IMMUNOTHERAPY IN BREAST CANCER

Adding the immune-checkpoint inhibitor durvalumab and the PARP inhibitor olaparib to standard neoadjuvant chemotherapy may improve outcome in women with high-risk, HER2-negative breast cancer, according to results of the I-SPY 2 trial.

The benefit was apparent in both the hormone-receptor-positive (HR+) and triple-negative breast cancer (TNBC) subgroups.

The I-SPY 2 study enrolled women with high-risk, HER2-negative stage-II/III tumors measuring 2.5 cm or greater. The 73 women randomized to the experimental arm (21 with TNBC and 52 with HR+ tumors with high-risk features on MammaPrint) received neoadjuvant durvalumab and olaparib concurrent with paclitaxel followed by doxorubicin and cyclophosphamide. The 299 women in the control arm received paclitaxel followed by doxorubicin and cyclophosphamide.

The results showed that adding durvalumab and olaparib to standard chemotherapy increased rates of pathologic complete response (pCR) for the overall HER2-negative group (from 20% to 37%) and in HER2-negative/HR+/high-risk status (from 14% to 28%) and TNBC (27% to 47%) subtypes.

"Immune-rich cancers showed higher pCR rates in all subtypes and in both treatment arms," Dr. Lajos Pusztai of Yale Cancer Center in New Haven, Connecticut, reported April 27 at the American Association for Cancer Research (AACR) virtual annual meeting.

"The estimated probability that the experimental (treatment) is superior to chemotherapy alone is greater than 98% in all subsets," he said.

Exploratory analysis suggested several potential predictive markers of benefit of durvalumab/olaparib over chemotherapy alone. These include ultra-high MammaPrint status in HR+ cancers, as well as low CD3/CD8 ratio, high macrophage/Tc-class 2 ratio and high proliferation signature in the TNBC subtype.

There were no unexpected safety signals. Adverse events were consistent with known side effects of these drugs. Overall 19% of patients in the durvalumab/olaparib arm experienced immune-related grade-3 adverse events compared with 1.6% in the control arm.

Dr. Pamela Munster of the University of California, San Francisco, who was invited to discuss the study at the AACR meeting, said it shows "promising activity of durvalumab and olaparib in addition to paclitaxel. This combination may be of particular interest for a subgroup of women with tumors expressing ultra-high MammaPrint" molecular profile.

"The toxicity as presented appears incomplete and one should consider the financial toxicity from this combination," she added.

"Placing this trial in context with other studies, the contribution of PARP inhibitors to immunotherapy in early-stage breast cancer remains uncertain. Thus we should await confirmatory, randomized controlled trials . . . before using combined immune-checkpoint inhibitors and PARP inhibitors in early-stage breast cancer," Dr. Munster concluded.

Dr. Pusztai and Dr. Munster have disclosed financial relationships with AstraZeneca, which makes durvalumab and olaparib.

SOURCE: https://bit.ly/3fqil5b AACR 2020 annual meeting, presented April 27, 2020.