Metastasis-free Survival — A New End Point in Prostate Cancer Trials
Mené sur 1 401 patients atteints d'un cancer de la prostate résistant à la castration et non métastatique présentant une augmentation rapide du taux de PSA, cet essai de phase III évalue l'efficacité, du point de vue de la survie sans métastase, et la toxicité de l'enzalutamide
Earlier this year, the Food and Drug Administration (FDA) approved apalutamide, an androgen receptor inhibitor, for treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). The approval was based on SPARTAN, a randomized, placebo-controlled trial involving 1207 patients that demonstrated a statistically significant improvement in metastasis-free survival, defined as the time from randomization to either imaging-detectable distant disease or death.1 It was the first drug approval for nmCRPC and the first use of metastasis-free survival as a primary end point to support drug approval.
Nonmetastatic CRPC is a disease state defined by rising levels of prostate-specific antigen (PSA) despite castrate levels of testosterone and the absence of radiographic evidence of distant metastatic disease. The U.S. incidence of nmCRPC is estimated to be 50,000 to 60,000 cases per year.2 PSA screening is common in the United States, and most men with prostate cancer are initially diagnosed with localized asymptomatic disease. Despite early detection and advances in surgical and radiation techniques, disease can recur, and many patients continue to have rising PSA levels after salvage local therapy and subsequent androgen-deprivation therapy. Yet many years may elapse between detection of rising PSA levels and metastasis or death. In one trial of a bone-targeted agent, only a third of control patients had progression to radiographically detectable metastatic disease by 2 years, and median survival was not reached.3 Such long survival periods, along with the availability of multiple subsequent therapies that could confound results, render overall survival an impractical end point and have spurred interest in earlier efficacy end points.
Recognizing growing interest in developing therapies for nmCRPC, the FDA convened an Oncologic Drugs Advisory Committee (ODAC) meeting in 2011 to discuss clinical trial end points and trial designs that might be used to support drug approval.4 The committee examined the risks for metastases, symptoms, complications, and medical interventions associated with disease progression and the practicality of using an overall survival end point in nmCRPC trials. Committee members recognized that the transition from nmCRPC to detectable metastatic disease is a clinically relevant event that can be associated with pain and illness and result in the need for additional interventions. Their recommendations emphasized that though metastasis-free survival is a reasonable end point, ensuring clinical benefit of a drug would require a substantial magnitude of improvement and a favorable benefit–risk evaluation.(...)
New England Journal of Medicine , commentaire, 2017