Cisplatin with veliparib or placebo in metastatic
triple-negative breast cancer and BRCA mutation-associated breast cancer
(S1416): a randomised, double-blind, placebo-controlled, phase 2 trial
by Eve Rodler,
Priyanka Sharma, William E Barlow, Julie R Gralow, Shannon L Puhalla, Carey K
Anders, Lori Goldstein, Debu Tripathy, Ursa A Brown-Glaberman, Thu-Tam Huynh,
Christopher S Szyarto, Andrew K Godwin, Harsh B Pathak, Elizabeth M Swisher,
Marc R Radke, Kirsten M Timms, Danika L Lew, Jieling Miao, Lajos Pusztai,
Daniel F Hayes, Gabriel N Hortobagyi
The Lancet Oncology: VOLUME
24, ISSUE 2, P162-174, FEBRUARY 2023
Background
Poly(ADP-ribose)
polymerase (PARP) inhibitors are effective in germline BRCA1 or BRCA2 (BRCA1/2) mutation-associated
metastatic breast cancer. However, studies evaluating PARP inhibitors plus
platinum-based chemotherapy in germline BRCA1/2-wildtype triple-negative
breast cancer are scarce. A large proportion of germline BRCA1/2-wildtype
triple-negative breast cancer shows homologous recombination deficiency (HRD),
resulting in a BRCA-like phenotype that might render sensitivity to PARP
inhibitors. The S1416 trial assessed the efficacy of cisplatin combined with
the PARP inhibitor veliparib in three predefined groups of metastatic breast
cancer: germline BRCA1/2-mutated, BRCA-like, and non-BRCA-like.
Methods
S1416 was a
randomised, double-blind, placebo-controlled, phase 2 trial conducted at 154
community and academic clinical sites across the USA. Eligible patients aged 18
years or older had metastatic or recurrent triple-negative breast cancer or
germline BRCA1/2-associated metastatic or recurrent breast cancer, an
Eastern Cooperative Oncology Group performance status of 0–2, and had received
up to one line of chemotherapy for metastatic disease. Patients were randomly
assigned (1:1) via the National Clinical Trials Network open interactive system
with dynamic balancing on number of previous cytotoxic regimens for metastatic
disease to receive intravenous cisplatin (75 mg/m2, day 1) combined with either
veliparib or matching placebo (300 mg orally twice a day, days 1–14) on a
21-day cycle. Investigators, patients, and the sponsors were masked to
treatment assignment; the study statisticians were unmasked. Central testing
after ran domisation classified patients as having mutated or wildtype
germline BRCA1/2. A biomarker panel established a priori was used to
classify patients with wildtype germline BRCA1/2 into BRCA-like and
non-BRCA-like phenotype groups, with BRCA-like status based on at least one of the
biomarkers: genomic instability score (≥42), somatic BRCA1/2 mutations, BRCA1 promoter
methylation, or non-BRCA1/2 homologous recombination repair germline
mutations. The primary endpoint was investigator-assessed progression-free
survival, analysed separately for the three predefined biomarker groups with a
prespecified α value for each analysis. Efficacy analyses were done by
intention to treat and included all eligible patients. Safety analyses of
toxicities attributed to treatment included all patients who received at least
one dose of veliparib or placebo. The study is ongoing and registered
with ClinicalTrials.gov,
NCT02595905.
Findings
Between July 7,
2016, and June 15, 2019, 335 patients were enrolled and randomly assigned. 320
patients (n=162 to cisplatin plus veliparib, all women; and n=158 to cisplatin
plus placebo, 157 women and one man) were eligible for efficacy evaluation. 247
patients were classified into the three biomarker groups: germline BRCA1/2-mutated
(n=37), BRCA-like (n=101), and non-BRCA-like (n=109). 73 patients could not be
classified due to missing biomarker information. Median follow-up was 11·1
months (IQR 5·6–20·8). In the germline BRCA1/2-mutated group, median
progression-free survival was 6·2 months (95% CI 2·3–9·2) in the cisplatin plus
veliparib group and 6·4 months (4·3–8·2) in the cisplatin plus placebo group
(HR 0·79 [95% CI 0·38–1·67]; log-rank p=0·54). In the BRCA-like group, median
progression-free survival was 5·9 months (95% CI 4·3–7·8) in the cisplatin plus
veliparib group versus 4·2 months (2·3–5·0) in the cisplatin plus placebo group
(HR 0·57 [95% CI 0·37–0·88]; p=0·010). In the non-BRCA-like group, median
progression-free survival was 4·0 months (95% CI 2·5–4·7) in the cisplatin plus
veliparib group versus 3·0 months (2·2–4·4) in the cisplatin plus placebo group
(HR 0·89 [95% CI 0·60–1·33]; p=0·57). The most common grade 3 or worse adverse
events attributed to treatment were neutropenia (71 [46%] of 155 patients in
the cisplatin plus veliparib group vs 29 [20%] of 147 in the
cisplatin plus placebo group), leukopenia (42 [27%] vs 11 [7%]),
anaemia (35 [23%] vs 12 [8%]), and thrombocytopenia (29 [19%] vs four
[3%]). Serious adverse events attributed to treatment occurred in 48 (31%)
patients in the cisplatin plus veliparib group and 53 (36%) patients in the
cisplatin plus placebo group. Treatment-related adverse events led to death in
one patient in the cisplatin plus veliparib group (sepsis) and one patient in
the cisplatin plus placebo group (acute kidney injury due to cisplatin plus
heart failure from previous doxorubicin exposure).
Interpretation
The addition of
veliparib to cisplatin significantly improved progression-free survival in
patients with BRCA-like metastatic triple-negative breast cancer, but not in
patients with non-BRCA-like metastatic breast cancer. PARP inhibitors combined
with platinum-based chemotherapy should be explored further in BRCA-like
triple-negative breast cancer.
