Data from Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast Cancer

Abstract

<div>AbstractPurpose:<p>We had previously reported on the safety and the recommended phase 2 dose (RP2D) of olaparib in combination with the PI3Kα-specific inhibitor alpelisib in patients with high-grade serous ovarian cancer as studied in a phase 1b trial (NCT01623349). Here, we report on the breast cancer cohort from that study.</p>Patients and Methods:<p>Eligible patients had recurrent triple-negative breast cancer (TNBC) or recurrent breast cancer of any subtype with a germline <i>BRCA</i> mutation and were enrolled to a dose-escalation or -expansion cohort. After definition of the RP2D, secondary end points included safety and objective response rate (ORR). Exploratory analyses were performed using circulating-free DNA (cfDNA).</p>Results:<p>Seventeen patients with TNBC were enrolled with a median of three prior lines of chemotherapy. The most common treatment-related grade 3–4 adverse events were hyperglycemia (18%) and rash (12%). The ORR was 18% (23% for patients treated at the RP2D) and 59% had disease control. The median duration of response was 7.4 months. Analysis of cfDNA tumor fractions (TFx) revealed that patients with TFx < 15% after completion of the first cycle had a longer progression-free survival compared with those with TFx ≥ 15% (6.0 vs. 0.9 months; <i>P</i> = 0.0001).</p>Conclusions:<p>Alpelisib in combination with olaparib is tolerable in patients with pre-treated TNBC, with evidence of activity in non-<i>BRCA</i> carriers. cfDNA provided important prognostic information. Results highlight potential synergistic use of a PI3K inhibitor to sensitize HR-proficient (BRCA wild-type) TNBC to PARP inhibition and suggest the potential to expand the use of PARP inhibition beyond <i>BRCA</i>-mutant tumors.</p></div>