TBCRC 032 IB/II Multicenter Study: Molecular Insights to AR Antagonist and PI3K Inhibitor Efficacy in Patients with AR Metastatic Triple-Negative Breast Cancer.

Lehmann BD, Abramson VG, Sanders ME, Mayer EL, Haddad TC, Nanda R, Van Poznak C, Storniolo AM, Nangia JR, Gonzalez-Ericsson PI, Sanchez V, Johnson KN, Abramson RG, Chen SC, Shyr Y, Arteaga CL, Wolff AC, Pietenpol JA, Translational Breast Cancer Research Consortium
Clin Cancer Res. 2020 26 (9): 2111-2123

PMID: 31822498 · PMCID: PMC7196503 · DOI:10.1158/1078-0432.CCR-19-2170

PURPOSE - Preclinical data demonstrating androgen receptor (AR)-positive (AR) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR (≥10%) breast cancer.

PATIENTS AND METHODS - Phase Ib patients [estrogen receptor positive (ER) or TNBC] with AR breast cancer received 160 mg enzalutamide in combination with taselisib to determine dose-limiting toxicities and the maximum tolerated dose (MTD). Phase II TNBC patients were randomized to receive either enzalutamide alone or in combination with 4 mg taselisib until disease progression. Primary endpoint was clinical benefit rate (CBR) at 16 weeks.

RESULTS - The combination was tolerated, and the MTD was not reached. The adverse events were hyperglycemia and skin rash. Overall, CBR for evaluable patients receiving the combination was 35.7%, and median progression-free survival (PFS) was 3.4 months. Luminal AR (LAR) TNBC subtype patients trended toward better response compared with non-LAR (75.0% vs. 12.5%, = 0.06), and increased PFS (4.6 vs. 2.0 months, = 0.082). Genomic analyses revealed subtype-specific treatment response, and novel fusions and AR splice variants.

CONCLUSIONS - The combination of enzalutamide and taselisib increased CBR in TNBC patients with AR tumors. Correlative analyses suggest AR protein expression alone is insufficient for identifying patients with AR-dependent tumors and knowledge of tumor LAR subtype and AR splice variants may identify patients more or less likely to benefit from AR antagonists.

©2019 American Association for Cancer Research.

MeSH Terms (14)

Androgen Receptor Antagonists Antineoplastic Combined Chemotherapy Protocols Class I Phosphatidylinositol 3-Kinases Female Humans Imidazoles Middle Aged Neoplasm Metastasis Oxazepines Phenylthiohydantoin Protein Kinase Inhibitors Receptors, Androgen Survival Rate Triple Negative Breast Neoplasms

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