Adding Carboplatin to Neoadjuvant Paclitaxel Improved Outcomes in TNBC

Article

Although the addition of carboplatin to neoadjuvant paclitaxel followed by cyclophosphamide helped to improve outcomes for those with treatment-naïve triple-negative breast cancer, the addition of veliparib did not have an impact on pathologic complete response or event-free survival.

Carboplatin and neoadjuvant paclitaxel plus doxorubixin and cyclophosphamide had a notable impact on pathologic complete response (pCR) rate and event-free survival among those with treatment-naïve triple-negative breast cancer (TNBC), according to the results of the phase 3 BrighTNess trial (NCT02032277) which were presented during the 2021 European Society of Medical Oncology Congress.1

At a median follow-up of 4.5 years, the addition of the PARP inhibitor veliparib to carboplatin and paclitaxel resulted in a 37% reduction in the risk of events or death compared with paclitaxel alone (HR, 0.63; 95% CI, 0.43-0.92; P = .02). However, when the veliparib regimen was compared with carboplatin/paclitaxel, no event-free survival (EFS) benefit was observed (HR, 1.12; 95% CI, 0.72-1.72; P = .62). Post-hoc analyses showed that EFS was most improved with carboplatin/paclitaxel compared with paclitaxel (HR, 0.57; 95% CI, 0.36-0.91; P = .02).

“Adding carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the pathologic complete response significantly, and this translated into an improved EFS by an absolute 11% after a median follow-up of 4.5 years,” Sibylle Loibl, MD, lead study author and chair of the German Breast Group in Germany, said in a virtual presentation on the findings. “The addition of veliparib did not impact pCR, EFS, or [overall survival]. These findings, overall, support the inclusion of carboplatin into neoadjuvant chemotherapy for stage II to III TNBC, regardless of germline BRCA status.”

TNBC is known to have the highest risk of recurrence and a worse overall prognosis for survival compared with other breast cancers. Standard treatment is comprised of neoadjuvant chemotherapy followed by surgery.

In the double-blind, placebo-controlled, phase 3 BrighTNess trial, 634 patients with treatment-naïve stage II/III TNBC were randomized 2:1:1 to receive paclitaxel at 80 mg/m2 weekly for 12 doses in up to 16 weeks plus carboplatin at area under the curve (AUC) 6 mg/mL every 3 weeks for 4 cycles plus veliparib at 50 mg orally twice daily (arm A; n = 316); carboplatin plus paclitaxel plus placebo (arm B; n = 160); or paclitaxel plus placebo (arm C; n = 158).

Doxorubicin was then given at a 60-mg/m2 dose with cyclophosphamide at 600 mg/m2 every 2 or 3 weeks for 4 cycles. Patients underwent surgery 2 to 8 weeks following the last dose of chemotherapy. A postsurgical assessment was done every 3 months until 1 year after surgery, followed by every 6 months until 2 years after surgery, and then annually until 4 years after surgery or until an EFS event.

To be eligible for enrollment, patients had to be at least 18 years old, have histologically or cytologically confirmed invasive stage II/III TNBC, have an ECOG performance status of 0 or 1, and be eligible for potentially curative surgery with documented germline BRCA status.

Those who received prior anticancer therapy, had prior or concurrent cancer, or were on ovarian hormonal replacement therapy were excluded from study enrollment.

Patients were stratified based on germline BRCA status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration.

The primary end point of the trial was pCR; secondary end points were EFS and OS using a fixed testing procedure that ordered arm A vs arm C; and then arm A vs arm B. Both coprimary end points had to be statistically significant to continue formally testing secondary end points, Loibl noted.

Efficacy evaluations were done in all randomized patients; safety was analyzed in those who received at least 1 dose. In the primary pCR analyses, arm A was found to be superior to arm C, but not to arm B.

