Abstract OT2-05-04: The Talazoparib Beyond BRCA (TBB) trial: A phase II clinical trial of talazoparib (BMN 673) in BRCA1 and BRCA2 wild-type patients with (i) advanced triple-negative breast cancer (TNBC) and homologous recombination deficiency (HRD) as assessed by myriad genetics HRD assay, and (ii) advanced HER2-negative breast cancer (BC) with either a germline or somatic mutation in homologous recombination (HR) pathway genes
Authors: Afghahi A , Chang P-J , Ford JM , Telli ML 
Published: May 2016

Background: Poly-ADP-ribose polymerase (PARP) inhibition induces synthetic lethality in tumor cells bearing deleterious mutations in the genes BRCA1/2. Talazoparib (BMN 673) is a novel, dual-mechanism PARP inhibitor that potently inhibits the PARP enzyme and effectively traps PARP on DNA. Talazoparib has shown promising single-agent anti-tumor efficacy in several BRCA1/2 mutation-associated advanced cancers. The efficacy of PARP inhibition in BRCA1/2 wild-type TNBC with HR defects and in breast tumors with mutations in other non-BRCA1/2 HR pathway genes is currently unknown.

Trial Design & Eligibility: This Phase 2 trial (TBB) explores the activity of single agent talazoparib in BRCA1/2 wild-type BC patients using an optimal Simon two-stage design. Eligible subjects will be assigned to one of two parallel cohorts: 1) Cohort A: Subjects (n=29) with advanced TNBC with underlying HR defects as assessed by the HRD assay and, 2) Cohort B: Subjects (n=29) with advanced HER2-negative BC with a somatic or germline deleterious mutation in a non-BRCA1/2 HR pathway gene. Gene mutations of interest are: PTEN, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, MRE11, ATR, Fanconi anemia complementation group of genes (FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL). Other key eligibility criteria include metastatic disease treated with at least one prior line of chemotherapy, no deleterious BRCA1/2 mutation, and no prior platinum exposure. In cohort A, TNBC patients must have a HRD score of ≥ 42. Eligible patients will receive oral talazoparib (1.0 mg/day, 28-day cycles) until disease progression or unacceptable toxicity.

Endpoints & Statistical Plan: The primary endpoint is objective response rate (ORR). Secondary endpoints include clinical benefit rate (CBR), progression free survival (PFS), and safety. In this study, we have set a null hypothesis of ≤ 5% objective response rate and alternative response rate of ≥ 20% based on RECIST 1.1. Interim analysis will be performed after accrual of 10 patients in each cohort. If at least one out of the 10 patients responds, then we will accrue 19 additional patients for a total of 29 patients in each cohort. At least four patients have to respond out of the 29 patients in each cohort to declare statistical significance at a one-sided 5% level with 80% power or better.

This trial is enrolling patients at Stanford University in California (NCT 02401347).

Citation Format: Afghahi A, Chang P-J, Ford JM, Telli ML. The Talazoparib Beyond BRCA (TBB) trial: A phase II clinical trial of talazoparib (BMN 673) in BRCA1 and BRCA2 wild-type patients with (i) advanced triple-negative breast cancer (TNBC) and homologous recombination deficiency (HRD) as assessed by myriad genetics HRD assay, and (ii) advanced HER2-negative breast cancer (BC) with either a germline or somatic mutation in homologous recombination (HR) pathway genes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-05-04.