Revisiting Intermittent Therapy in Metastatic Prostate Cancer: Can Less Be More in the "New World Order"?

Androgen deprivation therapy (ADT) is the standard of care for men with metastatic hormone-sensitive prostate cancer (HSPC) and a potential treatment option in those with prostate-specific antigen relapse after local therapy. Based on promising biological and preclinical data, several clinical trials compared the efficacy of intermittent androgen deprivation (IAD) versus continuous androgen deprivation (CAD) with the objective of delaying disease progression and improving survival and quality of life (QoL).

The objective of this review is to revisit the concept of IAD in the "new world order" and reconsider whether it has a potential clinical role in an era where we have seen unprecedented progress in the management of patients with metastatic HSPC.

MEDLINE, Embase, and the Cochrane Library databases were searched for randomized controlled trials comparing IAD and CAD therapies. References of retrieved articles were also searched. Articles with at least 100 randomized patients, which were published in 2008 or later and had data on overall survival or QoL outcomes, were included.

The evidence to date cannot exclude inferiority of IAD compared with CAD with respect to survival outcomes. The hazard ratios in metastatic disease indicate less favorable survival with IAD. No superiority trial conclusively favored IAD or CAD. Two trials demonstrated noninferiority of IAD, although the noninferiority margins (NIMs) are clinically concerning. Another trial could not exclude noninferiority. A modest but temporary QoL and symptom benefit generally favoring IAD was observed.

IAD has not conclusively demonstrated an impact on disease progression or survival, and has only modest effects on QoL and symptoms measured in the short term. As such, it is not the standard of care, particularly in the era where we have seen unprecedented survival impact with combination ADT+docetaxel or abiraterone +prednisone. IAD may need to be reassessed in the context of current therapies, ideally driven by biological rationale, with the goal of minimizing physical and financial toxicities with appropriately designed informative clinical trials.

In this report, we looked at two hormone therapy approaches for prostate cancer that is still sensitive to castration: one with treatment breaks and one without. Patients may tolerate therapy with breaks more easily, but this effect is not sustained and is not associated with better longevity. The best longevity is seen in patients who receive newer hormone therapies or chemotherapy in addition to continuous hormone therapy. Whether these newer therapies would be as effective if given intermittently is an important but unanswered question.