J Clin Oncol 2020 Oct 29
TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes.
Abstract
Purpose
Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g)BRCA1/2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)BRCA1/2 mutations or g/s mutations in homologous recombination (HR)-related genes other than BRCA1/2.
Methods
Eligible patients had MBC with measurable disease and germline mutations in non-BRCA1/2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1/2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS).
Results
Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, sBRCA1/2, ATM, or CHEK2. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with gPALB2 (ORR, 82%) and sBRCA1/2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for gPALB2 and 6.3 months (90% CI, 4.4 months to NA) for sBRCA1/2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone.
Conclusion
PARP inhibition is an effective treatment for patients with MBC and gPALB2 or sBRCA1/2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond gBRCA1/2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.
Related Questions
Would you consider a PARPi for a patient with PALB2 mutated metastatic triple negative breast cancer?
PARP inhibitors currently have FDA approval for treatment of breast cancer in patients with HER2 negative disease who carry a BRCA 1 or BRCA 2 mutation, but not other familial (germline) genetic mutations and they are not approved for tumor (acquired) genetic mutations. Theoretically, PARP inhibito...
Will you offer adjuvant olaparib to patients with somatic BRCA mutated breast cancer given that OlympiA only enrolled germline BRCA+?
I agree that the 3-year DFS benefit is quite compelling for considering adjuvant olaparib in patients meeting the eligibility criteria in NSABP B55 (Tutt et al., PMID 34081848). This also raises the possibility of clinical benefit in other scenarios, particularly those where PARPi have shown meaning...
Would you use a PARP inhibitor in metastatic ER/PR positive breast cancer with somatic BRCA1 mutation but negative for germline mutation?
I certainly would. This is based on data from TBCRC 048 that showed efficacy in sBRCA1/2 as well as gPALB2. Tung et al., PMID 33119476
Would you consider use of PARP inhibitors in patients with metastatic breast cancer with moderate penetrance germline mutations such as CHEK2, ATM, RAD51?
In the Olaparib Expanded (TBCRC 048) study published by @Dr. First Last in JCO, there were no responses to olaparib in metastatic breast cancer with germline or somatic CHEK2 or ATM pathogenic variants (mutations). In contrast, responses were seen in metastatic breast cancer with PALB2 pathogenic va...