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.

Keywords: antineoplastic agents; neoadjuvant therapy; poly(ADP-ribose) polymerase inhibitors; triple-negative breast neoplasms.

Figure 1.

Study design. Abbreviations: BC, breast cancer; EFS, event-free survival; gBRCA1/2, germline breast cancer susceptibility genes 1 and 2; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; ICR, independent central review; N, regional lymph nodes; OS, overall survival; pCR, pathologic complete response; T, primary tumor. ^aStudy design was amended to include HR-positive, HER2-negative patients with BC and the patient numbers were reduced from 122 to 60 to address lower than expected enrollment. ^bBreast/axillary tumor tissue must be removed by either lumpectomy or mastectomy with clinically appropriate axillary surgery. Patients who had disease progression were to discontinue treatment on study and switch to alternative systemic therapy or go straight to surgery. ^cLong-term follow-up was planned to be at least 3 years, starting from the date of surgery for EFS and after the first dose of drug for OS. However, Pfizer decided to make a strategic change in the development program for talazoparib in neoadjuvant BC and decided not to pursue further development in this setting. The study was closed after all patients completed safety follow-up, and EFS/OS was not reached. ^dBreast ultrasound scans at week 12 were used to assist in clinical response assessment during treatment and to provide investigator reassurance that the patient was not progressing. Breast ultrasound was not used to assess response.

Figure 2.

Patient populations. Abbreviations: ITT, intent-to-treat; pCR, pathologic complete response; PD, progressive disease.

Figure 3.

Pathologic complete response. Abbreviations: CI, confidence interval; ICR, independent central review; INV, investigator; ITT, intent-to-treat; pCR, pathologic complete response. ^aThe denominator is N, the number of patients in the evaluable/ITT analysis set as per ICR/INV. ^bThe exact CI was calculated using the Blaker’s method.

Figure 4.

(A) Residual cancer burden (all patients); (B) Residual cancer burden among patients who had surgery. Abbreviations: CI, confidence interval; ICR, independent central review; ITT, intent-to-treat; PD, progressive disease; RCB, residual cancer burden. ^aThe denominator is N, the number of patients in the evaluable/ITT analysis set as per ICR. ^bThe simultaneous exact CI was calculated using Goodman’s method. ^cNone of the patients who had pathology submitted are classified as RCB III. ^d10 patients in the evaluable and ITT population had PD and are counted in the “Missing” category. Two patients did not have surgery for other reasons (early discontinuation and consent withdrawal; ITT population), and 1 patient was unable to be assessed because of missing a required axillary specimen. ^eOne patient was unable to be assessed because of missing a required axillary specimen.