Addition of Denosumab to Neoadjuvant Chemo Does Not Lead to Significant iDFS Differences in Early Breast Cancer

Sibylle Loibl, MD, PhD

The addition of denosumab (Prolia) to neoadjuvant nab-paclitaxel (Abraxane) did not lead to a statistically significant difference in invasive disease-free survival (iDFS) compared with nab-paclitaxel alone in patients with early-stage breast cancer, according to long-term data from the phase 2 GeparX trial (NCT02682693). Furthermore, no statistically significant iDFS difference was observed between the 2 nab-paclitaxel dosing schedules examined in the study.¹

Findings presented at the 2024 ESMO Breast Cancer Congress showed that at a median follow-up of 62.3 months, patients treated with denosumab plus nab-paclitaxel (n = 390) achieved a 5-year iDFS rate of 81.9% compared with 78.9% for those given nab-paclitaxel alone (n = 390; HR, 0.86; 95% CI, 0.62-1.21; P = .3905). Furthermore, irrespective of denosumab use, patients given weekly nab-paclitaxel (n = 390) experienced a 5-year iDFS rate of 81.6% compared with 79.2% for those given nab-paclitaxel on days 1 and 8 every 3 weeks (n = 390; HR, 0.87; 95% CI, 0.62-1.22; P = .4139).

“The most interesting outcome of this trial is the subgroup of [patients with] triple-negative breast cancer [TNBC]. The increase in pathological complete response [pCR] by 10% [from 50% to 60%] with a weekly [nab-paclitaxel] schedule compared with 2 out of 3 weeks translated into increased iDFS, especially in the non-pCR patients,” lead study author Sibylle Loibl, MD, PhD, chair of the German Breast Group and chief executive officer of the GBG Forschungs GmbH, said in a presentation of the data.

Previously reported data showed that weekly nab-paclitaxel—irrespective of denosumab use—led to a pCR rate of 44.9% (90% CI, 41%-49%) compared with 39.0% (90% CI, 35%-43%) for days 1 and 8 every 3 weeks (difference, 5.9%; P = .062). Notably, the addition of denosumab did not lead to a statistically significant improvement in pCR rate, which was 41% (90% CI, 37%-45%) for denosumab plus nab-paclitaxel vs 43% (90% CI, 39%-47%) for nab-paclitaxel alone (difference, –1.8%; P = .582).^1,2

GeparX was a multicenter, prospective, open-label, 2 × 2 randomized trial that enrolled patients with unilateral or bilateral primary breast cancer that was stage cT2 to cT4a-d or cT1c. Patients needed to have either clinically/pathologically node-positive disease or hormone receptor–negative disease; a Ki-67 proliferation index greater than 20%; or HER2-positive disease.²

Patients were randomly assigned to receive 120 mg of subcutaneous denosumab once every 4 weeks in combination with nab-paclitaxel, or nab-paclitaxel alone for 6 cycles. Patients were also randomly assigned to receive nab-paclitaxel at 125 mg/m² once per week for 12 weeks or on days 1 and 8 of every 3-week cycle for 4 cycles. After completing any nab-paclitaxel regimen, all patients received epirubicin at 90 mg/m² plus cyclophosphamide at 600 mg/m² once every 2 weeks or once every 3 weeks before undergoing surgery. Notably, patients with HER2-positive breast cancer also received the trastuzumab (Herceptin) biosimilar ABP908 plus pertuzumab (Perjeta), and patients with TNBC also received carboplatin.²

Patients were stratified by stromal tumor-infiltrating lymphocytes (sTILs), disease subtype, epirubicin/cyclophosphamide schedule, and denosumab use (for nab-paclitaxel randomization).¹

Loibl noted that baseline characteristics were well balanced between the 4 arms. In the overall population (n = 780), the median age was 49.0 years (range, 22.0-80.0); most patients were pre- or peri-menopausal (58.1%) and had cT1 or cT2 disease (94.0%). Additionally, 40.0% of patients had node-positive disease; 39.7% of patients had hormone receptor–positive/HER2-negative disease; 40.6% had TNBC; and 19.6% had HER2-positive disease. Notably, 83.1% of patients had a Ki-67 proliferation of more than 20%, and sTIL levels above 50% were reported in 7.9% of patients. Biweekly epirubicin/cyclophosphamide was given to 53.1% of patients.

