TBCRC 032 IB/II Multicenter Study: Molecular insights to AR antagonist and PI3K inhibitor efficacy in patients with AR+ metastatic triple-negative breast cancer.

Purpose: Preclinical data demonstrating androgen receptor (AR)-positive (AR+) 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 (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 towards better response compared to non-LAR (75.0% vs. 12.5%, p=0.06), and increased PFS (4.6 vs. 2.0 months, p=0.082). Genomic analyses revealed subtype-specific treatment response; and novel FGFR2 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.