Dr. Pusztai on Rationale for the I-SPY 2 Trial With Durvalumab/Olaparib Combo in HER2- Breast Cancer

Lajos Pusztai, MD, DPhil, professor of medicine and co-leader of Genetics, Genomics, and Epigenetics at Yale Cancer Center, discusses the rationale for the phase 2 I-SPY 2 trial examining the addition of durvalumab (Imfinzi) and olaparib (Lynparza) to neoadjuvant paclitaxel in HER2-negative breast cancer.

The preclinical rationale to combine PARP inhibitors with immunotherapy is quite compelling, says Pusztai. A number of mechanisms are induced by PARP inhibitors in various cell-like models and preclinical animal models that would make the pairing of these inhibitors with immunotherapy manageable. Impaired nucleotide and base excision repair increase mutation and neoantigen load, DNA fragments activate intracellular STING pathway, and PARP inhibition upregulates PD-L1 expression in breast cell lines, according to Pusztai. Three major lines of evidence led to the combination of durvalumab plus olaparib, adds Pusztai.

In the multicenter I-SPY trial, investigators sought to estimate whether the combination of durvalumab, olaparib, and paclitaxel neoadjuvant therapy would increase the pathologic complete response (pCR) rate versus chemotherapy alone in patients with high-risk HER2-negative stage II/III breast cancer.

Results presented at the 2020 AACR Annual Virtual Meeting I showed that in all patients with HER2-negative breast cancer, the predicted probability of pCR with the combination was 37% versus 20% with paclitaxel alone. When broken down by subset, the respective pCR rates were 28% versus 14% in patients with hormone receptor—positive disease and 47% versus 27% in those with triple-negative breast cancer.

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