Clinical Trial Challenges in Metastatic CRPC

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Multiple agents are available for patients with metastatic castration-resistant prostate cancer (mCRPC), notes Charles J. Ryan, MD, such as radium-223, sipuleucel-T, and several chemotherapy agents. Once an individual receives a series of therapies, all of which have survival benefits, it becomes difficult to demonstrate statistically significant survival gains in clinical trials.

In many situations, mCRPC is becoming a chronic disease, which creates challenges in the way that phase III trials are designed. Median survival for patients with mCRPC is about 3 years, explains Ryan, which makes designing, running, and reading out a phase III trial approximately a 5-to-6-year endeavor. While this long-term survival is clinically positive, the longevity of the patients and trials can create a financial resource impediment.

PSA kinetics remain an important read-out and potential surrogate marker for clinical trials that can aid in assessing prognosis and other outcome for patients with mCRPC, states Ryan. Rapid PSA doubling time may be a negative prognostic indicator, along with rapid alkaline phosphatase doubling time.

A 50% PSA decline is a very useful surrogate endpoint, because multiple studies have demonstrated that survival is almost uniformly better in patients who have a greater PSA decline. As PSA is driven by the androgen receptor, the utility of PSA decline is probably more effective in individuals receiving androgen receptor targeted therapy, adds Ryan. PSA decline may be a useful marker for practicing physicians when counseling their patients as to whether or not the therapy that they are receiving is working.

Two exceptions to the utility of PSA decline exist. First, in individuals receiving radium-223, treatment is administered based on palliation and schedule, and, Ryan explains, if PSA rises, it is not a definitive sign that therapy is not effective. Second, when receiving sipuleucel-T in clinical trials, even with a demonstrated survival benefit, there were no discernible changes in PSA levels. As a result, Ryan advises clinicians and patients to not pay much attention to PSA measures when using sipulecuel-T.