Measuring therapeutic efficacy in the changing paradigm of castrate-resistant prostate cancer

Abstract

One of the current challenges in the evaluation of novel agents for the treatment of advanced prostate cancer is the identification of a surrogate end point for overall survival (OS). Prostatespecific antigen (PSA) levels have been used as a screening tool and a biomarker of response to both hormonal and cytotoxic agents. However, PSA levels do not seem to be a suitable surrogate end point for OS in trials of targeted agents for castrate-resistant prostate cancer (CRPC). These findings suggest the need for adopting measures of efficacy that more accurately reflect the mechanisms of action of these agents in phase II trials, in order to realize improvements in OS in the phase III setting. The Prostate Cancer Clinical Trials Working Group (PCWG2) have recently made recommendations for the design of future trials and advised that PSA levels should not be the sole criterion on which to base clinical decisions. Here, we appraise the end points that have been used in phase II and III trials in patients with CRPC, and highlight the need for the adoption of the PCWG2 guidelines, the recommendations of which include radiographic imaging, in addition to bone scintigraphy, and symptomatic or radiographic disease progression criteria.

Quality of Life Associated with Treatment of Castration-Resistant Prostate Cancer: A Review of the Literature

“…PSA response was weakly associated with palliative response in another study, and a PSA decrease ≥50% versus baseline was predictive of longer survival (47). However, PSA is not a validated surrogate endpoint and improvements in survival are not consistently correlated with reductions in PSA (48)(49)(50).…”

18F-fluorodeoxyglucose PET/CT for detection of disease in patients with prostate-specific antigen relapse following radical treatment of a local-stage prostate cancer

“…When considering the inclination of PCa to metastasize to the bones and the limitations of current imaging tools for assessing these bone metastases, the quantitative evaluation a response has proved difficult. Obstacles include the inability to use response criteria, such as RECIST, for bone metastasis assessment by CT, the confounding effect of the flare phenomenon on standard bone scintigraphy, and the ambiguity associated with the clinical significance of serum PSA level changes (39,40). 18 F-FDG PET/CT will be particularly useful in PCa patients with lytic skeletal metastasis (11).…”

Prognostic, predictive and potential surrogate markers in castration-resistant prostate cancer

“…In 2008, the PCWG2 developed and published uniform criteria for definition of progression. Another aim was avoiding premature treatment interruption based on temporary biochemical or radiographic progression [104]. PSA-progression due to PCWG2 definition for clinical trials is currently defined as a progress of ‡25% above a nadir of ‡2 ng/ml with confirmation at least 3 weeks later [45].…”