A feasibility study of neoadjuvant talazoparib for operable breast cancer patients with a germline BRCA mutation demonstrates marked activity

Abstract

This study was undertaken to determine the feasibility of enrolling breast cancer patients on a single-agent-targeted therapy trial before neoadjuvant chemotherapy. Specifically, we evaluated talazoparib in patients harboring a deleterious BRCA mutation (BRCA+). Patients with a germline BRCA mutation and ≥1 cm, HER2-negative primary tumors were eligible. Study participants underwent a pretreatment biopsy, 2 months of talazoparib, off-study core biopsy, anthracycline, and taxane-based chemotherapy ± carboplatin, followed by surgery. Volumetric changes in tumor size were determined by ultrasound at 1 and 2 months of therapy. Success was defined as 20 patients accrued within 2 years and <33% experienced a grade 4 toxicity. The study was stopped early after 13 patients (BRCA1 + n = 10; BRCA2 + n = 3) were accrued within 8 months with no grade 4 toxicities and only one patient requiring dose reduction due to grade 3 neutropenia. The median age was 40 years (range 25–55) and clinical stage included I (n = 2), II (n = 9), and III (n = 2). Most tumors (n = 9) were hormone receptor-negative, and one of these was metaplastic. Decreases in tumor volume occurred in all patients following 2 months of talazoparib; the median was 88% (range 30–98%). Common toxicities were neutropenia, anemia, thrombocytopenia, nausea, dizziness, and fatigue. Single-agent-targeted therapy trials are feasible in BRCA+ patients. Given the rapid rate of accrual, profound response and favorable toxicity profile, the feasibility study was modified into a phase II study to determine pathologic complete response rates after 4–6 months of single-agent talazoparib.

PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

“…Neoadjuvant studies exploit the possibility of PARP inhibitors to potentially spare patients the detrimental toxicities and likely impact on quality of life of chemotherapy, while also obtaining vital information on the underlying tumor biology and responsiveness to PARP-targeted therapy. Recent phase II neoadjuvant trial data for the use of single-agent neoadjuvant talazoparib for patients with BRCA1/2 mutant, HER2 normal (predominantly triple negative) operable breast cancer were very encouraging, with 53% of women on study achieving a pathologic complete response, and over 60% ORR reported during preliminary analysis (74). Toxicities observed were similar to those reported in studies of talazoparib administered in the metastatic setting, including grade 4 thrombocytopenia in 1 of 18 patients, and dose reductions were required in 9 of 18 patients.…”

Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy

“…27 The use of PARP inhibition is also being explored in patients with early-stage breast cancer and germline BRCA mutations, including in the neoadjuvant and adjuvant settings. [28][29][30][31] The randomized OlympiA phase III study will examine adjuvant use of olaparib in patients with high-risk HER2-negative breast cancer with gBRCA mutations and should reveal whether PARP inhibition can improve outcomes in breast cancer if given in an earlier setting. 31 NOTE.…”

Resurrection of PARP Inhibitors in Breast Cancer

“…A pilot study by the same group investigated single-agent talazoparib for 2 months in a similar patient cohort, followed by standard chemotherapy, and results showed that all 13 patients enrolled had a decrease in tumor volume, with an average reduction of 78% (range, 30%-98%). 30…”