Abstract

Background: Poly(ADP-ribose) polymerase inhibitors (PARPis) are U.S. Food and Drug Administration (FDA) approved for treatment of BRCA-mutated metastatic breast cancer. Further-more, the BROCADE studies demonstrated benefitofadding an oral PARPi, veliparib, to carboplatin and paclitaxel in patients with metastatic breast cancer harboring BRCA mutation. Given multiple possible dosing schedules and the potential benefit of this regimen for patients with defective DNA repair beyond BRCA, we sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple-negative (TNBC) or hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2) negative with defective Fanconi anemia (FA) DNA-repair pathway based on FA triple staining immunofluorescence assay.

Materials and Methods: Patients received escalating doses of veliparib on a 7-, 14-, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-30-deoxythymidine (18FLT) positron emission tomography (PET) imaging.

Results: Forty-four patients (39 TNBC, 5 HR positive/HER2 negative with a defective FA pathway) received a median of 5 cycles (range 1–36). Observed dose-limiting toxicities were grade (G) 4 thrombocytopenia (n = 4), G4 neutropenia (n =1), and G3 akathisia (n =1).Commongrade3–4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of the 43 patients evaluable for response, 18.6%achieved partial response and 48.8% had stable disease. Median progression-free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1–21 along with carboplatin at area under the curve 5. Patients with partial response had a significant drop in maximum standard uptake value (SUVmax) of target lesions between baseline and early in cycle 1 based on 18FLT-PET (day 7–21; ptrend = .006).

Conclusion: The combination of continuous dosing of veliparib and every-3-week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUVmax on 18FLT-PET scan during the first cycle of this therapy can identify patients who are likely to have a response.

Publication Date

2020

Content Type

Article

PubMed ID:

32452601

Additional Authors:

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Comments

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adapta-tions are made.

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