The Who, What, and How of Cabazitaxel Treatment in Metastatic Castration-Resistant Prostate Cancer
Mené sur 1 200 patients atteints d'un cancer de la prostate résistant à la castration et de stade métastatique, cet essai de phase III compare l'efficacité, du point de vue de la survie globale, et la toxicité de deux doses de cabazitaxel (25 mg/m2 et 20 mg/m2) après un traitement par docétaxel
Since 2004, taxane chemotherapies have improved the outcomes of men with metastatic castration-resistant prostate cancer (mCRPC). When compared with mitoxantrone, both docetaxel and cabazitaxel have been shown to improve overall survival (OS) in studies in the first-line setting (TAX327)1 and after docetaxel (TROPIC).2 The National Comprehensive Cancer Network (NCCN) guidelines currently recommend docetaxel for first-line chemotherapy treatment and cabazitaxel for second-line chemotherapy treatment of mCRPC.3 Although these guidelines help with clinical management, the following important issues arose after the approval of cabazitaxel: the relative efficacy of cabazitaxel versus docetaxel; the efficacy of a lower, less toxic dose of cabazitaxel compared with the approved dose of 25 mg/m2 every 3 weeks; and how to use circulating biomarkers to identify optimally responding patients to maximize clinical benefit. In the articles that accompany this editorial, three important studies inform on these important topics in men with mCRPC. These studies evaluated first-line cabazitaxel compared with docetaxel (FIRSTANA),4 cabazitaxel dosing strategies (FIRSTANA and PROSELICA),5 and a prostate-specific antigen (PSA)– and circulating tumor cell (CTC)–based biomarker strategy linked to taxane response (TAXYNERGY).6 FIRSTANA is a multicenter, multinational, phase III study that randomly assigned 1,168 patients 1:1:1 to cabazitaxel 20 mg/m2 (C20), cabazitaxel 25 mg/m2 (C25), or docetaxel 75 mg/m2 (D75) every 3 week. This trial did not meet its primary end point of demonstrating the superiority of cabazitaxel versus docetaxel in regard to OS (24.5 months for C20 v 25.2 months for C25 v 24.3 months for D75).4 It is important to point out that FIRSTANA was not powered for a noninferiority end point, and therefore, although the progression-free survival (PFS) and OS outcomes were similar across all three treatment arms, cabazitaxel cannot be deemed noninferior to docetaxel. It is possible that had this trial been designed as a noninferiority trial, the conclusions of the study may have differed, given that the 95% CI of the hazard ratio (HR) for OS was quite narrow (HR, 0.97; 95% CI, 0.82 to 1.16), indicating that a 20% relative increase in the HR for death with C25 is unlikely. However, a noninferiority trial would have required a larger sample size, and we are left to make conclusions based on the trial as designed and analyzed. Toxicity profiles of cabazitaxel and docetaxel differed, with patients treated with D75, versus C25 or C20, experiencing higher levels of any grade peripheral sensory neuropathy (25.1% v 12.3% v 11.7%, respectively) and stomatitis (13.7% v 6.6% v 4.9%, respectively). Meanwhile, patients treated with C25, versus those treated with C20 and D75, experienced more diarrhea (49.9% v 32.5% v 37%, respectively), febrile neutropenia (12% v 2.4% v 8.3%, respectively), and hematuria (25.1% v 20.3% v 3.6%, respectively). The rates of nausea, fatigue, and asthenia were similar across the three treatment arms. Although the three treatment arms were similar in the primary end point of OS, as well as for the key secondary efficacy end point of PFS, these different toxicity profiles should allow clinicians flexibility when deciding which first-line taxane to choose for patients with existing comorbidities.