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

Abstract

Purpose: 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.

Patients and methods: Eligible patients had recurrent triple-negative breast cancer (TNBC) or recurrent breast cancer of any subtype with a germline BRCA 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).

Results: 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; P = 0.0001).

Conclusions: Alpelisib in combination with olaparib is tolerable in patients with pre-treated TNBC, with evidence of activity in non-BRCA 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 BRCA-mutant tumors.

Conflict of interest statement

Disclosures

FB reports personal fees from Curio Science, outside of the submitted work. LCC is a co-founder and member of the senior advisory board of Volastra Therapeutics. He is a founder, former member of the senior advisory board of Agios Pharmaceuticals and served as member of the senior advisory board of Ravenna Pharmaceuticals (previously Petra Pharmaceuticals). These companies are developing novel therapies for cancer. LCC holds equity in Volastra, Agios, and Ravenna. LCC’s laboratory also received some financial support from Ravenna Pharmaceuticals. No drugs from these companies are discussed in this manuscript. GIS reports grants and personal fees from Eli Lilly, Pfizer, Merck/EMD Serono, and Sierra Oncology; and personal fees from Roche, Bicycle Therapeutics, Fusion Pharmaceuticals, G1 Therapeutics, Cybrexa Therapeutics, Bayer, Ipsen, Astex, Almac, Boehringer Ingelheim, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics and Blueprint Medicines outside the submitted work. In addition, he holds a patent entitled, “Dosage regimen for sapacitabine and seliciclib,” also issued to Cyclacel Pharmaceuticals, and a pending patent, entitled, “Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition,” together with Liam Cornell. VAA has patent applications filed with the Broad Institute and is a member of the scientific advisory boards of AGCT GmbH and Bertis Inc, which were not involved in this study. EPW reports institutional research funding from Genentech/Roche, serving in advisory boards at Leap, and receiving personal fees from Athenex, Carrick Therapeutics, Genentech/Roche, Gilead, GSK, Jounce, Leap, and Syros. PAK reports institutional research funding from AstraZeneca and Novartis during the conduct of the study. PAK also reports serving in advisory boards at AstraZeneca, Pfizer, and Merck outside the submitted work. UAM reports personal fees from Astrazeneca, Merck, Novartis, Blueprint Medicine, and NextCure. GMW reports institutional research funding from Glaxo Smith-Kline, has a patent US 20090258352 A1, “Pin1 as a marker for abnormal cell growth” licensed to Cell Signaling (R&D Systems) and received grant funding from Merck & Co outside of the submitted work. ELM also reports serving as consultant at Lilly, Novartis, AstraZeneca, and Gilead. The other authors declare no competing interests.

©2022 American Association for Cancer Research.

Figures

Figure 1.

Intensity of responses and genomic alterations in the PI3K pathway or DNA damage repair in patients with metastatic breast cancer on this study. In the waterfall plot (top), there are 5 blank bars with asterisks (patients 78, 86, 99, 110, 118). Three of them (patients 99, 110, and 118) had DLT or progression in the brain before the first restaging scan so target lesion was unevaluable. Two participants (patients 78 and 86) did not have evaluable target lesions. Mutations in FANCB, FANCM, and TSC2 were not found. U = “Unknown BRCA status”. N = “Non-BRCA carrier”.

Figure 2.

Duration of responses of 17 patients with TNBC treated with alpelisib plus olaparib. Interval from date of enrollment to date of progression or death. Patients are labelled according to their best response per RECIST 1.1 criteria. Three patients (patients 99, 110, and 118) had DLT or progression in the brain before the first restaging scan so target lesion was unevaluable. U = “Unknown BRCA status”. N = “Non-BRCA carrier”. C = “BRCA carrier”. PD = “Progressive disease”.

Figure 3.

Impact of ctDNA analysis of tumor fraction (TFx) on progression-free survival (PFS). A. At C1D1, the median PFS was 1.6 months for patients with TFx ≥ 25% and 4.7 months for patients with TFx < 25% (p < 0.0001) B. At C2D1, the median PFS was 0.9 months for patients with TFx ≥ 15% and 6.0 months for patients with TFx < 15% (p = 0.0001).