Combining PARP Inhibitor With Immunotherapy—Does the Promise of Preclinical Data Translate to Clinic?
Menés respectivement sur 223 patients atteints d'une tumeur solide et sur 200 patients atteints d'un cancer de stade avancé présentant des altérations des gènes BRCA ou ATM, ces deux essais non randomisés (de phase IB/II et de phase IIB) évaluent la dose maximale tolérée et l'efficacité, du point de vue du taux de réponse objective, de l'avélumab en combinaison avec le talazoparib
Defects in DNA damage repair (DDR) cause accumulation of genomic alterations and genomic instability, promoting tumorigenesis. Homologous recombination repair (HRR), a primary mechanism for double-strand DNA repair, relies on presence of sister chromatid, is error free compared with the nonhomologous end-joining pathway of DDR, and occurs during the S/G2 phases of the cell cycle. Aberrations in DDR, such as those caused by alterations in BRCA1, BRCA2, ATM, CHK2, and PALB2 genes, are associated with increased risk of cancer.Synthetic lethality refers to the concept where a defect in either 1 of 2 genes does not affect viability but cooccurrence of defects in both genes leads to cell death. This forms the basis of targeting the base excision repair pathway of DDR by using poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors to treat tumors carrying defects in HRR, especially germline or somatic alterations in BRCA1 and BRCA2 genes. PARP inhibitors are approved for the treatment of nonmetastatic high-risk and metastatic breast cancer in patients with inherited BRCA1 and BRCA2 alterations, as maintenance therapy for ovarian cancer in patients with platinum-sensitive disease, pancreatic cancer in patients with BRCA1 or BRCA2 alterations, and metastatic castration-resistant prostate cancer (mCRPC) with inherited alterations in BRCA1 or BRCA2 or HRR genes.
JAMA Oncology , éditorial, 2021