Abstract CT142: TALAVE: Induction talazoparib (tala) followed by combined tala and avelumab in patients (pts) with advanced breast cancer (ABC)

Abstract

Abstract Background: PARP inhibitors (PARPi) significantly extend progression-free survival (PFS) compared to chemotherapy in pts with BRCA1/2 mutated (BRCA1/2m) ABC, but responses are not durable. PARPi activate the cGAS-STING pathway leading to increased PD-L1 expression and cytotoxic T-cell recruitment, creating a tumor microenvironment (TME) that may be more vulnerable to immunotherapy. This study was conducted to evaluate the safety, efficacy and effects on the TME of the PARPi tala combined with the PD-L1 inhibitor avelumab in ABC, and to assess the impact of BRCA1/2 status on clinical outcomes. Methods: TALAVE was an open-label, multi-institutional trial (NCT03964532) for pts with HER2-negative ABC. Pts were enrolled in two cohorts: cohort 1 - BRCA1/2m and HER2-negative ABC; cohort 2 - BRCA1/2 wildtype TNBC. Pts received a 4-week induction of tala (1mg po daily D1-D28), followed by a combination of daily tala and avelumab (800mg IV D1, D15). The primary objective was the safety and tolerability of the combination. Secondary objectives included ORR, OS and PFS. Pts underwent serial biopsies to investigate molecular signatures associated with BRCA status or clinical benefit using multiple omics techniques: RNA profiling by NanoString PanCancer IO 360™ Panel, GeoMx® Digital Spatial Profiler (DSP) Whole Transcriptome Atlas (WTA) and protein spatial analysis by multiplex immunofluorescence (mIF) and Cyclic Immunofluorescence (CyCIF). Results: 12 pts were enrolled in each cohort. In cohort 1, 5 pts had gBRCA1, 6 had gBRCA2 and 1 had sBRCA2 mutation. The median age was 50 [IQR:43-59.5]; all pts were female, with median of 1 prior therapy for ABC [IQR: 0-2.5]. 42% pts had prior platinum. ORR was 42% (83% in cohort 1; 0% in cohort 2). There were 10 PRs, all in cohort 1. mPFS was 5.1 months (mo) (95% CI: 3.7-7.3 mo); 9.3mo in cohort 1 and 2.9mo in cohort 2. 5 out of 24 pts remain on treatment, all in cohort 1. Treatment related adverse events (TRAEs) included anemia 33%, neutropenia 25% (gr3+ 13%), thrombocytopenia 21% (gr3+ 13%), fatigue 33% and nausea 29%. Other TRAEs gr3+ included dyspnea (4%) and AST elevation (4%). There were no gr5 events. RNA analysis showed that in cohort 1, tala monotherapy disrupted MMEJ, induced antiproliferative effects and expression of genes in the cGAS-STING pathway, including TBK1-mediated IRF3 activation, with downstream induction of T-cell, dendritic cell and cytokine gene expression. These effects were not seen in biopsies post tala monotherapy in cohort 2. mIF analyses demonstrated T-cell and macrophage infiltration in BRCA1/2m tumors. Analyses of post-combination biopsies is ongoing. Conclusions: There were no new safety signals of PARPi combined with immunotherapy. Responses were limited to pts with BRCA1/2m. RNA and protein analyses indicate cGAS-STING activation and immune cell infiltration in BRCA1/2m tumors, validating murine preclinical findings. Citation Format: Filipa Lynce, Kenichi Shimada, Xue Geng, Edward T. Richardson, Candace Mainor, Mei Wei, Julie M. Collins, Paula P. Pohlmann, Arielle L. Heeke, Kelly F. Zheng, Madeline Townsend, Jane Staunton, Stuart J. Schnitt, Joan S. Brugge, Hongkun Wang, Claudine Isaacs, Geoffrey I. Shapiro, Jennifer L. Guerriero. TALAVE: Induction talazoparib (tala) followed by combined tala and avelumab in patients (pts) with advanced breast cancer (ABC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT142.