OBJECTIVES:: Although gains in overall survival (OS) are irrefutable benefits associated to novel cancer drugs, many innovative therapies get regulatory approval based on progression-free survival (PFS) gains. The objective of this study was to evaluate factors that might limit the interpretation of OS results and highlight the need to consider more carefully PFS as a relevant primary endpoint in randomized controlled trials for oncology drugs. METHODS:: A literature review was carried out to identify parameters that affect the interpretation of OS results in the design of a trial and justify the need to use PFS as the main efficacy endpoint. RESULTS:: The main parameters impacting the interpretation of OS gains are: i) cross-over: usually after an interim analysis showing efficacy gains to the intervention group, it’s allowed for patients in the control arm to switch to the intervention drug after progression. In this case, both groups end up being impacted by the benefits associated to using the new drug and, therefore, it’s no longer possible to evaluate unaffected overall survival gains; ii) confounding effects of post-study therapies: similar to crossover, post-study therapies produce contamination effects that can impede the confirmation of OS benefits for a single regimen; iii) study duration: as the median survival of different types of cancer continues to increase, a longer follow-up might be needed to be able to prove statistically significant differences between treatment groups; iv) quality of life is sometimes more affected by disease progression, so looking at the overall survival of the patient might not be so relevant and the focus on avoiding progression may be a better predictor of quality of life. CONCLUSIONS:: There are critical factors affecting the impartial interpretation of OS gains and, therefore, PFS should be used to complement the estimation of clinical benefits for innovative oncology drugs.