Durvalumab/olaparib/paclitaxel combo improves pCR in high-risk HER2-negative breast cancer

The use of durvalumab in combination with olaparib and paclitaxel significantly improves pathological complete response (pCR) rate vs paclitaxel alone in patients with high-risk HER2-negative stage II/III breast cancer, new results of the I-SPY 2 trial have shown.

Improvements in pCR rates were also observed with the durvalumab/olaparib/paclitaxel (DOP) regimen in patients with triple-negative breast cancer (TNBC), and in those with HER2-negative and oestrogen receptor (ER)-positive disease with a MammaPrint high-risk molecular profile. [Pusztai L, et al, AACR 2020 Virtual Annual Meeting I, abstract CT011]

In the phase II, multicentre trial with a response-adaptive randomization design, women with HER2-negative breast cancer with tumours ≥2.5 cm, adequate organ function and a performance status of 2 received 12 weeks of neoadjuvant therapy with paclitaxel (80 mg/m² Q2W x12) or DOP (durvalumab 1,500 mg Q4W x 3, olaparib 100 mg BID in weeks 1–11, and paclitaxel 80 mg/m² Q2W x12), followed by 8–12 weeks of doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m² x 4) Q2W or Q3W. The primary endpoint was pCR (ypT0/is and ypN0) rate.

The DOP arm graduated for efficacy in June 2019 (13 months after commencement of enrollment), having demonstrated a ≥85 percent Bayesian predictive probability of success in a 300-patient phase III randomized neoadjuvant trial based on pCR for patients who underwent surgery and MRI response over time for patients still on therapy.

At graduation, there were 73 patients (median age, 48 years) in the DOP arm, including 21 patients (29 percent) with TNBC and 52 patients (71 percent) with ER-positive, HER2-negative and MammaPrint high-risk tumours. In the chemotherapy alone group, there were 299 patients (median age, 48 years), including 142 patients (47 percent) with TNBC, and 157 patients (53 percent) with ER-positive, HER2-negative and MammaPrint high-risk tumours.

 

Improved pCR in all biomarker subsets

“pCR rates were improved with DOP vs chemotherapy alone in all three biomarker subsets,” reported investigator Dr Lajos Pusztai of Yale Cancer Center, New Haven, Connecticut, US.

In the HER2-negative subset (n=73), pCR rate was 37 percent with DOP vs 20 percent with chemotherapy alone, with an 81.4 percent predicted probability of success in a 300-patient phase III randomized trial. In the TNBC subset (n=21), pCR rate was 47 percent vs 27 percent, with an 80.6 predicted probability of success in a phase III trial. In the ER-positive, HER2-negative and MammaPrint high-risk subset (n=52), pCR rate was 28 percent vs 14 percent, and the predicted probability of success in a phase III trial was 74.5 percent.

“The residual cancer burden [RCB] was reduced with DOP vs chemotherapy alone, with fewer RCB-II and RCB-III patients in all biomarker subsets except RCB-III in TNBC,” said Pusztai.

Higher expression of most immune markers was associated with higher pCR rates in both treatment arms and in most biomarker subsets, with no significant marker-treatment interaction.

“Exploratory analyses suggest that in ER-positive and HER2-negative tumours, an ultra-high-risk MammaPrint molecular profile [MP2; n=77] may be a potential predictive marker of benefit with DOP vs chemotherapy alone, with a pCR rate of 64 percent vs 22 percent, as compared with 9 percent vs 10 percent in the MP1 subgroup [n=132],” Pusztai continued.

“In patients with TNBC, low CD3/CD8 ratio, high macrophage/T-cell-MHC class II ratio, and high proliferation signature were associated with higher pCR in the DOP vs chemotherapy alone arm,” he noted.

 

Safety data

No unexpected safety signals were reported in the current cohort. Grade 3/4 adverse events (AEs) occurred in 58 percent of patients in the DOP arm vs 41 percent of those in the chemotherapy alone arm, while grade ≥3 immune-related AEs were experienced by 19 percent vs 1.6 percent of the patients.

According to Pusztai, the AEs were consistent with the known AE profiles of the drugs. The most common grade 3/4 AEs associated with DOP vs chemotherapy alone were febrile neutropenia (16.3 vs 8.4 percent with chemotherapy alone), colitis (7 percent vs 0.4 percent), adrenal insufficiency (7 percent vs 0 percent), alanine aminotransferase increase (4.7 percent vs 2 percent), dehydration (4.7 percent vs 0.8 percent), and vaginal infection (4.7 percent vs 0 percent).

 

ICI/PARP inhibitor combo in early breast cancer: Ready for use?

“These results demonstrate promising activity of durvalumab and olaparib in addition to paclitaxel in patients with early-stage HER2-negative breast cancer, and the potential of a MammaPrint ultra-high-risk molecular profile as a criterion to select patients with early-stage ER-positive and HER2-negative breast cancer who may benefit from immune checkpoint inhibitors [ICIs] and/or PARP inhibitors,” said invited discussant Dr Pamela Munster of the University of California, San Francisco, California, US.

“The benefits of ICIs previously demonstrated in early or metastatic TNBC are likely related to PD-L1 expression. However, the contribution of PARP inhibitors to immunotherapy in patients with early-stage breast cancer who are BRCA mutation carriers remain uncertain,” she commented. “Confirmatory randomized studies in patients stratified for PD-L1 expression as well as BRCA mutation and homologous recombination deficiency [HRD] status are awaited.”

In contrast to the results of most studies, I-SPY 2 showed lower rates of anaemia (grade 1/2, 14 percent vs 17.9 percent; grade 3/4, 2.3 percent vs 4.8 percent) and fatigue (grade 1/2, 46.5 percent vs 80.9 percent; grade 3/4, 2.3 percent vs 1.6 percent) with DOP vs chemotherapy alone, Munster pointed out. “The toxicity data appears incomplete. The financial toxicity of adding both durvalumab and olaparib to a preoperative regimen should also be considered,” she added.