TY - JOUR
T1 - TBCRC 048
T2 - Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes
AU - Tung, Nadine M.
AU - Robson, Mark E.
AU - Ventz, Steffen
AU - Santa-Maria, Cesar A.
AU - Nanda, Rita
AU - Marcom, Paul K.
AU - Shah, Payal D.
AU - Ballinger, Tarah J.
AU - Yang, Eddy S.
AU - Vinayak, Shaveta
AU - Melisko, Michelle
AU - Brufsky, Adam
AU - DeMeo, Michelle
AU - Jenkins, Colby
AU - Domchek, Susan
AU - D’Andrea, Alan
AU - Lin, Nancy U.
AU - Hughes, Melissa E.
AU - Carey, Lisa A.
AU - Wagle, Nick
AU - Wulf, Gerburg M.
AU - Krop, Ian E.
AU - Wolff, Antonio C.
AU - Winer, Eric P.
AU - Garber, Judy E.
N1 - Funding Information:
Supported by AstraZeneca.
Funding Information:
We thank the Breast Cancer Research Foundation and Susan G. Komen for the Cure for supporting the Translational Breast Cancer Research Consortium.
Publisher Copyright:
Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
PY - 2020/12/20
Y1 - 2020/12/20
N2 - 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.
AB - 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.
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U2 - 10.1200/JCO.20.02151
DO - 10.1200/JCO.20.02151
M3 - Article
C2 - 33119476
AN - SCOPUS:85098467843
SN - 0732-183X
VL - 38
SP - 4274
EP - 4282
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 36
ER -