Best of ASCO 2021: new data from triple-negative breast cancer

This year’s ASCO Annual Meeting has been a showcase for the overwhelming success of novel, targeted therapies, particularly in a tumor entity that has – until recently – been felt to be only treatable with chemotherapy. New data are extremely encouraging, but also highlight the need for target identification beyond the classical clinicopathological factors. Both, the Olympia and the Neotala study have been performed in BRCA-mutated tumors, and their results clearly point to the necessity to offer germline testing to HER2-negative high risk early breast cancer. In addition, GeparNuevo once more highlights the fact that immunotherapy is here to stay, not only in the advanced breast cancer setting, but also in early stage breast cancer. The side effect profile is acceptable, and long-term outcome a real improvement to conventional chemotherapy.


NEOTALA-neoadjuvant talazoparib in gBRCA1/2-associated TNBC
A second PARPi trial investigated the efficacy of neoadjuvant talazoparib monotherapy: the openlabel single-arm phase II NEOTALA trial study evaluated talazoparib at 1 mg/day in 61 patients with stage I-III HER2-negative, ER/PR-negative breast cancer and germline BRCA1/2 mutations. Most women (90%) received talazoparib for at least 20 weeks, and 74% received the drug for the full 24-week study period. The primary endpoint was pathologic complete response rate by independent review in the evaluable population, which included patients who received at least 80% of the talazoparib dose and underwent surgery and assessment, plus patients who experienced disease progression before response could be assessed. Treatment with talazoparib resulted in pathologic complete responses in 45.8% of 48 evaluable patients and 49.2% of the intentionto-treat population of 61 patients. Event-free survival and overall survival had not been reached at the time of analysis. The investigators also looked at residual cancer burden (RCB). In the evaluable population, approximately 46% of patients had RCB0 and 31% had RCBII (moderate burden). No patients had RCBI (minimal burden) or RCBIII (extensive burden), and 23% had RCB "other," which included patients who experienced disease progression on study and those who lacked surgery or assessment. Talazoparib was generally well tolerated, and treatment-emergent adverse events were consistent with the established safety profile, with mostly grade 1 or 2 fatigue, nausea, and alopecia. Grade 3 events were observed in 43%; one grade 4 event occurred, which was decreased neutrophil count. Grade 3 anemia, a known toxicity associated with this drug, was observed in 39% of patients. The authors therefore concluded that talazoparib monotherapy was active in the neoadjuvant setting and showed pathologic complete response rates comparable to those historically observed with combination anthracycline-and taxane-based chemotherapy regimens [2].

GeparNuevo-long-term outcome after durvalumab treatment in TNBC
The German Breast Group presented the long-term outcome data of a neoadjuvant phase II study conducted in women with early breast cancer. In this trial, the addition of durvalumab, an anti-PD-L1 checkpoint inhibitor (CPI), was investigated when given to standard neoadjuvant chemotherapy in 174 patients with early TNBC, who were enrolled between June 2016 and September 2017. GeparNuevo randomized patients with cT1b-cT4a-d tumors and centrally confirmed TNBC to durvalumab 1.5 g i.v. or placebo every 4 weeks. Durvalumab/placebo monotherapy (0.75 g i.v.) was given for the first 2 weeks (window phase), followed by durvalumab/placebo plus nab-paclitaxel 125 mg/m 2 weekly for 12 weeks, followed by durvalumab/placebo plus epirubicin/cyclophosphamide (EC) q2 weeks for 4 cycles. Randomization was stratified by stromal tumor infiltrating lymphocytes (sTILs): low (≤ 10%), intermediate (11-59%), high (≥ 60%). The primary objective was pCR (ypT0 ypN0). Secondary time-to-event endpoints included invasive diseasefree survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). The primary objective was reported previously and was less impressive: overall, durvalumab only offered a modest and nonsignificant improvement in pCR rates in response to durvalumab addition. There was, however, a small increase in pRR rates which appeared to be limited to patients treated with durvalumab alone before start of chemotherapy [3]. These results were, however, in striking contrast to the long-term outcome data, which were presented at this year's ASCO meeting: after a median follow-up of 42. 2  no continuation after surgery. These phase II data need to be confirmed by a larger, phase III study which-among other research questions-needs to address the question whether adjuvant therapy with PD-L1 targeting drugs is needed at all [4].

Take home message
Data presented at ASCO 2021 now pave the way for the use of olaparib in early high-risk breast cancer in germline BRCA1/2 carriers. Encouraging results from the use of a PD-L1 antibody in the neoadjuvant treatment of TNBC allows improvement of long-term outcome and challenge our belief that improved long-term outcome is only limited to therapies that increase pCR rates.
Funding Open access funding provided by Medical University of Vienna.
Conflict of interest C. Singer reports financial and non-financial study support from Novartis, AstraZeneca, Sanofi, Daiichi-Sanyko, Amgen, Gilead, and travel grants and speaker's honorary from Roche, Novartis, AstraZeneca, Gilead Sciences, and Amgen.
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