Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint risk to evaluate novel agents as neoadjuvant therapy for breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/is ypN0)). DNA repair deficiency in cancer cells can lead to immunogenic neoantigens, activation of the STING pathway, and PARP inhibition can also upregulate PD-L1 expression. Based on these rationales we tested the combination of durvalumab (anti-PDL1), olaparib (PARP inhibitor) and paclitaxel in I-SPY2.
Methods: Women with tumors ≥ 2.5 cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone receptor positive (HR+) patients had to have MammaPrint high molecular profile. Treatment included durvalumab 1500 mg every 4 weeks x 3, olaparib 100 mg twice daily through weeks 1-11 concurrent with paclitaxel 80 mg/m2 weekly x 12 (DOP) followed by doxorubicin/cyclophosphamide (AC) x 4. The control arm was weekly paclitaxel x 12 followed by AC x 4. All patients undergo serial MRI imaging and imaging response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Regimens “graduation with success” when the Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial in the appropriate biomarker groups reaches > 85%.
Results: A total of 73 patients received DOP treatment including 21 HR- tumors (i.e. triple-negative breast cancer, TNBC) and 52 HR+ tumors between May 2018 - June 2019. The control group included 299 patients with HER2- tumors. The DOP arm graduated in June 2019, 13 months after enrollment had started, for all HER2- negative and the HR+/HER2- cohorts with > 0.85% predictive probabilities of success. 72 patient completed surgery and evaluable for pCR, the final predicted probabilities of success in a future phase III trial to demonstrate higher pCR rate with DOP compared to control are 81% for all HER2- cancers (estimated pCR rate 37%), 80% for TNBC (estimated pCR rate 47%) and 74.5% for HR+/HER2- patients (estimated pCR rate 28%). Association between pCR and germline BRCA status and immune gene expression including PDL1 will be presented at the meeting. No unexpected toxicities were seen, but 10 patients (14%) had possibly immune or olaparib related grade 2/3 AEs (3 pneumonitis, 2 adrenal insufficiency, 1 colitis, 1 pancreatitis, 2 elevated LFT, 1 skin toxicity, 2 hypothyroidism, 1 hyperthyroidism, 1 esophagitis).
Conclusion: I-SPY2 demonstrated a significant improvement in pCR with durvalumab and olaparib included with paclitaxel compared to chemotherapy alone in women with stage II/III high-risk, HER2-negative breast cancer, improvement was seen in both the HR+ and TNBC subsets.