For a patient with metastatic castration-resistant prostate cancer to the bones with rising PSA but no evidence of radiographic or symptomatic progression, would you continue with the same treatment or change therapy based on biochemical progression?

This question emphasizes the importance of radiographic monitoring while on treatment for mCRPC. In a recent study from the PREVAIL trial of enzalutamide in chemo naive men with mCRPC, we found that radiographic progression occurred in about 1 out of 4 men (25%) without evidence of formal PSA progression, indicating that in some patients a disconnect between PSA secretion and tumor volume occurs over time.  This may reflect more AR-indifferent cancer development or simply lower amounts of PSA production per unit volume of tumor (Bryce et al Prostate Cancer and Prostatic Diseases 2017).  It also emphasizes the importance of both soft tissue (CT/MRI/PET) and bone imaging over time during treatment.  I typically do imaging every 3 months for the first year or two, and space the imaging interval out individually based on the overall response and disease burden/symptoms of the patient.

In terms of PSA drifting upwards during therapy, all studies conducted to date of enzalutamide and abiraterone maintained treatment despite PSA rises alone.  In PCWG3 (Scher et al JCO 2017) we emphasized the importance of treating the patient, not just the PSA, and the survival benefit of these agents was demonstrated by treating until radiographic or clinical progression.  Certainly if the PSA is rising briskly, imaging is warranted and more frequent imaging is reasonable, as is starting discussions of alternative approaches and clinical trial consideration.  This consideration applies to all currently available therapies including sip-T, radium, taxanes, and novel AR-therapies.