The debate over which clinicalendpoints best measure theefficacy of a cancer interventionpersists. Value is in the eye of thebeholder. For patients with advancedmalignancies, improving overall survival(OS) remains the “holy grail,”the gold standard in most randomizedclinical trials. Either a drug statisticallyextends your life or it does not.
Critics justifiably have argued thatOS is not the only important measureof the success of a pharmacologicintervention. Other primary and secondary endpoints include progression-free survival (PFS), disease-free survival (DFS), metastasisfreesurvival (MFS), overall response rates (ORR), complete durableresponses, patient reported outcomes, and other surrogate (oftenbiomarker) endpoints. Effective clinical trial design and ultimatelydrug approval require careful consideration of the endpoints selected,and, increasingly, a dialogue with investigators and regulatory agenciesregarding their willingness to accept survival endpoints short of OS.
In prostate cancer (PCa), this debate is particularly sharp, whereasthe natural history of advanced PCa often extends for years. Therefore, apatient who progresses to castration-resistant disease may be exposed tomultiple treatments over several years prior to his death. As novel, sequentialand combination therapies improve longevity, measuring the effects on OSby a medication tested years earlier becomes incrementally problematic.
The FDA approval of apalutamide on February 14, 2018 for patients with non-metastatic castrate-resistant prostatecancer (nmCRPC) reflects the agency’s growing awareness that clinicallymeaningful cancer endpoints exist in PCa short of OS.1 Approval wasbased on the results of the SPARTAN trial (NCT01946204), whichrandomized 1,207 patients with nmCRPC (2:1) to receive either apalutamide,an oral non-steroidal antiandrogen, or placebo in combinationwith ADT. MFS (time from randomization to first evidence of distantmetastasis or death) was 40.5 months for apalutamide vs 16.2 monthsfor placebo (hazard ratio 0.28; 95% CI: 0.23, 0.35; p<0.0001).2 WhileOS data are not yet mature, there are tantalizing hints that MFS maybe a good surrogate for OS. Moreover, living metastasis free for anadditional 2+ years may not only decrease the risks of skeletal-relatedevents such as pathologic fractures, but likely provides a measurablepsychological boost to patients.
These debates bring us back to the concept of value in health care.That requires a conversation between multiple stakeholders. It shouldbe recognized that the FDA is increasingly listening.