Additional data showed that the incidence of iDFS events were similar between the 4 arms. Specifically, 16.2% of patients who were randomly assigned to receive denosumab experienced iDFS events compared with 19.2% of patients who did not receive denosumab. iDFS events included invasive locoregional relapse (5.4% vs 3.8% for denosumab vs nab-paclitaxel alone, respectively), invasive contralateral breast cancer (0.5% vs 0.3%), secondary malignancy (1.3% vs 2.6%), and death (1.0% vs 0.8%). Loibl explained that fewer distant relapses were reported for patients given denosumab (7.9%) vs nab-paclitaxel alone (11.8%); however, she said this difference did not reach statistical significance.

Furthermore, 16.9% of patients given weekly nab-paclitaxel experienced iDFS events vs 18.5% of patients given the agent on days 1 and 8 every 3 weeks. iDFS events in these arms included invasive locoregional relapse (4.4% for weekly nab-paclitaxel vs 4.9% for day 1 and 8 nab-paclitaxel), invasive contralateral breast cancer (0.3% vs 0.5%), distant relapse (10.0% vs 9.7%), secondary malignancy (1.8% vs 2.1%), and death (0.5% vs 1.3%).

Loibl and colleagues also analyzed survival after stratifying patients by pCR status. In patients treated with denosumab who achieved a pCR (n = 171), the 5-year iDFS rate was 91.1% compared with 85.6% for patients who experienced a pCR without denosumab (n = 187; HR, 0.670; 95% CI, 0.350-1.28; P = .228). The 5-year iDFS rates were 76.6% for patients given denosumab who did not achieve a pCR (n = 187) compared with 71.6% for patients who did not receive denosumab and did not have a pCR (n = 190; HR, 0.857; 95% CI, 0.566-1.30; P = .467).

The 5-year distant disease–free survival (DDFS) rate was 95.5% for patients who received denosumab and achieved a pCR vs 87.9% for patients who had a pCR without denosumab (HR, 0.462; 95% CI, 0.210-1.01; P = .054). The 5-year DDFS rates were 78.4% and 73.9% for patients who did not have a pCR with denosumab and without denosumab, respectively (HR, 0.821; 95% CI, 0.532-1.27; P = .372).

The 5-year overall survival rates were 96.8% for patients treated with denosumab who experienced a pCR vs 94.0% for patients who had a pCR with nab-paclitaxel alone (HR, 0.708; 95% CI, 0.252-1.99; P = .513). Those rates were 88.2% and 84.2% for patients who did not have a pCR with or without denosumab, respectively (HR, 0.807; 95% CI, 0.456-1.43; P = .460).

Notably, patients with TNBC who received weekly nab-paclitaxel and achieved a pCR (n = 99) experienced a 5-year iDFS rate of 89.4% compared with 92.2% for patients who had a pCR with day 1 and 8 nab-paclitaxel (n = 84; HR, 1.060; 95% CI, 0.393-2.83; P = .915). In patients with TNBC who did not have a pCR, the 5-year iDFS rates were 72.0% with weekly nab-paclitaxel (n = 50) vs 58.4% for day 1 and 8 nab-paclitaxel (n = 59; HR, 0.582; 95% CI, 0.294-1.15; P = .119).

Disclosures: Dr Loibl reported receiving research grants from AbbVie, AstraZeneca, Celgene, Daiichi-Sankyo, Immunomedics/Gilead, Menarini Stemline, Molecular Health, Novartis, Pfizer, and Roche; serving on an advisory board with honoraria paid to the institution for AbbVie, Amgen, AstraZeneca, BMS, Celgene, DSI, EirGenix, Gilead, GSK, Lilly, Merck, Novartis, Olema, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi, and Seagen; and serving as an invited speaker with honoraria paid to the institution for AstraZeneca, DSI, Gilead, Novartis, Pfizer, Roche, Seagen, and Medscape.

References

1. Loibl S, Reinisch M, Just M, et al. Denosumab added to 2 different nab-paclitaxel regimens as neoadjuvant therapy in patients with primary breast cancer: time to event analysis from the GeparX 2 × 2 randomized clinical trial. Presented at: 2024 ESMO Breast Cancer Congress; May 15-17, 2024; Berlin, Germany. Abstract LBA1.
2. Blohmer JU, Link T, Reinisch M, et al. Effect of denosumab added to 2 different nab-paclitaxel regimens as neoadjuvant therapy in patients with primary breast cancer: the GeparX 2 × 2 randomized clinical trial. JAMA Oncol. 2022;8(7):1010-1018. doi:10.1001/jamaoncol.2022.1059