BROCADE3: a challenge to the treatment paradigm in BRCA breast cancer?
Mené dans 36 pays sur 513 patientes atteintes d’un cancer du sein de stade avancé et présentant une mutation constitutionnelle BRCA, cet essai de phase III évalue l’efficacité, du point de vue de la survie sans progression, et la toxicité de l’ajout du véliparib à un traitement combinant carboplatine et paclitaxel (durées médianes de suivi : 35,7 et 35,5 mois)
15 years ago, the first reports of chemical synthetic lethality with inhibition of poly(ADP-ribose) polymerase (PARP) in the context of tumour BRCA1 or BRCA2 deficiency were published. 1 , 2 Since that time, the clinical development of PARP inhibitors in patients with advanced breast cancer associated with a germline mutation in BRCA1 or BRCA2 has moved forward in gradual steps. It was gratifying to finally see these drugs cross the finish line, with regulatory approvals from the US Food and Drug Administration and European Medicines Agency for olaparib and talazoparib in 2018 for the treatment of metastatic breast cancer associated with a germline BRCA1 or BRCA2 mutation. These approvals were based on the phase 3 OlympiAD and EMBRACA trials, which compared PARP inhibitor monotherapy with non-DNA-damaging chemotherapy of physician's choice (in the first-line to third-line settings in OlympiAD and in the first-line to fourth-line settings in EMBRACA). 3 , 4 Despite speculation about potentially differential activity based on potency of PARP1 inhibition and degree of PARP trapping, both of these trials yielded similar clinical results in a population of patients with advanced or metastatic breast cancer who had not previously shown platinum resistance. Objective response rates were robust at approximately 60%, and PARP inhibitor monotherapy offered an absolute median progression-free survival advantage of approximately 3 months over chemotherapy (range 7–8·6 months). Despite the initial high rates of response, the duration of response ranged from 5·4 to 6·4 months and no improvement in overall survival was recorded (median overall survival was 19·3 months with PARP inhibitor monotherapy vs 17·1–19·5 months with chemotherapy).
The Lancet Oncology , commentaire, 2019