Durvalumab and olaparib in combination with paclitaxel significantly improved pathologic complete response compared with chemotherapy alone among women with stage II or stage III high-risk, HER2-negative breast cancer, according to results of the randomized phase 2 I-SPY 2 study presented at the virtual American Association for Cancer Research Annual Meeting.
Researchers observed improvement among subsets of women with hormone receptor-positive and triple-negative disease.
“Sequencing and combination of the experimental drugs was driven by pragmatic considerations,” Lajos Pusztai, MD, professor of medicine and director of breast cancer translational research at Yale University and co-director of the Yale Cancer Center Genomics, Genetics and Epigenetics Program, said during the presentation. “This is a relatively nontoxic chemotherapy regimen that requires minimal immunosuppression with a low-dose of Decadron [dexamethasone, Merck] that can even be omitted in some cases.”
The I-SPY 2 trial evaluated novel agents as neoadjuvant therapy for breast cancer using response-adaptive randomization within molecular subtypes defined by receptor status and risk as determined by the MammaPrint (Agendia) 70-gene signature assay.
Researchers tested a combination of the anti-PD-L1 therapy durvalumab (Imfinzi, AstraZeneca), the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza, AstraZeneca) and paclitaxel based on the rationale that DNA repair deficiency in cancer cells can result in immunogenic neoantigens and activation of the sting pathway, as well as the understanding that PARP inhibition can upregulate PD-L1 expression.
The study included women with HER2-negative breast cancer and tumors of 2.5 cm or less, and those with hormone receptor-positive disease had to have a MammaPrint high molecular profile.
Seventy-three women received the combination regimen of durvalumab dosed at 1,500 mg every 4 weeks for three cycles, olaparib dosed at 100 mg twice daily for 11 weeks, and paclitaxel dosed at 80 mg/m2 weekly for 12 weeks, followed by four cycles of doxorubicin and cyclophosphamide. Women in the control group (n = 299) received the weekly paclitaxel and doxorubicin/cyclophosphamide regimen.
The combination group included 21 women with hormone receptor-negative tumors and 52 women with hormone receptor-positive tumors.
Pathologic complete response served as the primary endpoint.
Researchers estimated — and continually updated — the predicted pathologic complete response rate based on serial MRI imaging and imaging response at weeks 3 and 12, combined with accumulating pathologic complete response data. “Graduation” occurred when the Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial in the appropriate biomarker groups exceeded 85%.
Results showed the combination group graduated 13 months after enrollment, with at least 85% predictive probabilities of success for all HER2-negative and the hormone receptor-positive/HER2-negative cohorts.
Seventy-two women completed surgery and were evaluable for pathologic complete response. Final predicted probabilities of success in a future phase 3 trial were 81% for all HER2-negative cancers (estimated pathologic complete response rate, 37%), 80% for the triple-negative subset (estimated pathologic complete response rate, 47%) and 74.5% for patients with hormone receptor-positive/HER2-negative disease (estimated pathologic complete response rate, 28%).
Researchers observed no unexpected toxicities.
“Follow-up is too short to report on PFS or OS in these patients, but that is something we will look at once the data mature,” Pusztai said. – by John DeRosier
Pusztai L, et al. Abstract CT011. Presented at: AACR Annual Meeting; April 27-28, 2020.