Denosumab as an add-on Neoadjuvant Treatment (GeparX)

Summary

Pharmacologic inhibition of RANKL attenuates the development of mammary carcinoma and inhibits metastatic progression in multiple mouse models. In a retrospective analysis it could be demonstrated that elevated expression of RANK was found in 14.5% of patients overall, with a significant predominance in patients with hormone-receptor-negative disease. Expression of RANK was associated with a higher pathological complete response rate but with a shorter disease-free and overall survival. The ABCSG-18 study showed that adjuvant denosumab reduces clinical fractures, improves bone health, and can be administered without added toxicity. It appears therefore reasonable to test denosumab, a clinically available antibody against RANKL in patients with hormone-receptor-negative primary breast cancer as an adjunct to neoadjuvant chemotherapy for its ability to increase pCR rate and improve outcome in relation to the expression of RANK.

Timeline

Start

2017-02-13

Primary completion

2019-12-31

Completion

2020-12-31

Outcome

Mixed primary results

paper 41.0% (90% CI, 37%-45%) with denosumab vs 42.8% (90% CI, 39%-47%) (P = .58) without denosumab PMID 35588050 ↗

paper Nab-paclitaxel at a dosage of 125 mg/m2 weekly significantly increased the pCR rate compared with the days 1 and 8, every-3-weeks schedule overall and in TNBC PMID 35588050 ↗

Publications

• Adams A, Jakob T, Huth A, Monsef I, Ernst M, Kopp M, Caro-Valenzuela J, Wockel A, Skoetz N. Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis. Cochrane Database Syst Rev. 2024 Jul 9;7(7):CD013451. doi: 10.1002/14651858.CD013451.pub2.
• Blohmer JU, Link T, Reinisch M, Just M, Untch M, Stotzer O, Fasching PA, Schneeweiss A, Wimberger P, Seiler S, Huober J, Thill M, Jackisch C, Rhiem K, Solbach C, Hanusch C, Seither F, Denkert C, Engels K, Nekljudova V, Loibl S; GBG and AGO-B. Effect of Denosumab Added to 2 Different nab-Paclitaxel Regimens as Neoadjuvant Therapy in Patients With Primary Breast Cancer: The GeparX 2 x 2 Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1010-1018. doi: 10.1001/jamaoncol.2022.1059.
• Denkert C, Seither F, Schneeweiss A, Link T, Blohmer JU, Just M, Wimberger P, Forberger A, Tesch H, Jackisch C, Schmatloch S, Reinisch M, Solomayer EF, Schmitt WD, Hanusch C, Fasching PA, Lubbe K, Solbach C, Huober J, Rhiem K, Marme F, Reimer T, Schmidt M, Sinn BV, Janni W, Stickeler E, Michel L, Stotzer O, Hahnen E, Furlanetto J, Seiler S, Nekljudova V, Untch M, Loibl S. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021 Aug;22(8):1151-1161. doi: 10.1016/S1470-2045(21)00301-6. Epub 2021 Jul 9.

Drugs

Indications