Abstract OT3-03-02: A phase 2, open-label, single-arm, multi-center study of talazoparib for neoadjuvant treatment of germline BRCA1/2 mutation patients with early-stage triple-negative breast cancer (TNBC)
Authors: Litton J , Symmans F , Gogineni K , Saltzman M , Telli ML , Usha L , Chakrabarti J , Tudor IC , Quek RG , Czibere A 
Published: May 2019

Abstract
Background: Approximately 15% of all breast cancers are triple negative and deleterious BRCA1/2 mutations are found in ˜11% of unselected TNBC. In the phase 3 EMBRACA trial (NCT01945775), the poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib was superior to chemotherapy in prolonging progression-free survival in BRCA1/2 mutation patients with advanced breast cancer. A recent pilot study (NCT02282345) of 20 patients, explored the feasibility of neoadjuvant talazoparib in BRCA1/2 mutation patients; pathologic complete response (pCR) was reported at 53% with 6 months of single agent talazoparib.
Trial Design: This phase 2, single-arm, open-label, multi-center study has a Simon 2-stage design. Eligible pts have stage I-III invasive TNBC (ER and PR &lt;10%), with germline BRCA1/2 mutations who are suitable for neoadjuvant therapy. Pts will receive talazoparib 1 mg daily for 24 weeks, followed by breast surgery, which should occur within 4 to 6 weeks of the last dose. Ultrasound will be performed serially to assess tumor response. The primary objective is to evaluate pCR after 24 weeks of neoadjuvant talazoparib. pCR (ypT0/is ypN0) will be assessed by independent central review. Safety will also be assessed. Pts will be followed for at least 5 years to assess long term outcomes (event-free and overall survival). After surgery, any further adjuvant therapy will be given at the discretion of the treating physician. Pt reported outcomes will be assessed electronically including the global health status/quality of life, functions, and symptoms using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and BR23. Plasma pharmacokinetic (PK) samples for determination of talazoparib concentrations will be collected at defined timepoints to describe the steady-state PK of talazoparib. Exploratory biomarker research will also take place. Approximately 122 men and women will be enrolled in the study, of which 112 evaluable pts are planned. With 112 evaluable pts and one interim futility look, the null hypothesis that the true pCR rate is 35% will be tested against a 1-sided alternative. This design yields a 1-sided type 1 error rate of 2.5% and power of 90% when the true pCR rate is 50%. An interim analysis will be performed to evaluate the efficacy of talazoparib after 28 evaluable pts undergo talazoparib treatment for 24 weeks, followed by surgery, and are assessed for pCR by central review. This trial is currently recruiting and is registered at clinicaltrials.gov (NCT03499353).
Funding: This study is sponsored by Pfizer, Inc.
Citation Format: Litton J, Symmans F, Gogineni K, Saltzman M, Telli ML, Usha L, Chakrabarti J, Tudor IC, Quek RG, Czibere A. A phase 2, open-label, single-arm, multi-center study of talazoparib for neoadjuvant treatment of germline BRCA1/2 mutation patients with early-stage triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-03-02.