I-SPY 2: Durvalumab/Olaparib/Paclitaxel Combination for Breast Cancer “Graduates” to Phase 3 Study

July 2020 Vol 11, No 7


Breast Cancer

The combination of the checkpoint inhibitor durvalumab, the PARP inhibitor olaparib, and the taxane paclitaxel as neoadjuvant therapy improved pathological complete response (pCR) compared with physician’s choice of chemotherapy in high-risk HER2-negative stage II or III breast cancer. Improved pCR was also observed with the triplet combination in triple-negative breast cancer (TNBC). These results of the I-SPY 2 trial were presented at the opening plenary session of the 2020 virtual meeting of the American Association for Cancer Research and signal that the triplet regimen “graduates” for further study in a phase 3 trial.

Lajos Pusztai, MD, PhD

“Previous phase 2 studies established the safety of durvalumab added to taxane,” said lead author Lajos Pusztai, MD, PhD, professor of medicine and co-leader of Genetics, Genomics, and Epigenetics at Yale Cancer Center, New Haven, CT. “Olaparib has been shown to improve median progression-free survival and improve response rates. The idea behind the combination was to boost the immune response by adding an anti–PD-1 checkpoint inhibitor, since PARP inhibitors are known to increase the expression of the PD-L1 protein in the tumor. There is a biological and preclinical rationale to combine a PARP inhibitor and checkpoint inhibitor,” Dr Pusztai said.

Adaptive Study Design

The I-SPY trials are a series of multicenter phase 2 trials that use a response-adaptive randomization with in molecular subtypes defined by receptor status and MammaPrint to evaluate novel agents as neoadjuvant therapy for breast cancer with the primary end point of pCR (ie, no residual invasive cancer in the breast). Multiple concurrent arms are tested with a shared control arm. Regimens either “graduate” for further study or are dropped for futility if they have a low predictive probability of being superior to the control arm.

I-SPY 2 included patients with HER2-negative breast cancer and tumors ≥2.5 cm. Hormone receptor–positive (HR+) patients could be included. Patients in the experimental arm (73 patients, including 21 with TNBC) were treated with durvalumab 1500 mg every 4 weeks for 3 cycles, olaparib 100 mg/day weeks 1 through 11 concurrent with paclitaxel 80 mg/m2 weekly × 12 followed by 4 cycles of doxorubicin/cyclophosphamide (AC). The control arm (299 patients) received weekly paclitaxel for 12 weeks followed by 4 cycles of AC.

The experimental arm had a higher rate of probability of future success in a phase 3 trial compared with the control arm: 81% for all HER2– cancers (estimated pCR rate from 22% in controls to 37% with the experimental arm), 80% for TNBC (estimated pCR rate of 27% in controls to 47%, respectively), and 74.5% for HR+/ HER2– patients (estimated pCR rate of 14% for controls to 28%, respectively).

Biomarker Results

The MammaPrint ultra-high (MP2) subgroup accounted for most of the benefit of the experimental combination in the estrogen receptor–positive (ER+)/ HER2– patients. Estimated pCR rates were 64% in the MP2 group compared with 22% in MP1 for the experimental arm, and 9% versus 10%, respectively, for the control arm.

Among the TNBC subgroup, low CD3/CD8 gene signature ratio, high macrophage/T-cell major histocompatibility complex class II gene signature ratio, and high proliferation signature were associated with higher pCR in the experimental arm versus controls.

Correlative studies of BRCA mutation status, tumor mutational burden, and PD-L1 expression will be presented at a later meeting.

Adverse events were reported in 43 patients in the experimental arm and in 251 patients in the control arm. Any grade 3/4 adverse events occurred in 58% of patients in the experimental arm versus 41% in the control arm. More febrile neutropenia, colitis, and elevated liver enzymes were reported in the experimental arm. Grade 3 immune-related adverse events were reported in 19% of patients in the experimental arm versus 1.6% of controls.

Comment on Results

“The subset analysis presented by Dr Pusztai shows more benefit for the triple combination in the ultra-high MammaPrint group than in the lower-risk group. This may allow us to select patients who may benefit from checkpoint inhibitor plus PARP inhibitor, and not use chemotherapy,” said invited discussant Pamela N. Munster, MD, professor in the Department of Medicine, University of California San Francisco.

“The combination studied in I-SPY 2 is promising, and the potential selection of patients with ER+/ HER2– according to ultra-high MammaPrint status is important. Toxicity data are incomplete, and we need to consider financial toxicity. The contribution of PARP inhibitor to checkpoint inhibitor in early-stage breast cancer remains uncertain. We await the results of confirmatory trials stratified for PD-L1 expression and BRCA mutation and homologous repair deficiency status,” Dr Munster stated.

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