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26-04-2021 | Breast cancer | News

Alisertib addition may benefit metastatic breast cancer patients

Author:
Shreeya Nanda

medwireNews: Women with hormone receptor-positive, HER2-negative metastatic breast cancer derive a significant progression-free survival (PFS) benefit from the addition of alisertib to paclitaxel, indicate phase 2 trial findings.

The risk for progression or death was a significant 44% reduced for participants who received alisertib, an adenosine triphosphate–competitive and reversible inhibitor of Aurora kinase A (AURKA), alongside reduced-dose paclitaxel than those given standard-dose paclitaxel alone, report the researchers in JAMA Network Open.

They note, however, that “70% of patients required a dose reduction in alisertib, and 81% had at least 1 grade 3 or 4 AE [adverse event] with the combination.”

Joyce O’Shaughnessy (Baylor University Medical Center, Dallas, Texas, USA) and co-authors explain that “[e]levated expression of AURKA adversely affects prognosis in […] breast cancer and is associated with resistance to taxanes,” which has been shown to be overcome with administration of alisertib in breast cancer cells.

They therefore randomly allocated 139 patients with metastatic or inoperable locally recurrent disease to receive either alisertib 40 mg twice daily on days 1–3, 8–10, and 15–17 of each 28-day cycle alongside paclitaxel 60 mg/m2 on days 1, 8, and 15 or paclitaxel alone at a dose of 90 mg/m2 on the same schedule.

All participants had previously received endocrine therapy, 30% had received one line of chemotherapy in the metastatic setting, approximately a fifth had received the CDK4/6 inhibitor palbociclib, and 41% had previously been treated with neoadjuvant or adjuvant taxane therapy.

Over a median follow-up of 22 months, the primary endpoint of PFS was significantly prolonged for participants who received alisertib plus paclitaxel relative to those given paclitaxel alone, at a median of 10.2 and 7.1 months, respectively (hazard ratio=0.56). The corresponding PFS rates at 1 year were 44.0% and 15.4%.

The PFS curves separated at 6 months, “suggesting that alisertib may delay the development of acquired resistance to paclitaxel,” note the investigators.

At time of analysis, the secondary endpoint of overall survival did not differ significantly between the combination and paclitaxel alone arms (median, 26.3 vs 25.1 months), and neither did the objective response rate (31.0 vs 33.9%), nor the clinical benefit rate (67.2 vs 56.5%).

Neutropenia was the most frequent AE of grade 3 or 4 in the combination versus paclitaxel alone group, observed at rates of 59.5% and 16.4%, respectively, followed by stomatitis or oral mucositis (15.5 vs 0.0%), diarrhea (10.7 vs 0.0%), and anemia (9.5 vs 1.2%).

Among combination-treated patients, 62.1% and 16.7% required a dose delay and reduction of alisertib and paclitaxel, respectively, compared with just 31.4% of those given paclitaxel alone. One patient in the alisertib–paclitaxel group died due to treatment-related sepsis.

In light of the PFS data, the researchers believe that “the combination of alisertib plus paclitaxel warrants further evaluation in a larger confirmatory trial in patients with endocrine therapy–resistant [metastatic breast cancer].”

And they continue: “In addition, the ease of dosing alisertib orally 3 days per week may allow it to be combined with oral taxanes in future trials.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group

JAMA Netw Open 2021; 4: e214103

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