Baseline characteristics were similar across all 3 arms. The median age was 50 years (range, 22-79), and 46.6% of patients were from North America compared with 38.6% from Europe and 15% from Asia-Pacific. Moreover, 14.6% of patients had deleterious germline BRCA mutations; most patients (71.3%) had T2 stage tumors and 58% had N0 stage disease. Additionally, 55.3% of patients received doxorubicin/cyclophosphamide every 2 weeks. When breaking down patients by histological primary tumor grade, 59.6% had high grade, 20.3% had intermediate, 5.3% had low grade, and 14.3% of patients’ data were unknown/not reported.

Previously reported findings from the double-blind, placebo-controlled, phase 3 trial showed that the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the pCR rates in this patient population, but there was no benefit to adding veliparib to carboplatin and paclitaxel alone.

At that time point, the pCR rates were higher in the paclitaxel, carboplatin, and veliparib group, at 53% compared with 31% in patients who received paclitaxel alone (P <.0001) but was not superior vs the patients who received carboplatin/paclitaxel at 58% (P = .036).

However, the impact of neoadjuvant carboplatin on long-term outcomes remained uncertain, explained Loibl, who added that based on the primary analyses, the subsequent secondary analyses are descriptive with nominal P values.

At the 4.5-year median follow-up, additional results from a statistical analysis of OS showed that there were 38 deaths in arm A (12%), 16 in arm B (10%), and 22 deaths in arm C (14%). OS was not statistically significant different with the addition of veliparib to carboplatin/paclitaxel vs paclitaxel alone (HR, 0.82; 95% CI, 0.48-1.38; P = .45), but there was a trend for the carboplatin/paclitaxel (HR, 1.25; 95% CI, 0.70-2.24; P = .46). Carboplatin plus paclitaxel also showed a trend toward improved OS vs paclitaxel (HR, 0.63; 95% CI, 0.33-1.21; P = .17).

Additionally, the 4-year EFS rates were 78.2% (95% CI, 73.5%-83.2%) in arm A, 79.3% (95% CI, 72.9%-86.2%) in arm B, and 68.5% (95% CI, 61.3%-76.6%) in arm C.

In the patients who experienced events in arm A (n = 65), arm B (n = 30), and arm C (n = 47), few patients experienced progressive disease prior to surgery; this occurred in 1, 1, and 4 patients, respectively. Sixteen percent of patients in both arms A and B experienced any recurrence compared with 22% of patients in arm C. Secondary non-breast cancer malignancies occurred in 4% of patients on arm A, 2% on arm B, and 3% on arm C.

Investigators also studied the impact of pCR on EFS in all patients and subgroups by germline BRCA status. pCR had a positive correlation with EFS in all patients (HR, 0.26; 95% CI, 0.18-0.38; P <.0001), those with a germline BRCA mutation (HR, 0.14; 95% CI, 0.05-0.41; P = .0004), and those whose tumors were germline BRCA wild-type (HR, 0.29; 95% CI, 0.19-0.44; P <.0001).

Death as the first event occurred in 13 patients on arm A, 3 on arm B, and 6 on arm C.

Regarding safety, the rates of treatment-emergent and posttreatment-emergent myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and secondary malignancies were similar between all treatment arms. Pancytopenia occurred in 4, 3, and 0 patients on arms A, B, and C, respectively, and MDS occurred in 1, 0, and 1 patient(s), respectively.

In arm A with veliparib, secondary malignancies included acute leukemia (n = 1), AML (n = 2), chronic myeloid leukemia (n = 1), lung neoplasm (n = 1), and malignant melanoma (n = 1). In arm B with carboplatin/paclitaxel, these included AML (n = 3), basal cell carcinoma (n = 1), and colon cancer (n = 1). In the paclitaxel-alone arm, these were MDS (n = 1) and pancreatic carcinoma (n = 2).

References

  1. Loibl S, Sikov W, Huober J, 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 3 trial. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 119O.
  2. Loibl S, O’Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018;19(4):497-509. doi:10.1016/S1470-2045(18)30111-6
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