| The following article features coverage from the American Association for Cancer Research (AACR) 2020 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage. |
The combination of durvalumab with olaparib and chemotherapy improved pathologic complete response (pCR) compared with chemotherapy alone among women with stage II/III, HER2-negative, high-risk breast cancer, according to results from the response-adaptive, phase 2 I-SPY2 trial, presented at the American Association for Cancer Research (AAVR) Virtual Annual Meeting I.
In HER2-negative breast cancer, PARP inhibition in the setting of DNA repair deficiency promotes development of neoantigens, activation of the STING signaling pathway, and an increase in PD-L1 tumor expression. In addition, BRAF and MEK inhibition can increase the influx of T cells into the tumor microenvironment and decrease regulatory T cells. Therefore, the aim of the I-SPY2 trial was to test the combination of a PARP inhibitor with an anti–PD-L1 antibody with chemotherapy.
The multicenter, phase 2 I-SPY2 trial used response-adaptive randomization within molecular subtypes to assign patients with HER2-negative stage II/III breast cancer to receive neoadjuvant durvalumab plus olaparib and paclitaxel (DOP; 73 patients) or paclitaxel (299 patients).
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A third arm of the trial is evaluating an investigational agent with or without paclitaxel, but was not reported in this presentation.
Durvalumab was administered as 3 cycles of 1500 mg every 4 weeks, then 12 cycles of 100 mg olaparib twice daily during weeks 1 to 11 concurrently with 80 mg/m2 of weekly paclitaxel. Both treatments were followed by 4 cycles of doxorubicin and cyclophosphamide, then surgery.
There were 3 cohorts of patients: all HER2-negative disease, hormone receptor (HR)-positive/HER2-negative disease, and HR-negative/HER2-negative (ie, triple-negative breast cancer [TNBC]). Patients with HR-positive disease were screened by MammaPrint for risk status, and only patients with high-risk disease received the durvalumab-olaparib combination.
Serial MRI and pCR data were used to continuously estimate predicted pCR rate, and treatment arms graduated with success when their predicted probability of success reached at least 85% in a 300-patient phase 3 neoadjuvant trial. Accrual was stopped when an arm graduated.
Graduation with success of the DOP arm occurred 13 months after enrollment began for the HER2-negative and HR-positive/HER2-negative cohorts. There were 72 patients who underwent surgery and were evaluable for pCR.
At baseline, the median age was 47 years, and 80% of patients were white. HR status was positive in 71% of patients in the DOP arm compared with 53% in the paclitaxel arm. Palpable nodes were more common in the paclitaxel arm, at 36% of patients compared with 29% of patients in the DOP arm.
The final estimated pCR rate was higher in the DOP arm compared with the paclitaxel arm. The final estimated pCR rate was 37% with DOP and 20% with paclitaxel in the HER2-negative cohort, 28% and 14%, respectively, in the HR-positive/HER2-negative cohort, and 47% and 27%, respectively, in the TNBC cohort. Based on these values, the predicted probability of success of DOP in a future phase 3 trial was 81.4%, 74.5%, and 80.6% for HER2-negative, HR-positive/HER2-negative, and TNBC, respectively.
“Exploratory analyses suggested several potential predictive markers,” Lajos Pusztai, MD, DPhil, of Yale Cancer Center and the lead author and presenter of the study, said during the session.
In the HR-positive/HER2-negative cohort, the subgroup of patients with an ultra-high MammaPrint score appeared to drive the pCR benefit, at 64% with DOP compared with 22% with paclitaxel alone. In patients with a high MammaPrint score, the pCR was 9% with DOP compared with 10% with paclitaxel.
Among patients with TNBC, higher pCR rate with DOP was also associated with low CD3/CD8 gene-signature ratio, high macrophage/T-cell MHC-Class2 ratio, and high proliferation signature. Stratification by BRCA alterations is under way, Dr Pusztai said.
Residual breast cancer burden (RCB) was reduced with DOP in all cohorts. RCB-0/pCR was increased from 22% to 42% in the HER2-negative cohort, from 16% to 40% in the HR-positive/HER2-negative cohort, and from 29% to 45% in the TNBC cohort.
Dr Pusztai said that the follow-up time was too short to determine progression-free survival or relapse-free survival, but added that these endpoints will be evaluated as the data mature.
There were no unexpected toxicities. Immune-related adverse events occurred in 19% of patients; 1.6% of events were grade 3 to grade 4. Possible immune- or olaparib- grade 2/3 adverse events were reported.
Dr Pusztai concluded that these data suggest that “there may be promising activity with olaparib and durvalumab in addition to paclitaxel.” He added that the combination may be of “particular interest” among women with an ultra-high MammaPrint score.
Read more of Cancer Therapy Advisor‘s coverage of AACR 2020 meeting by visiting the conference page.
Reference
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-SPY 2 TRIAL. Presented at: American Association for Cancer Research (AAVR) Virtual Annual Meeting I; April 27-28, 2020. Abstract CT011.
