Formal I-SPY 2 trial discussant, Pamela N. Munster, MD, Professor in the Department of Medicine, University of California, San Francisco, found the study promising but said confirmatory trials are needed. “What we know so far in preoperative therapy for breast cancer is that pathologic complete response is associated with better outcomes. The association is strongest in triple-negative breast cancer and may be less so in less aggressive hormone-sensitive tumors,” she noted.

Pamela N. Munster, MD

“I-SPY 2 showed that the addition of durvalumab and olaparib to a standard-of-care neoadjuvant regimen was of benefit in all HER2-negative tumors. Other studies have found that a higher expression of PD-L1 [programmed cell death ligand 1] and other immune markers were associated with pathologic complete response,” continued Dr. Munster.

“There is much excitement about integrating a PARP inhibitor in the preoperative setting, possibly replacing chemotherapy,” she added. “The combination of a PARP inhibitor and a checkpoint inhibitor in early-stage breast cancer may enhance immune reactivity in the setting of high tumor mutational burden, but recent trials have dampened that enthusiasm.” Dr. Munster noted that Dr. Pusztai did not present results according to PD-L1 expression or BRCA mutational status.

Cautious Optimism

“The contribution of durvalumab to olaparib is not clear. This combination needs to be studied in a larger trial with a prespecified population,” Dr. Munster noted. “The subset analysis presented by Dr. Pusztai showed more benefit for the triple combination in the ultra-high MammaPrint group than in the lower-risk group. This may allow us to select patients who may benefit from a checkpoint inhibitor plus a PARP inhibitor and not use chemotherapy,” she continued.

Dr. Munster cautioned that side effects need to be considered. The addition of durvalumab to olaparib and the standard-of-care neoadjuvant regimen adds about a 17% excess in grade 3 and higher immune-related adverse events, she commented. “The data appear to be incomplete as the presented table showed fewer toxicities in the durvalumab/olaparib arm, for example, with regard to fatigue and anemia,” Dr. Munster said.

“We also need to consider the financial burden of a regimen that combines a checkpoint inhibitor, a PARP inhibitor, and standard therapy,” she told listeners. “The contribution of PARP inhibitors to checkpoint inhibitors in early-stage breast cancer remains uncertain. We await the results of confirmatory trials stratified for PD-L1 expression and BRCA mutation and homologous repair deficiency status.” 

DISCLOSURE: Dr. Munster has served in an advisory role for Alessa Therapeutics; holds stock or other ownership interests in Alessa Therapeutics; has received honoraria from AstraZeneca, Atlas MedX, CStone, Epigene Therapeutics, Jubilant, and McVeigh; has an immediate family member who has received honoraria from Prometheus Laboratories and Merck; has received institutional honoraria from Xynomic Pharma; has served as a consultant or advisor to HUYA Bioscience International; has received institutional research funding from Actuate, Amgen, Andes Biotechnologies, AstraZeneca, Bristol-Myers Squibb, Celgene, Corcept, Genentech/Roche, GlaxoSmithKline, Immune Design, Merck, Merrimack, Nektar, Novartis, OncoMed, Onconova Therapeutics, Oric, Pfizer, Piramal Life Science, Plexxikon, and Sanofi; and holds a patent for “using silastic implants to deliver anticancer agents.”