Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial
Menée à partir des données portant sur 160 patients atteints d'un cancer métastatique de la prostate résistant à la castration avec altérations au niveau des gènes BRCA et inclus dans un essai de phase III, cette étude compare l'efficacité, du point de vue de la survie sans progression mesurée par radiographie et de la survie globale, et la toxicité de l'olaparib par rapport à l'abiratérone ou l'enzalutamide
PURPOSE: Phase III PROfound trial (ClinicalTrials.gov identifier: NCT02987543) met its primary and key secondary objectives, demonstrating significantly longer radiographic progression-free survival (rPFS) and overall survival (OS) with olaparib monotherapy versus abiraterone or enzalutamide (control) in patients with metastatic castration-resistant prostate cancer (mCRPC) with alterations in BRCA1, BRCA2 (BRCA), and/or ATM (cohort A) whose disease had progressed on prior next-generation hormonal agent (NHA). We report exploratory post hoc analysis of the subgroup of patients with mCRPC with BRCA alterations in PROfound. METHODS: All patients had an alteration in a homologous recombination repair gene by tumor tissue testing, of which 160 had underlying BRCA alterations. rPFS and OS were estimated using the Kaplan-Meier method. Confirmed objective response rate and safety were also assessed. RESULTS: Olaparib was associated with longer rPFS (hazard ratio [HR], 0.22 [95% CI, 0.15 to 0.32]) and OS (HR, 0.63 [95% CI, 0.42 to 0.95]) than control. There was an rPFS benefit with olaparib in all zygosity subgroups (biallelic [n = 88]; HR, 0.08 [95% CI, 0.04 to 0.16], heterozygous [n = 15] and unknown [n = 57]; HR, 0.30 [95% CI, 0.16 to 0.60]). Patients with BRCA2 homozygous deletions experienced prolonged responses to olaparib (n = 16; median rPFS, 16.6 months [95% CI, 9.3 to not reached]). Some evaluations are limited by small patient numbers. Germline DNA analysis was performed for 112 (70%) patients; risk of disease progression was similar for patients with germline (n = 61; HR, 0.08 [95% CI, 0.03 to 0.18]) and somatic (n = 51; HR, 0.16 [95% CI, 0.07 to 0.37]) BRCA alterations. CONCLUSION: In all subgroups assessed, olaparib improved outcomes versus abiraterone or enzalutamide for patients with mCRPC with BRCA alterations whose disease had progressed on previous NHA.