Olaparib–Durvalumab Duo Active In BRCA-Mutated Metastatic Breast Cancer

Author: By Shreeya Nanda, Senior medwireNews Reporter

medwireNews: The combination of olaparib and durvalumab has promising tolerability and antitumour activity in individuals with metastatic breast cancer and germline BRCA1 or BRCA2 mutations, indicate findings from a phase I/II study.

“Preclinical data suggest that PARP inhibitors might elicit an antitumour immune response and provide the rationale for investigating olaparib in combination with durvalumab” in this setting, say the MEDIOLA investigators in The Lancet Oncology.

They report on the breast cancer cohort of the open-label, basket trial comprising 34 patients who had received no more than two lines of chemotherapy for progressive, locally advanced or metastatic triple-negative or hormone receptor (HR)-positive disease. Participants were initially given the PARP inhibitor olaparib 300 mg twice a day for 4 weeks, after which the anti-PD-L1 agent durvalumab was added at a fixed dose of 1.5 g every 4 weeks.

The study authors point out that “[n]o new safety signals, including no excess in immune-mediated adverse events [AEs], were observed”, even though “MEDIOLA employed full doses of both drugs”.

Just under a third (32%) of patients experienced an AE of grade 3 or 4, most frequently anaemia (12%), neutropenia (9%) and pancreatitis (6%), while just over a third (35%) had an immune-mediated AE, the majority of which were grade 1–2.

AEs led to olaparib dose reductions in 18% of participants, durvalumab dose delays in 21% and discontinuation of one or both drugs in 9%. There were no treatment-related deaths during the course of the study.

The primary efficacy endpoint of disease control at 12 weeks was achieved by 80% of participants, which “exceeded the prespecified target of 75%”, say the researchers. But they caution that “this target was based on a phase 2 trial of more heavily pre-treated patients” conducted before the phase III OlympiAD trial demonstrated a benefit from olaparib monotherapy versus standard chemotherapy.

The objective response rate (ORR) at 12 weeks was 63%, with one complete and 18 partial responses, and the median duration of response was 9.2 months.

Researcher Susan Domchek, from the University of Pennsylvania in Philadelphia, USA, and co-workers report median progression-free survival (PFS) and overall survival (OS) durations of 8.2 and 21.5 months, respectively, after a corresponding median follow-up of 6.7 and 19.8 months.

The outcomes were similar in the triple-negative and HR-positive subgroups, with a median PFS of 4.9 and 9.9 months, respectively, and a median OS of 20.5 and 22.4 months.

But the MEDIOLA investigators highlight the “two distinct outcome patterns” in the triple-negative subgroup, “with a group of patients having early disease progression and another group having responses that were mostly durable.”

Finally, noting that the ORR and median OS were “similar to those reported in OlympiAD (19.3 months and 60%)”, the authors comment that their study does not indicate further improvement in outcomes with the addition of immune checkpoint inhibition to olaparib.

And the team concludes: “Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy.”

Reference

Domchek SM, Postel-Vinay S, Im S-A, et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol; Advance online publication 6 August 2020. doi: 10.1016/S1470-2045(20)30324-7