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Ref Type Abstract
PMID
Authors Joshua James Gruber, Anosheh Afghahi, Alyssa Hatton, Danika Scott, Alex McMillan, James M. Ford, and Melinda L. Telli
Title Talazoparib beyond BRCA: A phase II trial of talazoparib monotherapy in BRCA1 and BRCA2 wild-type patients with advanced HER2-negative breast cancer or other solid tumors with a mutation in homologous recombination (HR) pathway genes.
Journal Vol Issue Date Pages Journal Short Title
Journal of Clinical Oncology 37 15_suppl 2019
URL https://ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.3006
Abstract Text Background: Talazoparib, a PARP inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 is unknown. We conducted a single institution phase II trial to evaluate talazoparib in patients (pts) with advanced HER2-negative breast cancer or other solid tumors with a germline (g) or somatic (s) alteration in HR pathway genes not including BRCA1/2. Methods: Eligible pts had measurable disease, lacked a germline or somatic mutation in BRCA1/2, received at least one prior therapy for advanced HER2-negative breast cancer or other solid tumor and had a HR pathway gene mutation: PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, PTEN, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL. Pts with no progression on or within 8 weeks of their last platinum dose were eligible. Pts were treated with talazoparib 1 mg po daily until disease progression. Response was assessed every 8 +/- 1 weeks. If 2 or more responses were observed in 10 pts in stage I, the study would proceed to stage II and enroll 10 additional pts. The null hypothesis of a ≤ 5% objective response rate would be rejected if at least 3 of 20 respond. Results: Twenty pts were enrolled; 13 breast cancer (12 HR+/HER2-, 1 TNBC) and 7 non-breast cancer (pancreas, colon, uterine, testicular, parotid salivary). Median age was 54 years. Of 12 response evaluable pts with breast cancer, 3 had a RECIST response (ORR = 25%, 2 gPALB2, 1 gCHEK2/gFANCA/sPTEN) and 3 additional pts (gPALB2, sATR, sPTEN) had SD ≥ 6 months (CBR = 50%). No responses were seen in non-breast tumors; 2 (gCHEK2 testicular, gATM colon) had SD ≥ 6 months. Talazoparib was well tolerated; 5 patients required dose reduction for hematologic toxicity. Results of tumor HR deficiency status assessment from metastatic biopsies and serial ctDNA profiling will be presented. Conclusions: In this proof-of-concept phase II study, single agent talazoparib demonstrated activity in HER2-negative advanced breast cancer pts with a HR pathway mutation beyond BRCA1/2. Further evaluation of talazoparib in this population is warranted. Clinical trial information: NCT02401347.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PALB2 inact mut Her2-receptor negative breast cancer predicted - sensitive Talazoparib Case Reports/Case Series Actionable In a Phase II trial, Talzenna (talazoparib) treatment was well tolerated, and among 12 evaluable ERBB2 (HER2)-negative breast cancer patients with a homologous repair pathway mutation resulted in response in 25% (3/12) of patients, including two patients with germline mutations in PALB2, and resulted in stable disease for >/= 6 months in 3 patients, including one patient with a germline PALB2 mutation (J Clin Oncol 37, no. 15_suppl (May 20, 2019) 3006). detail...
CHEK2 inact mut FANCA inact mut PTEN inact mut Her2-receptor negative breast cancer predicted - sensitive Talazoparib Case Reports/Case Series Actionable In a Phase II trial, Talzenna (talazoparib) treatment was well tolerated, and among 12 evaluable ERBB2 (HER2)-negative breast cancer patients with a homologous repair pathway mutation resulted in response in 25% (3/12) of patients, including a patient with germline mutations in CHEK2 and FANCA, and a somatic PTEN mutation (J Clin Oncol 37, no. 15_suppl (May 20, 2019) 3006). detail...