Neoadjuvant denosumab ineffective in breast cancer

Results from a new phase IIb, 2x2 randomized, open-label trial (GeparSEPTO) showed no improvement in pathologic complete response (pCR) rates when the RANKL inhibitor denosumab was added to anthracycline/taxane-based neoadjuvant chemotherapy in the treatment of primary breast cancer. The study found that a weekly anthracycline/taxane-based neoadjuvant chemotherapy led to improved pCR compared to an every 3-week schedule both overall and in patients with triple-negative breast cancer (TNBC), though it was associated with greater toxicity.

“Currently, I do not see a place for antiosteolytic agents as part of the neoadjuvant therapy in breast cancer,” said lead author Sibylle Loibl, MD, PhD, who is a breast cancer researcher at Goethe (Germany) University. The researchers can’t exclude the possibility of a long-term benefit, and patients will be followed for disease-free and overall survival.

The disappointing result comes after previous studies of denosumab or bisphosphonates as additions to adjuvant therapy reduced metastases and increased survival in breast cancer, prompting optimism that the agents might improve pCR rates and improve survival rates in the neoadjuvant setting.

The failure may be because of the shorter treatment duration, and it’s possible that pCR is not the best endpoint to study for a drug that has long-acting potential, according to Dr. Loibl.

Patients were randomized to 120 mg denosumab every 4 weeks for six cycles or to receive no supplementary treatment. Patients with or without denosumab either received nab-paclitaxel 125 mg/m² weekly for 12 weeks or on days 1 and 8 every 3 weeks, over four cycles (eight total doses), then epirubicin/cyclophosphamide, 90/600 mg/m² (every 2 and 3 weeks, respectively). Patients with triple-negative breast cancer also received carboplatin. Patients with ERBB2-positive breast cancer received the trastuzumab biosimilar ABP980 plus pertuzumab.

The study included 780 patients (1 male), with a median age of 49.0 years. There was no difference in pCR among denosumab recipients and nonrecipients (41.0% versus 42.8%; P = .58). Weekly nab-paclitaxel led to a higher pCR rate than a schedule of days 1 and 8 every 3 weeks (44.9% versus 39.0%; P = .06, significance level of alpha = .10). Among subgroups, there was only a difference in pCR rates among those with TNBC (60.4% versus 50.0%; P = .06). Grade 3-4 toxic effects were similar regardless of denosumab exposure, but nonhematologic grade 3-4 toxicity was higher with weekly nab-paclitaxel (33.7% versus 24.1%; P = .004).

“The overall pCR difference (with nab-paclitaxel as neoadjuvant chemotherapy) seems small, but looking at the data from the GeparSEPTO study we would expect a transformation into a better invasive disease-free survival. Looking specifically into patients with TNBC, there is clear pCR increase by using the weekly regimen. With just over 60%, this is the highest pCR rate reported so far for a chemotherapy-only regimen. I would prefer to use nab-paclitaxel also in early breast cancer and would use the weekly regimen for women with TNBC who are at high risk,” Dr. Loibl said.

The study was limited by an imbalance of tumor subtypes between the treatment groups. The authors wrote that the results should guide further research, but nab-paclitaxel should not currently be viewed as a standard neoadjuvant treatment of breast cancer.

The study was funded by the German Breast Group, Bristol Myers Squibb, and Amgen. Dr. Loibl has served on the advisory boards or given lectures for AbbVie, Amgen, Bayer, Celgene, EirGenix, GSK, Lilly, Merck, Puma, Seagen, AstraZeneca, Daiichi Sankyo, Novartis, Pierre Fabre, Prime/Medscape, Bristol Myers Squibb, Chugai, Ipsen, Roche, and Samsung. She also holds a related patent.