Phase 2 Trial: Optimal PSA-Triggered Intermittent Therapy for mHSPC

This Phase II study explores a novel approach to treating metastatic hormone-sensitive prostate cancer (mHSPC) through PSA-triggered intermittent therapy. Traditionally, men with mHSPC are managed with continuous androgen deprivation therapy (ADT) in combination with androgen receptor pathway inhibitors (ARPIs). This strategy has significantly extended survival but often leads to enduring side effects such as fatigue, metabolic disturbances, sexual dysfunction, and cardiovascular risks, all of which can severely impact quality of life. The concept of intermittent therapy—pausing treatment when the disease is under control and restarting it based on prostate-specific antigen (PSA) levels—has emerged as a way to mitigate these burdens while maintaining therapeutic benefit.

In this trial, patients with newly diagnosed mHSPC begin treatment with continuous relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, combined with an ARPI. Relugolix is particularly suited for this strategy because it suppresses testosterone rapidly and reversibly, allowing for faster hormonal recovery during treatment breaks. Once patients achieve a strong PSA response, defined by a deep decline to a low nadir, therapy is temporarily halted. Treatment resumes only when PSA levels rise beyond a predefined threshold, creating individualized treatment cycles rather than continuous suppression.

This study builds upon earlier research such as the SWOG 9346 trial, which showed that intermittent ADT was not inferior to continuous therapy in terms of overall survival and was associated with modest improvements in quality of life. However, those earlier trials were conducted before the widespread use of ARPIs, which have since become a cornerstone of therapy for mHSPC. Because ARPI-based regimens are more potent but also more toxic, there is a growing need to adapt the intermittent approach to this modern therapeutic context.

PSA kinetics play a central role in this design. PSA levels are among the most reliable indicators of tumor burden and treatment response in prostate cancer. Deep PSA nadirs, especially below 0.2 ng/mL, are linked to improved long-term outcomes. By using PSA as a dynamic biomarker to trigger treatment pauses and resumptions, the trial seeks to individualize therapy intensity according to each patient’s biological response. This adaptive design could minimize unnecessary exposure to therapy while preserving control of the disease.

The primary goal of the study is to determine the proportion of patients who can remain off treatment for at least one year using this PSA-guided intermittent strategy. Secondary objectives include evaluating overall survival, time to next therapy, safety, and patient-reported quality of life over an extended follow-up period. These endpoints will provide a comprehensive picture of whether intermittent therapy can truly balance efficacy and tolerability in the modern treatment era.

Clinical trial.