BrighTNess data may change guidelines

The long-term follow-up (4.5 years) of the phase 3 randomised BrighTNess trial supported that neoadjuvant carboplatin plus paclitaxel is superior to paclitaxel alone, with high pathologic complete response (pCR) rates and event-free survival (EFS) rate benefits in patients with triple-negative breast cancer, including patients with a germline BRCA mutation. However, the authors also noted that there were no significant differences in overall survival (OS) at this later timepoint.

Prof. Sibylle Loibl (German Breast Group, Germany) presented the newest update from the BrighTNess trial (NCT02032277) from patients with previously untreated histologically or cytologically confirmed stage 2 or stage 3 triple-negative breast cancer (n=634) who were candidates for potentially curative surgery and had a good performance status. Participants were randomly assigned to 3 arms: paclitaxel/carboplatin plus a poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (n=316), paclitaxel/carboplatin only (n=160), or paclitaxel only (n=158). All patients then underwent 4 cycles of chemotherapy with doxorubicin and cyclophosphamide. The primary endpoint was pCR, with key secondary endpoints EFS at 4 years, OS, and eligibility for breast conservation after therapy.

Initial results from this trial had previously shown that the addition of veliparib to carboplatin and paclitaxel improved pCR rates compared with paclitaxel alone, thus meeting the primary endpoint [2]. However, the arm receiving neoadjuvant paclitaxel/carboplatin had similar pCR rates as the triple therapy. Therefore, one of the major conclusions drawn at that time was that the addition of carboplatin to standard neoadjuvant chemotherapy benefitted triple-negative breast cancer patients, not veliparib. There was also no evidence at that time that patients with a germline BRCA mutation benefitted from adding carboplatin to paclitaxel in the neoadjuvant setting.

Now, at the ESMO 2021, Prof. Loibl presented longer follow-up results, which refined some of those initial conclusions. After a median follow-up of 4.5 years (see Figure), the EFS with the paclitaxel/carboplatin/veliparib combination was superior to paclitaxel alone (HR 0.63; 95% CI 0.43‒0.92; P=0.016). However, the addition of veliparib was still not better than just carboplatin/paclitaxel (HR 1.12; 95% CI 0.72‒1.72; P=0.620). Looking at the carboplatin/paclitaxel arm in post hoc analysis, these patients did just as well as the triple therapy arm (HR 0.57; 95% CI 0.36‒0.91; P=0.018). These data confirmed and extended the initial analysis.

Figure: 4-year EFS from the BrighTNess trial [1]



Very few patients in any of the treatment arms died. The lowest incidence of death occurred in patients randomised to carboplatin/paclitaxel (16/160, 10.0%), followed by carboplatin/paclitaxel/veliparib (38/316, 12.0%), and paclitaxel (22/158, 13.9%). While OS was not statistically different between treatment arms, OS was 18.0% better with carboplatin/paclitaxel/veliparib than with paclitaxel (HR 0.82; P=0.452) and 37.0% better with carboplatin/paclitaxel than with paclitaxel (HR 0.63; P=0.166). Comparing the triple to the double therapy showed that the addition of veliparib was associated with a 25.0% higher OS than carboplatin/paclitaxel, although this was not statistically significant (HR 1.25; P=0.455).

Comparing the initial 309 patients who achieved pCR to those who did not achieve pCR, patients reaching pCR had a 74% improvement in remaining event-free (HR 0.26; P<0.0001). Among patients with germline BRCA mutation, those who achieved a pCR were similarly likely to remain event-free (HR 0.14; P=0.0004) as those with germline wildtype BRCA who had achieved pCR (HR 0.29; P<0.0001). Benefit seemed to be equal for germline BRCA mutation carriers as well as germline BRCA wildtype carriers.

With regard to safety, there were no significant differences between the groups in the frequency of myelodysplastic syndrome, acute myeloid leukaemia, or other second primary malignancies. Overall, safety signals were manageable and no new safety signals were reported.

In summary, and taken in context of current guidelines, the results from BrighTNess could change guidelines, supporting that patients with high- or moderate-risk triple-negative breast cancer could be treated in the neoadjuvant setting with paclitaxel and carboplatin followed by standard chemotherapy concurrently with pembrolizumab, followed by surgery, and adjuvant therapy with pembrolizumab plus olaparib for patients with germline BRCA mutations, or capecitabine for patients without mutations. This trial, however, mainly demonstrated conclusively that there were no short- or long-term benefits to adding veliparib to the combination regimen.

1. Loibl S, et al. Event-free survival (EFS), overall survival (OS), and safety of adding veliparib (V) plus carboplatin (Cb) or carboplatin alone to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) after ≥4 years of follow-up: BrighTNess, a randomized phase III trial. Abstract 119O, ESMO Congress 2021, 16–21 September.
2. Loibl S, et al. Lancet Oncol. 2018;19(4):497-509.

 

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Posted on 19 November 202115 February 2024