Neoadjuvant Talazoparib in Patients With Germline BRCA1/2 Mutation-Positive, Early-Stage Triple-Negative Breast Cancer: Results of a Phase II Study

Abstract

Background The undetermined efficacy of the current standard-of-care neoadjuvant treatment, anthracycline/platinum-based chemotherapy, in patients with early-stage triple-negative breast cancer (TNBC) and germline BRCA mutations emphasizes the need for biomarker-targeted treatment, such as poly(ADP-ribose) polymerase inhibitors, in this setting. This phase II, single-arm, open-label study evaluated the efficacy and safety of neoadjuvant talazoparib in patients with germline BRCA1/2-mutated early-stage TNBC. Patients and Methods Patients with germline BRCA1/2-mutated early-stage TNBC received talazoparib 1 mg once daily for 24 weeks (0.75 mg for moderate renal impairment) followed by surgery. The primary endpoint was pathologic complete response (pCR) by independent central review (ICR). Secondary endpoints included residual cancer burden (RCB) by ICR. Safety and tolerability of talazoparib and patient-reported outcomes were assessed. Results Of 61 patients, 48 received ≥80% talazoparib doses, underwent surgery, and were assessed for pCR or progressed before pCR assessment and considered nonresponders. pCR rate was 45.8% (95% confidence interval [CI], 32.0%-60.6%) and 49.2% (95% CI, 36.7%-61.6%) in the evaluable and intent-to-treat (ITT) population, respectively. RCB 0/I rate was 45.8% (95% CI, 29.4%-63.2%) and 50.8% (95% CI, 35.5%-66.0%) in the evaluable and ITT population, respectively. Treatment-related adverse events (TRAE) were reported in 58 (95.1%) patients. Most common grade 3 and 4 TRAEs were anemia (39.3%) and neutropenia (9.8%). There was no clinically meaningful detriment in quality of life. No deaths occurred during the reporting period; 2 deaths due to progressive disease occurred during long-term follow-up (>400 days after first dose). Conclusions Neoadjuvant talazoparib monotherapy was active despite pCR rates not meeting the prespecified threshold; these rates were comparable to those observed with combination anthracycline- and taxane-based chemotherapy regimens. Talazoparib was generally well tolerated. ClinicalTrials.gov identifier NCT03499353

BRCA testing and management of BRCA-mutated early-stage breast cancer: a comprehensive statement by expert group from GCC region

“…In the phase II study, talazoparib monotherapy elicited pCR rates that were comparable to those observed with combination anthracycline and taxane-based chemotherapy regimens when used in the neoadjuvant settings in patients with BRCA1/2 positive, early HER2-negative BC ( 114 ). In the phase II single-arm NEOTALA trial, talazoparib yielded promising pCR rates in patients with BRCA mutated early BC comparable to those historically observed with combination anthracycline- and taxane-based chemotherapy regimens ( 115 ).…”

PARP Inhibitors for Breast Cancer Treatment

“…In the phase 2 NEOTALA trial, 24-week neoadjuvant talazoparib led to a pathologic complete response (pCR) rate of 53% in carriers of gBRCA1/2 variants with TNBC . This is similar to what was achieved with anthracycline-taxane–based neoadjuvant regimens, prior to the use of immune checkpoint inhibitors.…”

The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer

“…In addition, all recruited patients had basal-like TNBC on the basis of immunohistochemistry assessments, and the patients in the non-basal group were excluded. Non-basal TNBCs, although triple negative, share few of the biological and genomic features of basal-like TNBC, and respond less well to most systemic treatments 20 – 22 . Therefore, their inclusion in randomized controlled trials of TNBC add non-informative data to the analyses that could affect results.…”

“…Of note however, more patients required a blood transfusion for treatment-induced anaemia with olaparib (51.4% versus 30.5%). High rates of symptomatic anaemia have also been described with the use of talazoparib monotherapy (39.3%) in the neoadjuvant setting 22 . Our data are therefore consistent with the known toxicity profile of PARP inhibitors, enhanced by the additional effect of platinum on the bone marrow.…”