Neoadjuvant Talazoparib for Patients With Operable Breast Cancer With a Germline BRCA Pathogenic Variant

Abstract

PURPOSE Talazoparib has demonstrated efficacy in patients with BRCA-positive metastatic breast cancer. This study evaluated the pathologic response of talazoparib alone for 6 months in patients with a known germline BRCA pathogenic variant (g BRCA-positive) and operable breast cancer. METHODS Eligibility included 1 cm or larger invasive tumor and g BRCA-positive disease. Human epidermal growth factor receptor 2–positive tumors were excluded. Twenty patients underwent a pretreatment biopsy, 6 months of once per day oral talazoparib (1 mg), followed by definitive surgery. Patients received adjuvant therapy at physician’s discretion. The primary end point was residual cancer burden (RCB). With 20 patients, the RCB-0 plus RCB-I response rate can be estimated with a 95% CI with half width less than 20%. RESULTS Twenty patients were enrolled from August 2016 to September 2017. Median age was 38 years (range, 23 to 58 years); 16 patients were g BRCA1 positive and 4 patients were g BRCA2 positive. Fifteen patients had triple-negative breast cancer (estrogen receptor/progesterone receptor < 10%), and five had hormone receptor-positive disease. Five patients had clinical stage I disease, 12 had stage II, and three had stage III, including one patient with inflammatory breast carcinoma and one with metaplastic chondrosarcomatous carcinoma. One patient chose to receive chemotherapy before surgery and was not included in RCB analyses. RCB-0 (pathologic complete response) rate was 53% and RCB-0/I was 63%. Eight patients (40%) had grade 3 anemia and required a transfusion, three patients had grade 3 neutropenia, and 1 patient had grade 4 thrombocytopenia. Common grade 1 or 2 toxicities were nausea, fatigue, neutropenia, alopecia, dizziness, and dyspnea. Toxicities were managed by dose reduction and transfusions. Nine patients required dose reduction. CONCLUSION Neoadjuvant single-agent oral talazoparib once per day for 6 months without chemotherapy produced substantial RCB-0 rate with manageable toxicity. The substantive pathologic response to single-agent talazoparib supports the larger, ongoing neoadjuvant trial (ClinicalTrials.gov identifier: NCT03499353 ).

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

“…The PARP inhibitor AZD2881, also known as olaparib or Lynparza TM , showed promise in mouse models of breast cancer [18] and quickly moved into clinical trials, showing anti-tumour activity in BRCA-mutated cancers, even in phase I studies [19]. Olaparib, the first PARP inhibitor to gain regulatory approval, is now FDA-approved in advanced ovarian [20], breast [21], pancreatic [22] and prostate cancers [23], with the PARP inhibitors rucaparib [24], niraparib [25] and talazoparib [26] also FDA-approved in varying indications [17,27].…”

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

“…Currently, there is a trend for investigation of PARP inhibitors in earlier stages of the disease, given that fewer resistance mechanisms will be present in this setting. Singleagent talazoparib has been assessed preoperatively in BRCA -mutated metastatic breast cancer in a small phase II trial (NCT03499353) [77]. The treatment produced significant pathologic CR with manageable toxicity.…”

Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes

“…Talazoparib, the PARP inhibitor with the highest catalytic activity and the most efficient trapping mechanism, in a single arm phase II trial including patients with operable gBRCA1/2 mutated BC, achieved a pCR rate of 53% when administered in monotherapy for six months before surgery followed by standard adjuvant treatment [94]. Notably, the majority of patients enrolled had TNBC (15/20) and, among them, almost 50% achieved pCR.…”