Carboplatin added to paclitaxel confers EFS benefit in triple-negative breast cancer
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The addition of carboplatin to paclitaxel improved pathologic complete response and EFS with no increase in secondary malignancies among patients with triple-negative breast cancer, randomized phase 3 trial results showed.
Adding the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib to the combination, however, did not increase the benefit, according to long-term data from the BrighTNess trial presented during the virtual ESMO Congress 2021.
“These findings overall support the inclusion of carboplatin into the neoadjuvant chemotherapy for stage II and III triple-negative [patients with breast cancer], regardless of the germline BRCA status,” Sibylle Loibl, MD, PhD, CEO and chair of the German Breast Group and associate professor at University of Frankfurt, said during her presentation.
Previous results of the BrighTNess trial showed the addition of carboplatin to neoadjuvant chemotherapy, with or without veliparib (ABT-888, AbbVie), conferred a higher rate of pathologic complete response with acceptable safety among patients with operable triple-negative breast cancer.
During ESMO, Loibl reported EFS and OS data — as well as second malignancies, such as acute myeloid leukemia or myelodysplastic syndrome — after at least 4 years of follow-up.
The trial included 634 patients with untreated stage II to stage III triple-negative breast cancer. Researchers randomly assigned the patients 2:1:1 to 12 weekly doses of 80 mg/m2 paclitaxel plus carboplatin area under the curve 6 mg/mL every 3 weeks for four cycles and 50 mg veliparib orally twice a day (n = 316); paclitaxel plus carboplatin and placebo (n = 160); or paclitaxel plus placebo (n = 158). Patients then received doxorubicin and cyclophosphamide in four cycles every 2 to 3 weeks.
Pathologic complete response served as the primary endpoint, with EFS and OS as secondary endpoints. A fixed testing process evaluated the paclitaxel-carboplatin-veliparib combination first against paclitaxel, then against paclitaxel and carboplatin.
Researchers assessed efficacy among all patients and safety among those who received at least one dose.
Median follow-up was 4.5 years.
Results showed 4-year EFS rates of 78.2% (95% CI, 73.5-83.2) with paclitaxel, carboplatin and veliparib, 79.3% (95% CI, 72.9-86.2) with paclitaxel and carboplatin and 68.5% (95% CI, 61.3-76.6) with paclitaxel alone. HRs for EFS were 0.63 (95% CI, 0.43-0.92) with the three-drug combination vs. paclitaxel and 1.12 (95% CI, 0.72-1.72) with the three-drug combination vs. paclitaxel and carboplatin. A post hoc analysis showed an HR for EFS of 0.57 (95% CI, 0.36-0.91) with paclitaxel and carboplatin vs. paclitaxel.
“Patients with a pathologic complete response had a significantly better EFS, and this was similar regardless of the germline BRCA status,” Loibl said during the presentation.
Researchers reported low mortality rates among all three treatment groups (12% with the three-drug combination, 10% with paclitaxel and carboplatin and 14% with paclitaxel only). HRs for OS were 0.82 (95% CI, 0.48-1.38) with the three-drug combination vs. paclitaxel, 1.25 (95% CI, 0.7-2.24) with the three-drug combination vs. paclitaxel and carboplatin, and 0.63 (95% CI, 0.33-1.21) with paclitaxel and carboplatin vs. paclitaxel.
One patient who received the three-drug combination and another who received paclitaxel only developed myelodysplastic syndrome, compared with no patients in the paclitaxel-carboplatin group. Six patients in each of the carboplatin groups developed second malignancies vs. four patients in the paclitaxel group. The most common second malignancy was AML (0.6% of three-drug group; 1.9% of two-drug group; 0.6% of paclitaxel-only group).
“For those [patients with triple-negative breast cancer] who require chemotherapy, carboplatin should be added to the treatment,” invited discussant Monica Arnedos, MD, PhD, assistant professor in the department of medical oncology at Institut Gustave Roussy in France, said immediately after the presentation. “Soon we should add, as well, pembrolizumab [Keytruda, Merck], both based on the results of the BrighTNess study we have seen today and also the KEYNOTE-522 trials.”
Perspective
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The BrighTNess trial, after nearly 5 years of follow-up, establishes that carboplatin added to weekly paclitaxel increases not only the complete pathologic rate (pCR), but also EFS in triple negative breast cancer. Whereas five prior randomized trials confirmed that the addition carboplatin to paclitaxel statistically significantly increases the pCR rate, few trials have sufficient follow-up to report early positive EFS results. OS was not different between the groups.
One would think that the PARP inhibitor veliparib, because of its decreased ability to repair homologous recombination defects, would increase the pCR rate beyond carboplatin. However, in a prespecified analysis, veliparib failed to increase the pCR rate. Perhaps veliparib was the wrong PARP inhibitor, as there are differences preclinically between various agents in this therapeutic class.
What is most exciting is use of a checkpoint inhibitor, pembrolizumab, with neoadjuvant chemotherapy for triple-negative breast cancer in the KEYNOTE-522 trial. Unlike veliparib, pembrolizumab — when added to paclitaxel and carboplatin during and after neoadjuvant chemotherapy — statistically significantly increased the pCR rate and 3-year EFS. What's more, these results were independent of tumor PD-L1 status.
Slow but steady progress — first with carboplatin, then pembrolizumab — is evident in the treatment of triple-negative breast cancer.
Reference:
Schmid P, et al. Abstract 179. Presented at: ESMO Virtual Plenary; July 15, 2021.
Icahn School of Medicine at Mount Sinai
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Loibl S, et al. Abstract 119O. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
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