The I-SPY2 trial found that the combination of the checkpoint inhibitor durvalumab, the PARP inhibitor olaparib, and the taxane paclitaxel followed by doxorubicin/cyclophosphamide as neoadjuvant therapy improved pathologic complete responses vs paclitaxel followed by doxorubicin/cyclophosphamide alone in patients with high-risk HER2-negative stage II or III breast cancer, including women with triple-negative disease. The study also found that immune-rich cancers showed higher pathologic complete response rates in all subtypes as well as in the experimental and control arms.

“The probability that the experimental arm is superior to chemotherapy alone is greater than 90% for all three predefined subsets of patients who had HER2-negative disease. There were no unexpected safety signals with the regimen of durvalumab/olaparib/paclitaxel. Adverse events were consistent with the known side effects of each agent,” said Lajos Pusztai, MD, PhD, Professor of Medicine and Co-Leader of Genetics, Genomics, and Epigenetics at Yale Cancer Center, New Haven, Connecticut. Dr. Pusztai presented these results at the first-ever 2020 American Association for Cancer Research (AACR) Virtual Meeting, as necessitated by the COVID-19 pandemic.¹

“The probability of success in a 300-patient phase III neoadjuvant trial was greater than 90% for all three predefined subsets of patients who had HER2-negative disease.”

— Lajos Pusztai, MD, PhD

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“Previous phase II studies established the safety of durvalumab added to a taxane,” Dr. Pusztai said. “Olaparib has been shown to improve median progression-free survival and response rates in germline BRCA-mutant breast cancer. There is biologic and preclinical rationale to combining a PARP inhibitor and a checkpoint inhibitor. In animal studies, PARP inhibitors increase the expression of the programmed cell death ligand 1 (PD-L1) protein in the tumor and also could generate signals that attract and activate immune cells. It is expected that the anti–PD-L1 checkpoint inhibitor, durvalumab, would further increase antitumor immune response.”

Study Details and Findings

The I-SPY trials are a series of multicenter phase II trials using a response-adaptive randomization within molecular subtypes defined by receptor status to evaluate novel agents as neoadjuvant therapy for breast cancer, with the primary endpoint of pathologic complete response. 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.

Patients who participated in the durvalumab/olaparib/paclitaxel arm all had HER2-negative breast cancer that was at least 2.5 cm, and patients who had hormone receptor–positive disease also had to be high risk as defined by the MammaPrint assay.

Pathologic complete response, defined as no residual invasive cancer in the breast or lymph nodes, was used as the endpoint of the trial. It is a potential surrogate marker for disease-free survival, particularly in triple-negative breast cancer. The goal of the study Dr. Pusztai presented was to estimate whether the combination of durvalumab, olaparib, and paclitaxel would increase pathologic complete response rates compared with chemotherapy in HER2-negative stage II/III breast cancer.

In the experimental arm (73 patients, including 21 with triple-negative disease), treatment included durvalumab at 1,500 mg every 4 weeks for 3 cycles, olaparib at 100 mg/d through weeks 1 to 11 concurrently with paclitaxel at 80 mg/m² weekly × 12, followed by 4 cycles of doxorubicin/cyclophosphamide. The control arm (299 patients) received weekly paclitaxel for 12 weeks followed by 4 cycles of doxorubicin/cyclophosphamide. Imaging data were collected at weeks 3 and 12. The productive probability of success in a future phase III trial was calculated separately for three a priori defined biomarker subsets: all HER2-negative, hormone receptor–positive/HER2-negative, and hormone receptor–negative/HER2-negative (triple-negative breast cancer).

Treatment arms “graduate” for efficacy when the Bayesian predictive probability of success in a 300-patient phase III neoadjuvant trial in the appropriate biomarker groups reaches at least 85%. Graduation means that accrual to the experimental arm stops. The durvalumab/olaparib/paclitaxel arm graduated 13 months after enrollment started.

In HER2-negative cancers, the pathologic complete response rate increased from 20% to 37%; in triple negative cancers, it increased from 27% to 47%; and in the HER2-negative/hormone receptor–positive cohorts, from 14% to 28%. The estimated probability that the experimental arm is superior to chemotherapy alone is greater than 98% in all subsets. Durvalumab and olaparib not only increased the rate of pathologic complete response, it also shifted residual cancer burden categories toward lower values, indicating smaller residual cancers in the experimental arm even when cancers were not completely eradicated by the treatment.

Biomarker Results

“Higher expression of prespecified immune gene signatures and PD-L1 mRNA expression were associated with higher pathologic complete response rates in both study arms and in most biomarker subset interactions,” Dr. Pusztai said. “There was no significant marker-treatment interaction indicating that these markers could not identify the group of patients who selectively benefited from the combination therapy.”

“A higher expression of most immune markers was associated with higher pathologic complete response rates in both study arms and in all biomarker subsets.”

— Lajos Pusztai, MD, PhD

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In exploratory analyses, the MammaPrint ultra-high (MP2) subgroup experienced all the benefit of the experimental combination in patients who had estrogen receptor–positive/HER2-negative breast cancer. In this subset, the predicted pCR rate reached 64% in the experimental arm compared with 22% in the control arm. Among the triple-negative breast cancer 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 pathologic complete response in the experimental arm vs the control arm. Results of BRCA mutation status, tumor mutational burden, and PD-L1 protein expression analysis are underway and will be presented at a later meeting,” Dr. Pusztai reported.

In the preliminary toxicity analysis, including 43 patients in the experimental arm and 251 patients in the control arm, grade 3 or 4 adverse events were reported by 58% of patients in the experimental arm vs 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 the experimental arm vs 1.6% of the control arm. 

DISCLOSURE: Dr. Pusztai has served as a consultant or advisor to Almac Diagnostics, AstraZeneca, Athenex, Bristol-Myers Squibb, Clovis Oncology, Eisai, H3 Biomedicine, Immunomedics, Merck, Novartis, Roche/Genentech, Seattle Genetics, and Syndax; has received institutional research funding from AstraZeneca, Genentech, Merck, and Seattle Genetics; has been reimbursed for travel, accommodations, or other expenses by AstraZeneca; and has held an unpaid relationship with NanoString Technologies.

REFERENCE

1. Pusztai L, Han HS, Yau C, et al: Evaluation of durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY2 trial. 2020 AACR Virtual Annual Meeting. Abstract CT011. Presented April 27, 2020.