Overall survival: a gold standard in search of a surrogate: the value of progression-free survival and time to progression as end points of drug efficacy.

Overall survival (OS) has been the gold standard for demonstrating clinical benefit for cancer drugs. It is 100% accurate for the event and time, it is assessed daily, its importance is unquestioned, and it addresses both safety and efficacy. However, OS as the primary efficacy end point requires large studies, long periods of follow-up, and it is potentially confounded by effective crossover, subsequent therapies, and noncancer death. Progression-free survival (PFS) or time to progression (TTP) directly measures the treatment effects of drugs on cancer growth, and they are not confounded by subsequent or crossover therapy. Although PFS and TTP benefits do not translate into OS benefits in all clinical settings examined so far, PFS or TTP improvement with a sufficient magnitude and in the context of favorable benefit-risk ratio should also be considered an important clinical benefit. Acceptance of PFS and TTP improvement demonstrated by well designed and conducted studies as direct evidence of clinical benefit will accelerate cancer drug development and make effective therapy available to patients with cancer sooner. The availability of sequential therapies, each delivers incremental progress in tumor control and PFS, may collectively lead to transformation of cancer to a curable or controllable chronic disease.