Clinical utilization of olaparib,a PARP inhibitor,in BRCA1-mutant metastatic acral melanoma

Acral melanoma(AM)is a rare subtype of cutaneous melanoma linked to poor prognosis,largely due to a lacking of effective targeted therapeutic strategies.Whole-genome sequencing(WGS)data revealed that AM showed a different mutation landscape from cutaneous melanoma.1 BRCA1 and BRCA2 mutations appear in about 3%–16%of AMs.2,3 Pharmacologic inhibition of the DNA repair enzyme PARP has been approved by the FDA as monotherapy in patients with deleterious germline BRCA1/2 mutated advanced ovarian cancer,and the usage has been expanded to metastatic breast cancer,pancreatic cancer,and prostate cancer with homologous recombination repair(HRR)gene defects.4 However,whether AM with BRCA mutations is also sensitive to PARP inhibition is unknown.We identified a stageⅣAM patient with a germline BRCA1 frameshift mutation(BRAC1 G1384Nfs∗7)who was resistant to anti-PD1 therapy.Both patient-derived xenograft and cells(PDX/PDC)models from the same AM patient were established.PARP inhibitor olaparib significantly decreased cell proliferation and slowed tumor growth by increasing DNA double-strand breakage in AM cancer cells.Administration of olaparib to the patient achieved stable disease for 3 months.This study provides preclinical and clinical evidence that PARP inhibitors can slow tumor growth in BRCA1-mutant advanced acral melanoma.