In a German phase IIb trial (GeparX) reported in JAMA Oncology, Jens-Uwe Blohmer, MD, PhD, and colleagues found that the addition of denosumab to neoadjuvant chemotherapy did not improve pathologic complete response rate in patients with breast cancer. They also found that weekly vs less frequent nab-paclitaxel as part of chemotherapy was associated with a higher pathologic complete response rate.

Jens-Uwe Blohmer, MD, PhD

Study Details  

The multicenter, 2 x 2 design, open-label trial enrolled 780 patients (1 male) between February 2017 and March 2019. Patients had unilateral or bilateral primary disease, stage cT2-cT4a-d or cT1c, with either clinically node-positive or pathologically node-positive or HR-negative disease, or Ki-67 proliferation index > 20%, or HER2-positive disease.

Patients were first randomly assigned to receive denosumab at 120 mg subcutaneously every 4 weeks for six cycles (n = 390) or no denosumab (n = 390), and then randomly assigned to receive nab-paclitaxel at 125 mg/m² weekly for 12 weeks (n = 300) or on days 1 and 8 every 3 weeks for four cycles (8 doses; n = 300), both followed by four cycles of epirubicin at 90 mg/m² and cyclophosphamide at 600 mg/m² every 2 weeks or 3 weeks. Patients with triple-negative disease received carboplatin, and patients with HER2-positive disease received a trastuzumab biosimilar plus pertuzumab.

The primary outcome measure was pathologic complete response rate.

Pathologic Complete Response Rates

Pathologic complete response rates were 41.0% (90% confidence interval [CI] = 37%–45%) among patients receiving denosumab vs 42.8% (90% CI = 39%–47%) among those not receiving denosumab (P = .58). Weekly nab-paclitaxel was associated with a significantly higher pathologic complete response rate (predefined significance level of α = .10) vs nab-paclitaxel on days 1 and 8 every 3 weeks (44.9%, 90% CI = 41%–49%, vs 39.0%, 90% CI = 35%–43%; P = .06).

In subgroup analyses, a significantly higher pathologic complete response rate for weekly nab-paclitaxel vs nab-paclitaxel on days 1 and 8 every 3 weeks was observed only among patients with triple-negative breast cancer (60.4% vs 50.0%, P = .06).

Adverse Events

No significant differences in any-grade or grade 3 and 4 hematologic or nonhematologic adverse events were observed between the denosumab vs no denosumab groups. No differences in any-grade or grade 3 and 4 hematologic toxicity were observed between nab-paclitaxel groups, whereas the weekly group had a higher frequency of grade 3 and 4 nonhematologic adverse events (33.7% vs 24.1%, P = .004). Any-grade nonhematologic adverse events that were more common in the weekly group included increased bilirubin and increased aspartate aminotransferase, fatigue, decreased appetite, diarrhea, arthralgia, epistaxis, palmar-plantar erythrodysesthesia syndrome, and pneumonia. Both any-grade (74.9% vs 46.9%, P < .001) and grade 3 and 4 peripheral sensory neuropathy (5.3% vs 1.1%, P < .001) were more common with weekly nab-paclitaxel.

The investigators concluded, “In this randomized clinical trial, denosumab added to anthracycline/taxane-based neoadjuvant chemotherapy did not improve [pathologic complete response] rates. Nab-paclitaxel at a dosage of 125 mg/m² weekly significantly increased the [pathologic complete response] rate compared with the days 1 and 8, every-3-weeks schedule overall and in triple-negative breast cancer, but generated higher toxicity.”

Sibylle Loibl, MD, of the German Breast Group, c/o GBG Forschungs GmbH, Neu-Isenburg, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was funded by Bristol Myers Squibb and Amgen. For full disclosures of the study authors, visit jamanetwork.com.