Understanding Nonmetastatic CRPC

Matthew R. Smith, MD, PhD:Androgen deprivation therapy, or ADT, is the mainstay of treatment for metastatic prostate cancer and a routine part of care for many men without detectable metastases. Nearly all men with prostate cancer respond to initial ADT, but given enough time, they all progress to castration-resistant prostate cancer, or CRPC. CRPC is operationally defined as a rising PSA despite ongoing androgen deprivation therapy. The distinction between metastatic and nonmetastatic CRPC simply relates to the results of imaging scans to detect the burden of disease.

In men with nonmetastatic CRPC, a series of studies have shown that unfavorable PSA kinetics—meaning a shorter PSA beveling time—predict shorter time to metastasis and death. In unselected patients, for example, the median time to bone metastasis is on the order of about 3 years, whereas if you look at patients with shorter PSA doubling time, say less than 10 months, the median time to bone metastasis drops to about 2 years. And then if you look at time to all types of metastasis, that time drops to about 16 or 18 months. A very clearly shorter PSA doubling time predicts a worse clinical outcome, shorter time to metastasis, and shorter time to mortality.

Until recently, there was no compelling evidence to intervene in patients with nonmetastatic CRPC, other than to continue their standard androgen deprivation therapy. A series of studies to address novel therapies in that setting had failed. Studies of zoledronic acid, denosumab, and atrasentan, for example, all failed to demonstrate an improvement in clinical outcome in this important disease state. So, until recently, my standard approach has been to observe patients, to conduct imaging tests on a regular basis, and then to intervene when a patient first developed a detectable metastasis.

And the reason for that approach is all of the evidence for the approved therapies for metastatic CRPC comes from studies of patients who had detectable metastasis by conventional imaging. So, that’s really where the strength of the evidence came for intervening. And my approach has long been to observe patients with nmCRPC until they develop detectable metastases.

Transcript edited for clarity.