The invited discussant of BrighTNess,1 Monica Arnedos, MD, PhD, Head of the Breast Cancer Research Program at the Institut Bergonié in Bordeaux, France, said the findings add to growing support for using carboplatin in triple-negative breast cancer, but their clinical application could be complicated by the anticipated approval of PARP inhibitors for these patients.
Studies to date have suggested there is a benefit to carboplatin in the neoadjuvant setting, including a meta-analysis showing that the addition of carboplatin increases pathologic complete response rates from 37% to 52% (P < .001),2 but at the cost of more hematologic toxicity. Higher rates of treatment discontinuation and dose reduction without strong evidence of long-term benefit have also been concerns. “This has led to a lack of consensus in the guidelines to recommend platinum salts in this setting,” Dr. Arnedos said.
“BrighTNess showed that neoadjuvant carboplatin plus paclitaxel is superior to paclitaxel alone, with high pathologic complete response rates and benefit in event-free survival, and with manageable toxicity and no safety signals,” she said. The findings also contradict the idea that patients with germline BRCA mutations would not benefit from carboplatin because of their “extreme sensitivity” to standard neoadjuvant chemotherapy, she added.
Monica Arnedos, MD, PhD
“The BrighTNess study says otherwise,” she pointed out. “The study had already found no significant differences in pathologic complete response based on germline BRCA mutation status. We’ve seen that patients with pathologic complete responses had improved event-free survival regardless of germline BRCA status, so germline BRCA–mutated patients require neoadjuvant carboplatin,” she said.
Impact of Neoadjuvant Carboplatin on PARP Inhibitor Outcomes
However, in light of the anticipated approval of PARP inhibitors for the adjuvant treatment of patients with germline BRCA–mutated tumors, where does carboplatin fit? “Carboplatin given with olaparib would probably have a redundant effect, so there would be no benefit in giving the two of them together, so what is going to be the impact, if any, of neoadjuvant carboplatin in patients who will receive adjuvant PARP inhibitors?” she asked.
In the OlympiA trial, which established the benefit of adjuvant olaparib in patients with germline BRCA mutations, 26% of patients had been previously treated with a platinum and they still had a 23% reduction in risk with the PARP inhibitor later.3 “It does not seem that this neoadjuvant therapy had a detrimental effect on benefit from the PARP inhibitor, but the confidence intervals are wide (0.49–1.21),” she noted.
Further information on this issue comes from the treatment of patients with germline BRCA mutations in the metastatic setting. The OlympiAD trial also found no significant impact of previous carboplatin on olaparib benefit in the absence of progressive disease.4 More interestingly, the BROCADE3 trial evaluated veliparib, carboplatin, and paclitaxel with veliparib as maintenance, showing that the PARP inhibitor added no value to the platinum doublet but did improve progression-free survival as maintenance.5 Dr. Arnedos said the study more or less reflects “what would happen in the neoadjuvant/adjuvant setting.”
Putting this all together, Dr. Arnedos suggested this treatment algorithm, going forward: for patients who require chemotherapy, carboplatin should be added to the regimen. Based on KEYNOTE-522,6 pembrolizumab should be added as well. After surgery, patients not achieving a pathologic complete response need to receive capecitabine. For those with germline BRCA mutations, olaparib should be given. For low-risk or unfit patients, de-escalation strategies should be explored, she said.
DISCLOSURE: Dr. Arnedos has received honoraria, travel grants, and research grants from Novartis, AstraZeneca, Pfizer, and Roche.
REFERENCES
1. Loibl S, Sikov WM, Huober J, et al: Event-free survival, overall survival, and safety of adding veliparib plus carboplatin or carboplatin alone to neoadjuvant chemotherapy in triple-negative breast cancer after ≥ 4 years of follow-up: BrighTNess, a randomized phase 3 trial. ESMO Congress 2021. Abstract 1190. Presented September 17, 2021.
2. Poggio F, Bruzzone M, Ceppi M, et al: Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: A systematic review and meta-analysis. Ann Oncol 29:1497-1508, 2018.
3. Tutt ANJ, Garber JE, Kaufman B, et al: Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 384:2394-2405, 2021.
4. Robson M, Im SA, Senkus E, et al: Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523-533, 2017.
5. Diéras V, Han HS, Kaufman B, et al: Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21:1269-1282, 2020.
6. Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810-821, 2020.
