Abstract OT2-03-04: A trial of induction Talazoparib followed by a combination of Talazoparib and Avelumab in advanced breast cancer: The TALAVE study
Authors: Heeke Arielle L , Pishvaian Michael , Wang Hongkun , Cohen Adam , Schlom Jeffrey , Donahue Renee , Jochems Caroline , Gatti-Mays Margaret , Pohlmann Paula , Tan Antoinette , Isaacs Claudine , Lynce Filipa 
Published: March 2020

Abstract
Background: Patients with advanced breast cancer (ABC) have recently gained access to promising new therapies, including PARP inhibitors (PARPi) and immunotherapy. However, not all patients benefit from these approaches, with response rates highest in patients characterized by a particular biomarker (ie BRCA1/2 mutation or PD-L1 expression). Combination strategies may be more efficacious than single agents and may induce responses in otherwise non-responders. PARPi activate the STING pathway leading to T cell recruitment and stimulate antigen presentation via increased T cell cytotoxic activity, creating a tumor microenvironment that may be more susceptible to immunotherapy. A number of trials have assessed the antitumor efficacy of this combination, though the optimal drug scheduling and the impact of BRCA1/2 status on the effect of PARP inhibition on immunomodulation are unknown. In the TALAVE study, the PARPi talazoparib is combined with the PD-L1 inhibitor avelumab. Talazoparib is an oral small molecule selective inhibitor of PARP-1/2 with potent in vitro PARP trapping capacity. Avelumab is a human IgG1 anti-PD-L1 monoclonal antibody that prevents the interaction between PD-L1 and PD-1 and allows for an engagement of Fc-γ receptors on NK cells to induce tumor-directed ADCC in vitro.
Trial design: This is an open-label, multi-institutional trial (NCT03964532) for patients with ABC. During the phase I portion, 6 patients are enrolled regardless of BRCA1/2 mutation status to assess safety of the combination. A maximum of 24 patients will be enrolled. Eligibility criteria include willingness to undergo serial biopsies and no previous exposure to PARPi or prior disease progression on anti-PD1 or anti-PDL1 therapy or within 6 months of use. Patients will be enrolled to two pre-defined cohorts: cohort 1 - BRCA1/2 mutant and HER2 negative ABC (pre-identified presence of somatic or germline BRCA1/2 deleterious mutation) and cohort 2 - BRCA1/2 wild type and TNBC (patients with previous somatic or germline testing for BRCA1/2 that did not reveal a deleterious mutation). Enrolled patients will receive a 4-week induction of talazoparib (1mg orally daily, D1-D28), followed by a combination of talazoparib and avelumab (800mg IV D1 and D15). To assess the efficacy and immunomodulatory effects of PARP inhibition induction followed by anti-PD-L1 therapy, patients will undergo serial tumor biopsies (baseline, post 4 weeks of talazoparib, post 4 weeks of talazoparib and avelumab and at progression for patients who clearly benefitted from therapy) to assess tumor infiltrating lymphocytes (TILs) and PD-L1 expression. Patients will also undergo serial blood sample collection to gauge the peripheral immunoscore by flow cytometry, including an assessment of the number of immune cells and their function.
Specific aims: The primary objective is to evaluate the safety and tolerability of this combination. Secondary objectives includeassessment of anti-tumor efficacy of combined therapy as determined by measurement of ORR, OS, PFS, DOR and DCR and evaluation of the effect of BRCA1/2 mutation, talazoparib alone, and talazoparib plus avelumab on immunomodulation.
Statistical methods: The projected sample size is 24 patients. Sample size is based on a feasibility analysis. Statistics will be primarily descriptive, and toxicities will be tabulated according to grade. PFS and OS will be estimated using the Kaplan Meier method. DCR and DOR will be calculated according to RECIST v1.1 and compared descriptively to historical outcomes. Cox regression models will assess whether measures of immune activation are associated with ORR, PFS or OS.
Accrual: Patient accrual started in April 2019. To date, 3 of the maximum target accrual of 24 patients have been enrolled in the phase I portion of the study (2 on cohort 1 and 1 on cohort 2).
Citation Format: Arielle L Heeke, Michael Pishvaian, Hongkun Wang, Adam Cohen, Jeffrey Schlom, Renee Donahue, Caroline Jochems, Margaret Gatti-Mays, Paula Pohlmann, Antoinette Tan, Claudine Isaacs, Filipa Lynce. A trial of induction Talazoparib followed by a combination of Talazoparib and Avelumab in advanced breast cancer: The TALAVE study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-03-04.