 3 trials for mHSPC, which have demonstrated a survival benefit with these drugs over androgen deprivation or testosterone suppression alone, Choudhury begins. In all these trials, these drugs were administered continuously until disease progression, he reports. However, many patients achieve undetectable prostate-specific antigen (PSA) levels and have scan results showing no active cancer, raising the question of whether continuous treatment is necessary for maintaining optimal benefits, Choudhury elucidates.

Notably, this hypothesis also brings up the possibility of taking breaks from treatment to recover testosterone levels or mitigate adverse effects (AEs), including both short-term AEs, such as hot flashes, fatigue, and weakness, and long-term metabolic changes, such as weight gain, muscle loss, and bone loss, he says. Cardiovascular and cognitive risks, including dementia, have also been noted with the use of AR pathway inhibitors, Choudhury explains.

Given these concerns, the A-DREAM study aims to explore whether treatment breaks can be beneficial, he expands. By enrolling approximately 75 patients whose PSA levels have dropped below 0.2 ng/ml, the study will observe the duration of time that elapses before they need to resume treatment, Choudhury explains. If a significant proportion of these patients can remain off treatment for a substantial period, defined as 18 months, this finding would support the idea that intermittent treatment might be advantageous, he says.

This pilot study seeks to determine whether the harms of continuous treatment outweigh the benefits, and whether strategic treatment breaks could help manage the AEs associated with long-term androgen deprivation and still allow for this therapy to effectively control the cancer, Choudhury concludes.